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holds promise for preventing inherited diseases UK AND WORLD NEWS • bio pharmaceutical industry • drug delivery • gene editing • fighting malaria
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Gene editing success
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Welcome
Tackling the tough questions linked to gene editing John Dean
Editor in chief
Editor John Dean john.dean@distinctivepublishing.co.uk
Design Distinctive Publishing, Unit 6b, Floor B, Milburn House, Dean Street, Newcastle Upon Tyne NE1 1LE Tel: 0845 884 2385 www.distinctivepublishing.co.uk
Contributors John Dean & Francis Griss john.dean@distinctivepublishing.co.uk
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Every so often, news breaks of a medical breakthrough that excites some people, disturbs many others and forces us all to confront difficult questions. That is exactly what happened when scientists announced that they had, for the first time, corrected a mutation that causes heart disease in early stage human embryos. The work, which uses gene editing, means that the defect would not be passed on to future generations. The research, a collaboration between the Salk Institute, Oregon Health and Science University and Korea’s Institute for Basic Science, could pave the way for improved vitro fertilization as well as eventual cures for some of the thousands of diseases caused by mutations in single genes. This is exciting stuff. The word ‘breakthrough’ can be over-used in relation to medical research but it is entirely appropriate in this instance. Heart disease is one of the world’s biggest killers and, although many cases can be traced to poor living, many more are genetic. It’s the card you are dealt at birth and, until now, there was nothing you could do about it. Just about everyone is touched by heart disease in some way. I remember as a teenager being struck, following the death in her early sixties of a much-loved elderly grandmother, by the revelation that heart disease was always going to claim her because of her childhood ailments. The idea that the ending of her story was written regardless of decades of healthy living – she did not drink alcohol and ate sensibly – had a profound effect then and still does now. But what if we could change that? Correct the problem right at the beginning? Such a thought is hugely exciting and the more we learn about genetics, the more it becomes clear that we can head off, even eradicate, some diseases. What’s not to like?
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Well, for some people, there is not much to like and, once you start discussing the potential of gene editing, it is not long before the phrase ‘designer babies’ crops up. The critics’ big worry is not necessarily about the technology but the fear that the human race cannot be trusted to use it wisely.
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It is not a big step, say the opponents, from correcting a fault that causes heart disease to making other choices. What if someone decides they only want babies with blue eyes or black hair? What if the technology allows us to choose only the kind of children we want? Fanciful? History teaches us that there have been some powerful figures who have espoused such views and would have loved to get their hands on the technology to make it happen. When you stop to think about it, the idea is a disturbing one. Yes, we may trust and admire the scientists who achieve the breakthroughs but can we trust the decision-makers presented with the power that such technology gives us? But surely we cannot turn our backs on a technology that promises to ease such suffering? Gene editing offers hope to sufferers from so many genetic conditions who are haunted by the thought that they might pass it on to their children, who will, in turn, pass it on down the line. Given such strong yet conflicting views, it is no surprise that scientists have proceeded cautiously, in part to avoid introducing unintended mutations into the germ line as the research develops but also to allow a full and frank debate on the ethics of gene editing. Indeed, this latest research into heart disease is fully compliant with recommendations made in the 2016 document Human Genome Editing: Science, Ethics, and Governance. One of the team behind the research, Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory, worked on the document. Everyone involved in gene editing emphasises that, although the technology is immensely promising, it is also in its infancy. Many triumphs and setbacks lie ahead as the research develops; correcting genetic errors is fundamental stuff and who knows what sideeffects it may cause? However, for me, I still remember my mother’s anguished cry when she discovered that her mother had succumbed so early in life to to heart disease. And, for one, would not want anyone else to feel that kind of pain if there was a way of avoiding it.
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Gene editing success holds promise for preventing inherited diseases
Features
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Biopharmaceutical sector on the up
Changes in drug delivery open up commercial opportunities
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Contents 28
3
Introduction/Foreword
4-5
Contents
6-7
Biodigestables
8-13
UK News
14-17
World News
18-19
Bionics
20-21
Bio Pharmaceutical Industry
22-27
Drug Delivery
28-29
Gene editing
Gene editing success holds promise for preventing inherited diseases
32-35
Fighting Malaria
36-37
Gastroenterology Research
38-39
Anti Microbial Solutions
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Cell research could lead to more targeted cancer treatment
Concern at low immunisation rates
Hand that ‘sees’ offers hope to amputees
Biopharmaceutical sector on the up
Changes in drug delivery open up commercial opportunities
Fighting the battle against malaria
Impact of latest innovative gastroenterology research
Why we need to tackle resistant diseases
Fighting the battle against malaria
| biodigestables |
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BIODIGESTABLES
Cell insight
Warfarin research funding HIV treatment change
Scientists have gained new insight into a signalling process inside cells that could lead to blood cancer chemotherapy with fewer side effects.
Liverpool University’s Institute of Translational Medicine has been awarded £2 million to develop its work into the prevention of blood clots.
The researchers used stem cells to study small chemical packages that are released by cells in order to send signals to the surrounding environment. They discovered that these packages – extracellular vesicles – have the specific enzyme activity required to kill cancer cells, without starving healthy cells of the essential nutrients they need to function. The University of Cambridge research team, led by Dr Stefano Pluchino from the Wellcome Trust – MRC Cambridge Stem Cell Institute, and Dr Christian Frezza from the MRC Cancer Unit, say the finding suggests a way to develop the new form of new chemotherapy methods.
The funding from the National Institute for Health Research has been awarded to establish a new research group that aims to improve the effectiveness in Sub-Saharan Africa of warfarin, used to treat deep vein thrombosis and prevent strokes in patients with irregular heart rates, known as atrial fibrillation. Professor Sir Munir Pirmohamed, Director of the Wolfson Centre for Personalised Medicine and MRC Centre for Drug Safety Science, said: “By using our research and knowledge to improve the effectiveness of drugs, such as warfarin, we can provide help to improve the health and lives of those in developing countries.”
Treating people who start HIV treatment late with a package of low-cost drugs to prevent serious infections saves three lives for every 100 people treated, according to the findings of a trial led by the MRC Clinical Trials Unit at UCL. The REALITY trial, which involved 1805 adults, teenagers and children from Kenya, Malawi, Uganda and Zimbabwe, was funded by the MRC, the Department for International Development and Wellcome. The researchers recommend that people in Africa starting HIV treatment with low CD4 counts should be given the enhanced prevention package for the first 12 weeks of HIV treatment.
Investment is announced
Honour for Professor
Gene function investigated
Minister for Universities, Science, Research and Innovation Jo Johnson has announced a new multi-million pound commitment to develop cryoelectron microscopy in the UK.
Professor Marcus Munafò from the University of Bristol’s School of Experimental Psychology has been conferred with the 2017 President’s Award for Distinguished Contributions to Psychological Knowledge by the British Psychological Society.
Researchers from Cardiff University and Université Libre de Bruxelles have identified how a key gene significantly impacts nerve stem cell growth, and how it can lead to abnormal brain development in unborn babies.
A total of £11.3 million for cryo-EM facilities has been awarded to the universities of Glasgow, Oxford and Leicester.
Professor Munafò is a programme lead within the University’s MRC Integrative Epidemiology Unit which conducts some of the UK’s most advanced population health science research, including the use of genetics, to look for the underlying causes of chronic disease.
The discovery shows that the Dmrta2 gene mutation, if inherited from both the mother and father, leads to a form of brain malformations called lissencephaly, a rare nervous system disorder in which a baby’s brain is not fully developed.
Research provides new insight into bacteria Bacteria passed straight to children have more healthcare benefits than if they are transmitted via the surrounding environment, Oxford University research has shown. Researchers from the University of Oxford, Department of Zoology, tracked the evolutionary history of 106 bacterial symbioses, in a range of animal, plant and fungi species. The findings have revealed that how bacteria is passed and contracted is key to the intensity of symbiont relationships. When bacteria are passed vertically, straight from mother to offspring, they tend to be much better for their hosts than if they are transmitted via the environment.
Lead researcher Dr Fraser Young said: “If we can identify why some children are potentially predisposed to nurturing neurodevelopmental disorders, we will be much better placed to look at ways of effectively treating or preventing such conditions from occurring.”
Collaboration announced Experts from the UK and in developing countries across the world are joining forces to tackle some of the most serious global challenges in a new research programme. A total of £225 million has been invested across 37 projects overseen by the Research Councils UK. The projects aim to address challenges in fields such as health, humanitarian crises, conflict, the environment, the economy, domestic violence, society, and technology.
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The funding, awarded by the MRC after working in partnership with Wellcome, will establish two new consortia – one across Scotland, led by the MRC Centre for Virus Research at the University of Glasgow, and another in the Midlands, led by the University of Leicester. It will also support a new dangerous pathogens containment facility in Oxford. Over the past four decades, European researchers – including MRC-funded teams in the UK – have played a pivotal role in developing increasingly sophisticated cryo-electron microscopes.
Sugar research High maternal sugar intake during pregnancy may increase the risk of allergy and allergic asthma in the offspring, according to an early study led by Queen Mary University of London involving University of Bristol researchers and almost 9,000 mother and children pairs. The team used data from a world-leading birth cohort study, the Avon Longitudinal Study of Parents and Children, also known as Children of the 90s. The cohort recruited mothers who were pregnant in the early 1990s and has been following up their offspring ever since.
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BIODIGESTABLES
New collaboration
Work to continue
Fungi role investigated
Eli Lilly and Company and KeyBioscience AG have agreed to a new collaboration focused on the development of Dual Amylin Calcitonin Receptor Agonists (DACRAs), a potential new class of treatments for metabolic disorders such as type 2 diabetes.
Proclara Biosciences, a biotechnology company developing novel therapies for diseases caused by protein misfolding, has announced that it will continue its ongoing Phase 1b trial of NPT088 in patients with Alzheimer’s Disease.
Researchers have uncovered a key role for intestinal fungi in the liver damage seen in alcoholic liver disease.
Under the terms of the agreement, Lilly will receive worldwide rights to develop and commercialise the molecules. In exchange for these rights, KeyBioscience will receive an initial payment of $55 million and is eligible for additional payments.
Research agreement US-based Crown Bioscience (CrownBio), a wholly owned subsidiary of Crown Bioscience International, has announced an agreement with the Jackson Laboratory (JAX) to improve research models and pre-clinical services for the global biomedical research community. The agreement between Crown Bioscience, a global technology platform for oncology, and cardiovascular and metabolic disease, and JAX, a non-profit biomedical research institution, aims to accelerate and advance the rate of pre-clinical research.
Tumour research Biotechnology companies Aptevo Therapeutics, which focuses on immuno-oncology and hematology therapeutics, and Alligator Bioscience, which develops antibody-based pharmaceuticals, have announced an agreement to co-develop the immunotherapy antibody ALG.APV-527. Under the terms of the agreement, the companies will share the development costs associated with advancing the drug through to the end of Phase 2 clinical development. If successful, the new antibody could be used in the treatment of a broad spectrum of cancers including breast, cervical, non-small-cell-lung, prostate, renal, gastric, colorectal and bladder cancers
The decision follows the positive recommendation of the trial’s independent data monitoring committee, which reviewed data showing that NPT088 was safe and well-tolerated in patients treated at a dose of 0.6 mg/kg once monthly for six months. Proclara remains on track to report data from all trial participants in the summer of 2018.
New partnership announced African Biosciences Ltd has announced a partnership with the Nigerian Institute of Animal Science (NIAS), including a research packages for the Nigerian academic bioscience research community. African Biosciences Ltd. Research Project Package supports BSc, MSc and PhD students interested in biomolecular research in plants, animals, humans and microbes.
Bioscience plays strong economic role A new report has shown the significant effect of the bioscience industry on the economy of Ohio in the United States. The report by BioOhio, the state’s bioscience membership organisation, said that more than 75,000 employees, the highest on record, work with at least 3,186 bioscience-related organisations, generating $5.68 billion of payroll at an average wage of $75,640. Ohio bioscience firms range from Abbott, Battelle, Cardinal Health, Ethicon, a Johnson & Johnson company, Midmark, and STERIS, to young and growing companies including Abeona Therapeutics, AveXis, Genetesis, and Patients’ and Consumers’ Pharma. Bioscience companies continue to expand, with more than 9,000 projected new jobs and more than $1 billion in capital investment announced in 2015-17.
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Vaccinations contributions The World Health Organisation has welcomed contributions and pledges of US$1.2 billion for the Global Polio Eradication Initiative. The pledges were made at the Rotary Convention in Atlanta, USA, attended by Rotarians from around the world. A proportion of the money pledged will help WHO fund disease surveillance in more than 70 countries and enable it to provide expertise to help countries vaccinate 450 million children per year against polio.
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SCIENCETODAY
The collaboration includes access to the DACRA platform with multiple molecules, including KBP042, KBP-089 and KBP-056.
A team led by Dr Bernd Schnabl at the University of California, San Diego, and Dr. Derrick Fouts at the J. Craig Venter Institute found that people who were alcohol-dependent had differences in their intestinal fungi relative to healthy people. Blood samples revealed increased exposure and immune response to fungal products. The team says the elevated immune response was linked to the likelihood of death in patients with alcoholic cirrhosis but that a larger study will be required to confirm these findings.
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Cell research could lead to more targeted cancer treatment Scientists at the Babraham Institute in Cambridge have found a way to detect large-scale changes to the structure of the genome in cancer cells, which could enhance cancer diagnosis and the use of targeted treatments. Their report outlines a new application of a technique called Hi-C, which allows scientists to map how genetic material is arranged inside cells.
Their study reveals that each gene doesn’t have an ideal location in the cell nucleus. Instead, genes are always on the move.
By analysing this information, researchers can reliably identify major genetic changes that other methods may miss. This all comes at a lower cost than standard DNA sequencing methods.
Researchers examined the organisation of genes in stem cells from mice. They showed that the cells continually remix their genes, changing their positions as they progress through different stages.
First author on the paper, Dr Louise Harewood, said: “Chromosomal rearrangements are seen both in the general population and in the majority of cancers. Detection of chromosome rearrangements in patients can be troublesome and many can be missed. This can be detrimental, particularly in oncology where rearrangements can play both diagnostic and prognostic roles.”
The work suggests that moving genes about in this way could help cells to fine-tune the volume of each gene to suit the cell’s needs.
The scientists, led by Professor Peter Fraser, used Hi-C to examine the genome of cancer cells from six people with brain tumours. They were able to identify major genome changes, often with pinpoint accuracy.
Dr Nagano said: “We’ve never had access to this level of information about how genes are organised before. Being able to compare between thousands of individual cells is an extremely powerful tool and adds an important dimension to our understanding of how cells position their genes.”
Their approach allows doctors and scientists to study genetic changes in the wider context of the whole genome and Hi-C could become a powerful tool for understanding the complex genetic changes found in many cancers. Professor Fraser, said: “Hi-C could play a pivotal role in the detection of chromosomal abnormalities and may aid the discovery of new fusion genes. The technique works with much lower quality samples than current techniques and has the additional advantage of being able to provide copy number information from the same data. This all comes at a significantly lower cost than standard methods that use DNA sequencing.”
Co-first authors, Dr Takashi Nagano in the UK and Yaniv Lubling in Israel have collected and individually analysed information from more than 4,000 cells.
Lead author from the Babraham Institute, Professor Peter Fraser said: “We typically see that changes to gene activity have a great impact on health, disease and evolution. It’s now obvious that genome organisation may have a part to play in this and our research shows that the effects of location on genes may be a constantly moving target. Understanding how the genome is controlled during this constant re-shuffling is an important step towards understanding how our genomes and genes effect our lives.” The team now plan to carry out further research.
Moving genes about could help cells to respond to change according to scientists engaged in separate research at the Babraham Institute and the Weizmann Institute, Israel.
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HI-C COULD PLAY A PIVOTAL ROLE IN THE DETECTION OF CHROMOSOMAL ABNORMALITIES AND MAY AID THE DISCOVERY OF NEW FUSION GENES.
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Silk research offers hopes of new treatments Microscopic versions of the cocoons spun by silkworms have been manufactured by a team of researchers. The capsules, which are invisible to the naked eye, can protect sensitive molecular materials, and could prove a significant technology in areas including food science, biotechnology and medicine, say the researchers. The capsules were made at the University of Cambridge using a microengineering process that combines the power of microfluidic manufacturing with the value of natural silk. The process mimics on the microscale the way in which Bombyx mori silkworms spin the cocoons from which natural silk is harvested. The resulting micron-scale capsules comprise a solid and tough shell of silk nano-fibrils that surround and protect a centre of liquid cargo and are more than thousand times smaller than those created by silkworms. The same technology could also be used in pharmaceuticals to treat a wide range of severe and debilitating illnesses. In the study, the researchers successfully showed that silk micrococoons can increase the stability and lifetime of an antibody that acts on a protein implicated in neurodegenerative diseases. The work was carried out by an international team of academics from the Universities of Cambridge, Oxford and Sheffield in the UK; the Swiss Federal Institute of Technology in Zurich, Switzerland; and the Weizmann Institute of Science in Israel. The study was led by Professor Tuomas Knowles, a Fellow of St John’s College at the University of Cambridge and co-director of the Centre for Protein Misfolding Diseases. Professor Knowles said: “It is a common problem in a range of areas of great practical importance to have active molecules that possess beneficial properties but are challenging to stabilise for storage. “A conceptually simple, but powerful, solution is to put these inside tiny capsules. Such capsules are typically made from synthetic polymers, which can have a number of drawbacks, and we have recently been exploring the use of
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fully natural materials for this purpose. We are particularly excited by the potential to replace plastics with sustainable biological materials for this purpose.” Dr. Ulyana Shimanovich, who performed a major part of the experimental work as a St John’s College Post-Doctoral research associate, and now works at the Weizmann Institute of Science, said: “Silk is a fantastic example of a natural structural material but we had to overcome the challenge of controlling the silk to the extent that we could mould it to our designs which are more than a factor of a thousand smaller than the natural silk cocoons.” According to the team, making conventional synthetic capsules can be difficult to achieve in an environmentallyfriendly manner using biodegradable and biocompatible materials. Silk is not only easier to produce; it is also biodegradable and requires less energy to manufacture. Silk micro-cocoons could also expand the range and shelflife of proteins and molecules available for pharmaceutical use. Because the technology can preserve antibodies, which would otherwise degrade, in cocoons with walls that can be designed to dissolve over time, it could enable the development of new treatments for cancer, or neurodegenerative conditions. The study was carried out with the support of the Cambridge Centre for Misfolding Diseases, whose research programme is focused on the search for ways of preventing and treating neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases. Michele Vendruscolo, co-director of the Cambridge Centre of Misfolding diseases, said. “Some of the most efficacious and largest selling therapeutics are antibodies.” However, antibodies tend to be prone to aggregation at the high concentrations needed for delivery, which means that they are often written off for use in treatments, or have to be engineered to promote stability.” Professor Knowles said: “By containing such antibodies in micrococoons, as we did here, we could significantly extend not just their longevity, but also the range of antibodies at our disposal. We are very excited by the possibilities of using the power of microfluidics to generate entirely new types of artificial materials from fully natural proteins.“
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Alzheimer’s research unlocks secret
New research has unlocked one of the secrets of Alzheimer’s Disease. Researchers at the Medical Research Council Laboratory of Molecular Biology (LMB) have, for the first time, revealed the atomic structures of one of the two types of the abnormal filaments which lead to the disease. They say that understanding the structures of these filaments will be key in developing drugs to prevent their formation. The researchers believe that the structures could also suggest how tau protein may form different filaments in other neurodegenerative diseases. Alzheimer’s, the most common neurodegenerative disease, is characterised by the existence of two types of abnormal ‘amyloid’ forms of protein which form lesions in the brain. Tau forms filaments inside nerve cells and amyloid-beta forms filaments outside cells. Tau lesions appear to have a stronger correlation to the loss of cognitive ability in patients with the disease. Almost thirty years ago, scientists at the LMB, including Michel Goedert, one of the senior authors on the latest paper, identified tau protein as an integral component of the lesions found in Alzheimer’s and a range of other neurodegenerative diseases. However, until now, scientists have been unable to identify the atomic structure of the filaments. The researchers extracted tau filaments from the brain of a patient who had died with Alzheimer’s disease. The filaments were then imaged using cryo-electron microscopy (cryo-EM). Senior author Sjors Scheres and colleagues developed new software in order to calculate the structure of the filaments in sufficient detail to deduce the arrangement of the atoms inside them. Sjors Scheres said: “It’s very exciting that we were able to use this new technique to visualise filaments from a diseased brain as previous work depended on artificial samples assembled in the laboratory. Amyloid structures can form in
many different ways, so it has been unclear how close these lab versions resembled those in human disease. “Knowing which parts of tau are important for filament formation is relevant for the development of drugs. For example, many pharmaceutical companies are currently using different parts of tau in tests to measure the effect of different drugs on filament formation; this new knowledge should significantly increase the accuracy of such tests.” Fellow senior author Michel Goedert said: “We have known for almost three decades that the abnormal assembly of tau protein into filaments is a defining characteristic of Alzheimer’s disease. In 1998, the dysfunction of tau protein was shown to be sufficient for neurodegeneration and dementia. In 2009, the prion-like properties of assembled tau were identified. These properties allow the abnormal form to convert previously normal forms. “Until now the high-resolution structures of tau or any other disease-causing filaments from human brain tissue have remained unknown. This new work will help to develop better compounds for diagnosing and treating Alzheimer’s and other diseases which involve defective tau.” Dr Rob Buckle, chief science officer at the Medical Research Council, which funded the research, said: “This groundbreaking work is a major contribution to our understanding of Alzheimer’s disease. Nearly thirty years ago scientists at the LMB were the first to discover that tau protein plays a key role in the disease. Knowing the basic structure of these filaments in diseased tissue is vital for the development of drugs to combat their formation. “This research opens up new possibilities to study a range of other diseases where the accumulation of abnormal protein filaments plays a role, including Parkinson’s disease, motor neuron disease and prion diseases.” The work was funded by the MRC, the European Union, US National Institutes of Health and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine.
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ALZHEIMER’S, THE MOST COMMON NEURODEGENERATIVE DISEASE, IS CHARACTERISED BY THE EXISTENCE OF TWO TYPES OF ABNORMAL ‘AMYLOID’ FORMS OF PROTEIN WHICH FORM LESIONS IN THE BRAIN.
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Artificial bile ducts could help treat childhood liver disease Artificial human bile ducts have been grown and transplanted into mice by Medical Research Council-funded scientists, paving the way for the improved treatment of childhood liver diseases. The University of Cambridge researchers took healthy cells from bile ducts, called cholangiocytes, and grew these into functioning 3D duct structures known as biliary organoids. When transplanted into mice, the scientists observed that the organoids assembled themselves into bile duct-like structures Collaborating with colleagues in the university’s engineering department, the team then tested whether the biliary organoids could be grown on a 3D structure made from collagen, a natural substance in the body, which could be shaped into a tube. After four weeks, the cells had fully covered the miniature scaffolding, resulting in artificial tubes with the main features of a normal, functioning bile duct. These artificial ducts were then successfully used to replace damaged bile ducts in mice. Bile duct disorders are the leading cause for liver transplantation in children and the research shows that it is possible to generate and transplant human artificial bile ducts, offering hope for the future treatment of lifethreatening childhood diseases such as biliary atresia. The research was led by Professor Ludovic Vallier and Dr Fotios Sampaziotis from the Wellcome – MRC Cambridge Stem Cell Institute and Dr Kourosh Saeb-Parsy from the University of Cambridge.
Dr Sampaziotis said: “The capacity of these cholangiocyte organoids to grow successfully on biodegradable scaffolds, organise into functional cells and rescue bile duct function illustrates the power of tissue engineering and regenerative medicine.” Dr Rob Buckle, Chief Science Officer at the Medical Research Council, said: “These research findings pave the way for exciting new regenerative medicine treatments for this life-threatening childhood liver disease. The approach to engineering replacement tissue is also likely to have an impact for many other disorders.”
Brand new blending facility at Brenntag Lutterworth Brenntag Blending Solutions has expanded with a brand new state-of-the art facility at Brenntag Lutterworth, providing additional blending capabilities across the Middle and South of the UK. The multi-purpose vessel has a 25,000L capacity and has a 50,000L storage tank. With the ability to blend both liquid/ liquid and liquid/solid blends, the vessel is capable of providing a broad range of blends. The new comprehensive facility complements Brenntag’s other industrial blending across the rest of the UK & Ireland in Bradford, Newcastle, Glasgow and Belfast - as well as large scale food and solvent blending sites. Andrew Ferris, Business Manager for Blending Solutions, says: “We are delighted to announce the launch of our new facility at Brenntag Lutterworth, offering additional scope to provide blends across the south of the UK. Our Blending Solutions business adds real value to our customers and the new facility reinforces our commitment to developing this key area of our business.”
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Funding to speed up innovation The Government has announced new funding of up to £86 million for UK firms to develop medical breakthroughs. The package will allow small and medium sized enterprises (SMEs) to develop and test new technologies in the NHS. This could include digital technologies to help patients manage their conditions from home instead of a hospital, or to develop new medicines. Health Minister Lord O’Shaughnessy said: “The Government’s ambition is that NHS patients get worldleading, life-changing treatments as fast as possible. That can’t happen unless we support medical innovation and tear down the barriers – like speed to market and access to funding – that can get in the way, especially for SMEs.” The funding includes: • £39 million to the Academic Health Science Networks, enabling them to assess the benefits of new technologies and support NHS uptake of those that deliver real benefits to patients according to the local need • £35 million Digital Health Technology Catalyst for innovators – this will match-fund the development of digital technologies for use by patients and the NHS
need by testing in the real world, building on existing opportunities such as the Early Access to Medicine Scheme (EAMS) • £6 million Pathway Transformation Fund, which will help NHS organisations integrate new technologies into everyday practices - this will help overcome more practical obstacles such as training staff on how to use new equipment Ben Moody, Head of Health and Social Care at techUK, said: “The announcement recognises that the resources needed to generate evidence to show that a technology is worth reimbursing can be prohibitively difficult for SMEs so the fund to support evidence generation for innovative devices is particularly welcome. British In Vitro Diagnostics Association (BIVDA) Chief Executive, Doris-Ann Williams MBE, said: “BIVDA very much welcomes the Government’s announcement about funding towards practical support for the introduction of new medical technologies into the NHS. It is a constant source of frustration that implementation of new tests takes years to achieve. It means that not only are people not benefiting from improved diagnosis and disease management but also that the NHS is losing the chance to gain cost efficiencies along clinical pathways.”
• Up to £6 million over the next three years to help SMEs developing medicines and devices get the evidence they
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Study supports vitamins re-think Worldwide health authorities are being urged to rethink official guidance around vitamin D following a study from the University of Surrey, which dispels the myth that vitamin D2 and D3 have the same nutritional value. In the first ever study of its kind using low doses of vitamin D in fortified food, researchers investigated which of the two types of vitamin D, D2 or D3, was more effective in raising levels of the nutrient in the body. Vitamin D3 is derived from animal products, while D2 is plant-based. Researchers examined the vitamin D levels of 335 South Asian and white European women over two consecutive winters, a time when the nutrient is known to be lacking in the body.
“However, our findings show that vitamin D3 is twice as effective as D2 in raising vitamin D levels in the body, which turns current thinking about the two types of vitamin D on its head.” Professor Susan Lanham-New, Head of the Department of Nutritional Sciences at the University of Surrey, who was Principal Investigator of the BBSRC DRINC funded trial, said: “This is a very exciting discovery which will revolutionise how the health and retail sector views vitamin D.”
They found that vitamin D3 was twice as effective in raising levels of the vitamin in the body than its counterpart D2. Vitamin D levels in women who received vitamin D3 via juice or a biscuit increased by 75% and 74% compared to those who were given D2 through the same methods. Those given D2 saw an increase of 33% and 34% over the course of the 12-week intervention. The research also found that nutrient levels of both vitamin D2 and D3 rose as a result of both food and acidic beverages such as juice, which were found to be equally as effective. Current guidance given by a number of Government bodies around the world including the US National Institute of Health, state that the two forms of vitamin D are equivalent and can be used to equal effect. Lead author Dr Laura Tripkovic from the University of Surrey, said: “The importance of vitamin D in our bodies is not to be underestimated, but living in the UK it is very difficult to get sufficient levels of it from its natural source, the sun, so we know it has to be supplemented through our diet.
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“The importance of vitamin D in our bodies is not to be underestimated, but living in the UK it is very difficult to get sufficient levels of it from its natural source, the sun, so we know it has to be supplemented through our diet.”
| world news |
| BIOSCIENCE TODAY AUTUMN 2017 |
Concern at low immunisation rates A total of 12.9 million children, nearly one in ten, did not receive any vaccinations in 2016, according to the most recent estimations from the World Health Organisation (WHO) and UNICEF. According to the organisations, this means that the infants missed the first dose of diphtheria-tetanus-pertussis (DTP)-containing vaccine, putting them at serious risk of contracting the potentially fatal diseases. Additionally, an estimated 6.6 million infants who did receive their first dose of DTP-containing vaccine did not complete the full, three dose DTP series (DTP3) in 2016. Since 2010, the percentage of children who received their full course of routine immunisations has stalled at 86% (116.5 million infants), with no significant changes in any countries or regions during the past year. This falls short of the global immunisation coverage target of 90%. Dr Jean-Marie Okwo-Bele, Director of Immunization, Vaccines and Biologicals at WHO, said: “Most of the children that remain un-immunized are the same ones missed by health systems. “These children most likely have also not received any of the other basic health services. If we are to raise the bar on global immunization coverage, health services must reach the unreached. Every contact with the health system must be seen as an opportunity to immunize.” Immunisation currently prevents between 2–3 million deaths every year, from diphtheria, tetanus, whooping cough and measles. According to the new data, 130 of the 194 WHO Member States have achieved and sustained at least 90% coverage for
DTP3 at the national level, one of the targets set out in the Global Vaccine Action Plan. However, an estimated ten million additional infants need to be vaccinated in 64 countries, if all countries are to achieve at least 90% coverage. Of these, 7.3 million live in fragile surroundings, including countries affected by conflict. Four million of them live in just three countries – Afghanistan, Nigeria and Pakistan – where access to routine immunisation services is critical to achieving polio eradication. In 2016, eight countries had less than 50% coverage with DTP3 in 2016, including Central African Republic, Chad, Equatorial Guinea, Nigeria, Somalia, South Sudan, Syrian Arab Republic and Ukraine. Globally, 85% of children have been vaccinated with the first dose of measles vaccine by their first birthday through routine health services, and 64% with a second dose but coverage levels remain well short of those required to prevent outbreaks. A total of 152 countries now use rubella vaccines and global coverage increased from 35% in 2010 to 47% in 2016. Global coverage of more recently-recommended vaccines are yet to reach 50%. These include vaccines against major killers of children such as rotavirus, a disease that causes severe childhood diarrhoea, and pneumonia. Vaccination against both these diseases has the potential to substantially reduce deaths of children under five years of age, a target of the Sustainable Development Goals. Dr Robin Nandy, Chief of Immunizations at UNICEF, said: “Bringing life-saving vaccines to the poorest communities, women and children must be considered a top priority in all contexts.”
IMMUNISATION CURRENTLY PREVENTS BETWEEN 2–3 MILLION DEATHS EVERY YEAR, FROM DIPHTHERIA, TETANUS, WHOOPING COUGH AND MEASLES.
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| BIOSCIENCE TODAY AUTUMN 2017 |
| world news |
Research provides insight into Tourette Syndrome
Researchers have identified changes in two genes that may increase the risk of developing Tourette syndrome. Tourette syndrome is a neurological disorder that is usually diagnosed in childhood and causes repetitive, involuntary movements or noises called tics. Many with Tourette syndrome experience other problems including inattention, hyperactivity, and impulsivity, as well as obsessivecompulsive symptoms such as intrusive thoughts and worries.
more about its biology, we move closer to our ultimate goal of developing treatments to help children affected by the disease. “Tourette syndrome has a very strong genetic component but identifying the causal genes has been challenging,”
To investigate potential underlying causes, an international collaboration carried out a genetic analysis of people with Tourette syndrome.
In a separate NIH-backed study, researchers have found that immune cells recognize and react to alpha-synuclein, the protein that builds up in the brains of people with Parkinson’s disease.
The research team was co-led by Doctors Jeremiah Scharf at Massachusetts General Hospital, Giovanni Coppola at the University of California, Los Angeles, Carol Mathews at the University of Florida and Peristera Paschou at Purdue University.
A team led by Doctors David Sulzer of the Columbia University Medical Center and Alessandro Sette of the La Jolla Institute for Allergy and Immunology carried out a study comparing T cell responses to alpha-synuclein in people with Parkinson’s disease and healthy volunteers.
The study was funded in part by the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Mental Health (NIMH).
The study was supported in part by NIH’s National Institute of Neurological Disorders and Stroke and scientists collected blood samples from 67 people with Parkinson’s disease and 36 healthy adults.
The team compared more than 2,400 people with Tourette syndrome to more than 4,000 healthy people, focusing on changes in the genetic code resulting in deletions or duplications in sections of genes.
Samples taken from people with Parkinson’s disease were far more likely than samples taken from healthy adults to show strong immune responses to the alpha-synuclein fragments.
Deletions in the NRXN1 gene or duplications in the CNTN6 gene were each associated with an increased risk of Tourette syndrome. In the study, about one in 100 people with Tourette syndrome carried one of those variants.
Doctor Sulzer said: “ The idea that a malfunctioning immune system contributes to Parkinson’s dates back almost 100 years but until now, no one has been able to connect the dots.”
The researchers say that more research is needed to learn how NRXN1 and CNTN6 might affect the development of Tourette syndrome and whether they may be potential treatment targets.
Dr Sette said: “It remains to be seen whether the immune response to alpha-synuclein is an initial cause of Parkinson’s or if it contributes to neuronal death and worsening symptoms after the onset of the disease. This could, however, provide a much-needed diagnostic test for Parkinson’s disease and could help us to identify individuals at risk or in the early stages of the disease.”
Dr Scharf said: ““Our study is the tip of the iceberg in understanding the complex biological mechanisms underlying this disorder. With recent advancements in genetic research, we are at the cusp of identifying many genes involved in Tourette syndrome. Dr Jill Morris, programme director at NINDS, said: “As we find genes involved in Tourette syndrome and understand
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The findings for both studies were reported in NIH News in Health
| world news |
| BIOSCIENCE TODAY AUTUMN 2017 |
Vaccine offers hope of tackling horse virus An effective vaccine protecting against all nine strains of African Horse Sickness Virus (AHSV) is a step closer, according to new research. The virus has devastating effects on horse populations across sub-Saharan Africa and there have also been outbreaks in Spain and Portugal. A study, led by the London School of Hygiene & Tropical Medicine and funded by the UK-based Biotechnology and Biological Sciences Research Council (BBSRC), used a type of vaccine that possesses all the benefits of a traditional vaccine with none of the associated risk factors. The researchers’ work is the first to report a reverse geneticsbased vaccine for African Horse Sickness Virus. African Horse Sickness causes severe respiratory problems and approximately 90% of horses that catch it die within a week. The biting midges that transmit the disease are found all across Europe and there is concern regarding the influence of climate change on midge populations. Many countries use a ‘live’ vaccine to treat AHSV. These vaccines render pathogens harmless, vastly reducing their ability to infect a host. However, there are concerns about the possibility of the virus becoming infectious again due to mutations. In 2016, the school-led research team developed a reverse genetics system that enabled strains to mimic viruses, demonstrating their same abilities to enter host cells and initiate an immune response. However, unlike the natural virus the vaccine strains are unable to replicate, rendering them harmless. This ‘Entry Competent Replication-Abortive’ (ECRA) system allowed for
the development of virus strains for all nine types of AHSV and a successful mouse model displayed the potential for vaccine development. In the latest study, researchers tested the effectiveness of a single vaccine strain and a ‘cocktail’ of multiple ECRA-based vaccine strains in eight ponies. The vaccine viruses were able to enter the cell, triggering strong immune responses but were unable to replicate. None of the eight ponies suffered any adverse effects from the vaccine. When infected, all vaccinated ponies were protected from African Horse Sickness and only the non-vaccinated ponies had clinical symptoms of virus infection. Principal study investigator Polly Roy, Professor of Virology at the London School of Hygiene & Tropical Medicine, said: “The high volume of movement in the horse industry increases the risk of the introduction of exotic diseases such as African Horse Sickness. There are well-designed control measures for animal outbreaks in the UK, but measures taken during such an epidemic, such as the restriction of movement, could cost the UK economy approximately £4 billion. “Using our patented reverse genetics system, the study findings demonstrated that ECRA vaccines triggered strong immune responses in ponies that protected them completely against the virus infection. Our unique and cost-effective vaccine design could act as an example for the development of next generation of vaccines against other vector-borne diseases that undermine the horse industry.” It is hoped that the development of a safe and effective African Horse Sickness Virus vaccine can afford protection preventing major impact in the event of an outbreak in European countries.
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AFRICAN HORSE SICKNESS CAUSES SEVERE RESPIRATORY PROBLEMS AND APPROXIMATELY 90% OF HORSES THAT CATCH IT DIE WITHIN A WEEK.
| BIOSCIENCE TODAY AUTUMN 2017 |
| world news |
Team devises way to kill tumour cells Investigators from Brigham and Women’s Hospital (BWH) and the Harvard Stem Cell Institute in the United States say they may have discovered a way to kill tumour cells that have metastasized to the brain. The team developed cancer-killing viruses that can deliver stem cells via the carotid artery and applied them to metastatic tumors. The elimination of metastatic skin cancer cells in mice resulted in prolonged survival, the investigators say. Khalid Shah, director of the Center for Stem Cell Therapeutics and Imaging (CSTI) in the BWH Department of Neurosurgery, who led the study, said: “Metastatic brain tumors — often from lung, breast, or skin cancers — are the most commonly observed tumors within the brain and account for about 40% of advanced melanoma metastases. Current therapeutic options for such patients are limited, particularly when there are many metastases. “Our results are the first to provide insight into ways of targeting multiple brain metastatic deposits with stem-cellloaded oncolytic viruses that specifically kill dividing tumor cells.” In their search for novel, tumor-specific therapies that could target multiple metastases in the brain without damaging adjacent tissues, the research team first developed different BRAF wild-type and mutant mouse models that more closely mimicked what is seen in patients. They found that injecting patient-derived, brain-seeking melanoma cells into the carotid arteries of the preclinical models resulted in metastatic tumours forming throughout the brain, mimicking what is seen in advanced melanoma cancer patients. The injected cells express markers
that allow them to enter the brain and are labeled with bioluminescent and fluorescent markers to enable tracking by imaging technologies. To devise a potential new therapy, the investigators engineered a population of bone marrow-derived mesenchymal stem cells loaded with oncolytic herpes simplex virus (oHSV), which specifically kills dividing cancer cells while sparing normal cells. Khalid, who is also a professor at Harvard Medical School and a principal faculty member at the Harvard Stem Cell Institute, said: “We are currently developing similar animal models of brain metastasis from other cancer types, as well as new oncolytic viruses that have the ability to specifically kill a wide variety of resistant tumor cells. We are hopeful that our findings will overcome problems associated with current clinical procedures.” The study was supported by a Department of Defense Idea Award and a grant from the National Institutes of Health.
Toxin could help treat illnesses Research in the laboratory of Dr Michelle Linterman at the Babraham Institute ‘s Lymphocyte Signalling programme has provided fresh insights into the potentially beneficial effects that a toxin, produced by bacteria found in the gut, has on the immune system. This research, which was funded by US-based organisation Trident Pharmaceuticals, revealed that breathing in part of this toxin can lower the immune system’s response in the lungs of mice. The discovery could be adapted to treat severe allergies as well as autoimmune and inflammatory diseases, where the immune system is over-active and causes damage to healthy cells. One of the bacteria that can cause illness is Escherichia coli, which produces toxins that can potentially cause illness in the gut. Enterotoxin subunit B (EtxB) is a part of one of these toxins but on its own isn’t harmful to cells. Researchers have previously shown that it can reduce the activity of the immune system. Dr Linterman’s team have been investigating how this happens and whether it could help to control other illnesses.
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What the team at the Institute have found is that EtxB has two ways to weaken the immune system and prevent T cells from causing inflammation. It can reduce the function of dendritic cells, which normally push the immune system to become more active. Whilst at the same time it promotes cells called regulatory T cells that limit the activation of T cells and so reduce inflammation. First author on the paper, Dr Alexandre Bignon, said: “It’s interesting to see the effect that ExtB has on our immune system. It’s stopping dendritic cells from activating the immune system whilst using regulatory T cells to shut down the T cells that are already there, it’s a very effective way to stop inflammation happening.” Lead researcher Dr Linterman said: “This work has some great potential, EtxB could become a simple and powerful way of controlling inflammatory diseases. It’s an encouraging basis for the development of fast-acting new treatments.”
| bionics |
| BIOSCIENCE TODAY AUTUMN 2017 |
Hand that ‘sees’ offers hope to amputees
The science of bionics has made great strides in recent years but one big challenge remains – how do you make prosthetic limbs as real as possible? Now, researchers in Newcastle may have come with the answer in the form of a new generation of prosthetic limbs which will allow the wearer to reach for objects automatically, without thinking and which are to be trialled for the first time. Developed by biomedical engineers at Newcastle University and funded by the Engineering and Physical Sciences Research Council, the bionic hand is fitted with a camera which instantaneously takes a picture of the object in front of it, assesses its shape and size and triggers a series of movements in the hand. A small number of amputees have already trialled the new technology and now the Newcastle University team are working with experts at Newcastle upon Tyne Hospitals NHS Foundation Trust to offer the ‘hands with eyes’ to patients at Newcastle’s Freeman Hospital.
Dr Kianoush Nazarpour, a Senior Lecturer in Biomedical Engineering at Newcastle University, said: “Prosthetic limbs have changed very little in the past 100 years. The design is much better and the materials are of a lighter weight and more durable but they still work in the same way. “Using computer vision, we have developed a bionic hand which can respond automatically – in fact, just like a real hand, the user can reach out and pick up a cup or a biscuit with nothing more than a quick glance in the right direction. “Responsiveness has been one of the main barriers to artificial limbs. For many amputees, the reference point is their healthy arm or leg so prosthetics seem slow and cumbersome in comparison. “Now, for the first time in a century, we have developed an ‘intuitive’ hand that can react without thinking.” Recent statistics show that in the UK there are 600 new upper-limb amputees every year, of which 50% are in the age range of 15-54 years old. In the US there are 500,000 upper limb amputees a year.
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| BIOSCIENCE TODAY AUTUMN 2017 |
| bionics |
“Prosthetic limbs have changed very little in the past 100 years. The design is much better and the materials are of a lighter weight and more durable but they still work in the same way. Using computer vision, we have developed a bionic hand which can respond automatically – in fact, just like a real hand, the user can reach out and pick up a cup or a biscuit with nothing more than a quick glance in the right direction.” Dr Kianoush Nazarpour
Senior Lecturer in Biomedical Engineering at Newcastle University
Current prosthetic hands are controlled via myoelectric signals, electrical activity of the muscles recorded from the skin surface of the stump. Controlling them takes practice, concentration and time.
He said: “I had developed a rare form of cancer called epithelial sarcoma, which develops in the deep tissue under the skin, and the doctors had no choice but to amputate the limb to save my life.
Fellow Newcastle researcher Ghazal Ghazaei said that using neural networks – the basis for Artificial Intelligence – can help make responses quicker and easier for users of the prosthetic hand.
“Losing an arm and battling cancer with three young children was life changing. I left my job as a life support supervisor in the diving industry and spent a year fundraising for cancer charities. It was this and my family that motivated me and got me through the hardest times.”
Miss Ghazaei who carried out the work as part of her PhD in the School of Electrical and Electronic Engineering at Newcastle University, said: “We would show the computer a picture of, for example, a stick. But not just one picture, many images of the same stick from different angles and orientations, even in different light and against different backgrounds and eventually the computer learns what grasp it needs to pick that stick up.
Doug, a father of three from Aberdeen, has been working with the Newcastle team to trial the new hand and said: “The problem is there’s been nothing yet that really comes close to feeling like the real thing. Some of the prosthetics look very realistic but they feel slow and clumsy when you have a working hand to compare them to.
“So, the computer isn’t just matching an image, it’s learning to recognise objects and group them according to the grasp type the hand has to perform to successfully pick it up. “It is this which enables it to accurately assess and pick up an object which it has never seen before – a huge step forward in the development of bionic limbs.” Grouping objects by size, shape and orientation, according to the type of grasp that would be needed to pick them up, and using a 99p camera fitted to the prosthesis, the team programmed the hand to perform four different ‘grasps’: palm wrist neutral (such as when you pick up a cup); palm wrist pronated (such as picking up the TV remote); tripod (thumb and two fingers) and pinch (thumb and first finger). Led by Newcastle University, but also involving experts from the universities of Leeds, Essex, Keele, Southampton and Imperial College London, the aim is to develop novel electronic devices that connect to the forearm neural networks to allow two-way communications with the brain. Dr Nazarpour said of the new hand: “It’s a stepping stone towards our ultimate goal but, importantly, it’s cheap and it can be implemented soon because it doesn’t require new prosthetics – we can just adapt the ones we have.” Anne Ewing, Advanced Occupational Therapist at Newcastle upon Tyne Hospitals NHS Foundation Trust, who has been working with Dr Nazarpour and his team, said: “This project has provided an exciting opportunity to help shape the future of upper limb prosthetics, working towards achieving patients’ prosthetic expectations and it is wonderful to have been involved.” One of the people who could benefit from the pioneering work is Doug McIntosh, 56, who lost his right arm in 1997 through cancer.
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“In the end, I found it easier just to do without and learn to adapt. When I do use a prosthesis I use a split hook which doesn’t look pretty but does the job.” He described the new responsive hand developed in Newcastle as a ‘huge leap forward’. Doug said: “This offers for the first time a real alternative for upper limb amputees. For me, one of the ways of dealing with the loss of my hand was to be very open about it and answer people’s questions. But not everyone wants that and so to have the option of a hand that not only looks realistic but also works like a real hand would be an amazing breakthrough and transform the recovery time – both physically and mentally – for many amputees.”
| bio pharmaceutical industry |
| BIOSCIENCE TODAY AUTUMN 2017 |
Biopharmaceutical sector
on the The global biopharmaceutical manufacturing sector is continuing to grow at a rapid rate, according to a new report into its performance. According to the report by market researchers IMARC Group, the key drivers are the increasing popularity of biopharmaceuticals along with increases in production capacity, advances in technology and the emerging trend of outsourcing.
One of the major trends in the market, says IMARC, is the continuous improvement in technology aimed at increasing productivity. According to the researchers, manufacturers are focusing on continuous bioprocessing and the use of single-use or disposable devices to increase their yield. IMARC says that outsourcing is increasingly popular due to the significant cost savings, the potential for innovation and access to specialist capabilities.
The report, entitled Global Biopharmaceutical Manufacturing Market Report 2017-2021, says that global biopharmaceutical manufacturing capacity recorded a Compound Annual Growth Rate of more than 4% during 2009-2016, reaching a volume of 4.5 million litres in 2016.
The report says that contract manufacturers carry out activities ranging from the analytical testing of bioassays to testing cell line stability and product characterisation. A large number of contract manufacturers are based in emerging regions such China and India.
The result, says the report, is that biopharmaceuticals currently represent the fastest growing segment in the global pharmaceuticals market.
IMARC notes a division in the market, into mammalian and microbial cell cultures. Mammalian cell culture currently represents the largest category, accounting for the majority of the production volume because of the large number of drugs which are made using the technique.
IMARC says that the market will continue to grow because the high returns associated with production have prompted a number of companies to develop and manufacture biopharmaceutical drugs. Moreover, it says, the emergence of biosimilars is further expected to bolster the market growth; indeed, according to the report, the global biopharmaceutical manufacturing market is projected to reach a volume of 6.6 million litres by 2021.
IMARC says that the market has been segmented into recombinant proteins, monoclonal antibodies, interferons, erythropoietin, granulocyte colony-stimulating factor (G-CSF), recombinant human insulin, vaccines and human growth hormones (HGH). North America currently represents the largest market, accounting for nearly half of the total market share.
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| BIOSCIENCE TODAY AUTUMN 2017 |
| bio pharmaceutical industry |
New plant is inaugurated
up
Contract manufacturing company Boehringer Ingelheim has inaugurated its commercial production site for biopharmaceuticals in Zhang Jiang Hitech Park of Shanghai in China. The site, with a first-phase investment of more than €70 million, is the first facility established by a leading multinational biopharmaceutical manufacturer in China using mammalian cell culture technology. With its global network of biopharmaceutical production sites in Germany, Austria, the USA and now China, Boehringer Ingelheim says it is well positioned to fulfil strongly increasing demands from the biopharmaceutical industry for its products worldwide. Hubertus von Baumbach, Chairman of the Board of Managing Directors at Boehringer Ingelheim, said: “Our Shanghai facility plays an important role in our globally leading biopharmaceutical contract manufacturing business and embodies our continuous and long-term commitment to China. “With this investment, we expect to have a significant impact on the development of China’s biopharmaceutical industry to ultimately supply innovative medicines to patients following high quality standards.”
“the emergence of biosimilars is further expected to bolster the market growth; indeed, according to the report, the global biopharmaceutical manufacturing market is projected to reach a volume of 6.6 million litres by 2021.”
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| drug delivery |
www.thebiosciencejournal.co.uk
| BIOSCIENCE TODAY AUTUMN 2017 |
Changes in drug delivery open After centuries of delivering drugs to patients as pills, liquids and injectables a revolution is under way which will change everything for patients - from the dose needed to the frequency of administration. Life for patients will be transformed by drug delivery systems which will release a steady dose of many kinds of drugs over periods of days or weeks without relying on their memory. By delivering the drug directly to the site where it is needed, the dose can also be reduced with no loss of efficacy. Changing the way drugs are delivered turns on its head the oft-stated issue that there is a problem with the way patients comply with drug delivery regimens. Instead, the technology takes account of fallibility, patients who stop taking medication because they believe they no longer need it and plain bad memory, increasing the efficacy of existing medicines. For example, Intarcia announced the development of a subcutaneous osmotic mini-pump called Medici which can deliver compounds steadily for up to one year. Launching the technology, Kurt Graves, chairman, president and CEO of Intarcia, said: “One of the biggest problems in chronic diseases is millions of patients lack effective control of their condition due to sub-optimal effectiveness of their medication, and the fact is, the majority of patients with chronic conditions stop taking these pills and injections after just three-to-six months. “We are aiming to address these serious and costly unmet needs by introducing a new way to deliver once-yearly therapies that hold the potential for game-changing improvements in outcomes and patient adherence over time.” Once placed just beneath the skin, water from the extracellular fluid enters the pump device at one end – by diffusing through a semi-permeable membrane directly into a salt osmotic engine – that expands to drive a piston at a controlled rate. This forces the drug within the pump to be released in a steady, consistent fashion. The company says that Medici has the potential to be used in chronic conditions such as diabetes, obesity, autoimmune and other serious diseases. It is currently researching new therapies. Another area in which the new technology could have benefits is the battle against malaria. In rural areas with poor infrastructure and less direct access to healthcare malaria is one of the major health problems facing the population. Drugs exist to treat the infection but one of the greatest problems is enabling patients to take them in the right way. Researchers funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) at Massachusetts Institute of Technology (MIT) have come up with a novel solution to delivering the mosquito-killing drug Invermectin. The new system is a capsule which, when swallowed, opens up flower-like into a star-shaped structure which will not pass further through the digestive tract, releases its drug load slowly over about two weeks before eventually disintegrating.
“This drug delivery system is the kind of low-cost solution that could have a great impact on the spread and destructiveness of malaria,” said David Rampulla, Ph.D., director of the NIBIB program in Delivery Systems and Devices for Drugs and Biologics. In another, and very different, effort to reduce dosage and increase efficacy various companies have been developing microneedle systems, particularly for vaccinations. Using microneedles delivers the vaccine into the dermis, stimulating an immune response with a lower dose. Not only that, but it overcomes the objections of needle-phobic people, increasing take-up. In May, two companies announced their intention to cooperate in developing the market for this new technology. They are Vetter from Germany and Microdermics from Canada. Dr Claus Feussner, Vetter’s senior vice president development service, said: “We believe that microneedles are a particularly innovative technology and may prove to be a promising future alternative for selected areas of drug delivery.” A simple way to deliver drugs to a specific site would be with an adhesive patch but there are many practical problems to be overcome to produce a patch which can contain enough of the drug while maintaining its adhesive capabilities. Researchers at the University of Warwick have worked with Coventry-based Medherant, a Warwick spinout company, to produce and patent the world’s first ever ibuprofen patch delivering the drug directly through the skin to exactly where it is needed, at a consistent rate. The University of Warwick researchers and Medherant have found a way to incorporate significant amounts of the drug into the polymer matrix that sticks the patch to the patient’s skin with the drug being delivered over up to 12 hours. Now the problems have been overcome in the case of ibuprofen it opens the way for other drugs to be delivered in the same way for the treatment of chronic conditions such as chronic back pain, neuralgia and arthritis without the need to take potentially damaging doses of the drug orally. University of Warwick research chemist Professor David Haddleton said: “Our technology now means that we can for the first time produce patches that contain effective doses of active ingredients such as ibuprofen for which no patches currently exist. Also, we can improve the drug loading and stickiness of patches containing other active ingredients to improve patient comfort and outcome. “There are only a limited number of existing polymers that have the right characteristics to be used for this type of transdermal patches - that will stick to the skin and not leave residues when being easily removed. Furthermore, there are also only a limited number of drugs that will dissolve into these existing polymers. Medherant’s technology now opens up the field of transdermal drug delivery to previously non-compatible drugs. We believe that many other over the counter and prescription drugs can exploit our technology and we are seeking opportunities to test a much wider range of drugs and treatments within our patch.”
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| BIOSCIENCE TODAY AUTUMN 2017 |
www.thebiosciencejournal.co.uk
| drug delivery |
up commercial opportunities
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| drug delivery |
| BIOSCIENCE TODAY AUTUMN 2017 |
Enable drug delivery by selecting the right delivery system – and the right packaging partner By Victoria Morgan
• Drug/Container compatibility: There is no need to change from glass, which may help minimize pharmaceutical company expenditure and reduce time to market.
For patients with chronic illnesses, the use of self-injectable biologic therapies is on the rise and the most promising options for administering these treatments are easy to use, minimal step drug delivery systems. Injector systems combine the drug and its primary containment system in a patient-friendly system that delivers the prescribed dose easily. A truly successful injector system must consider both the pharmaceutical company’s needs for its drug, and that of the patient during different stages of a patient’s therapeutic journey.
• Container/delivery interface: Dimensional tolerances and design features minimize functional errors such as misfires.
Director, Segment Marketing – Global Biologics West Pharmaceutical Services, Inc.
West Pharmaceutical Services’ SelfDose® injector technology, for example, was designed to ease the burden of painful repeat injections thereby fitting more easily into a patients’ lifestyle. The system is a single-use, patientoperated injector that is ergonomically designed to help ease the challenges associated with patient dexterity issues. Intuitive, easy to use and designed to minimise fear, the SelfDose injector can incorporate any ISO 1mL long glass syringe. This design flexibility offers minimal changes to the existing primary container for drug companies, while the system allows a patient to self-administer medication outside of the clinical setting.
UNDERSTANDING PHARMACEUTICAL COMPANY NEEDS
• Ready to go: Production capacity already installed with capability for secondary assembly and drug handling in house.
UNDERSTANDING PATIENT NEEDS The SelfDose injector has been developed and used in extensive human factors testing to show: • Ease of use: Simple, two-step operation that offers the patient an intuitive design and is non-intimidating. • Dose notification: The SelfDose injector releases an audible click when the dose is complete allowing the patient reassurance that the full dose was given. • Reduces fear: The SelfDose injector’s hidden needle and passive safety features help to reduce fear and prevented needle stick injury.
CHOOSING THE RIGHT PARTNER The role drug packaging and delivery systems play in the drug development process, as well as how they fit into the regulatory and quality environment, is critical to success. By working with a partner with a deep knowledge of the complexity of design, testing, container selection and closure integrity associated with large molecules and sensitive drugs, regulatory and quality requirements, manufacturing at scale and speed to market allows drug manufacturers to make more informed decisions about the partner of choice. For example, West is working closely with a number of global pharmaceutical companies to ensure compatibility between the SelfDose injector and a multitude of drug products. The partnerships among West and its customers exemplifies the close collaboration West has with pharmaceutical and biotechnology companies to deliver advanced, integrated solutions for drug delivery and containment.
In order to design a drug delivery system that helps to address the needs of both the drug and the patient, pharmaceutical manufacturers must consider the interface between the drug, container, delivery device and patient. For the SelfDose system, the following considerations were key: • Primary container format: Many pharmaceutical companies with drugs in an existing pre-filled syringe format may be looking for lifecycle management offerings that eliminate the need to change the primary container, if already packed in an ISO 1mL long glass syringe.
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Partnering with a company like West, which can provide expertise in the field of drug packaging and delivery systems, should be an important part of the launch plan for any drug to be delivered in a self-injection system. In the future, it is imperative that the pharmaceutical industry remains focused on better understanding the interaction between patients, their medication and the drug delivery system, as this relationship may have a substantial impact on patient outcomes.
SelfDose™ is a trademark of West Pharmaceutical Services, Inc. or its subsidiaries, in the United States and other jurisdictions.
BRINGING YOUR BIOSIMILAR TO MARKET
QUICKLY AND ECONOMICALLY West’s unrivaled SelfDose injector platform provides a ready to go, easy to use, 2-step, intuitive, non-intimidating self-injection solution without the need to change your existing 1mL long glass syringe - allowing your biosimilar to get to market quickly.
2 Simple Steps
Off the Shelf n Extremely short time to market n Existing production capacity available n Limited additional capital investment needed n Capability for secondary assembly and drug handling n In-house regulatory and analytical lab support
Commercially Ready Platform n Accommodates an ISO 1mL long glass syringe n Injector design can be used for multiple biosimilar drugs irrespective of therapy n Compatible with various fill volumes and viscosities
Patient Friendly n Differentiated and ergonomic design to overcome dexterity challenges n Highly intuitive proven by Human Factor studies n Hidden needle helps reduce fear and prevent needlestick injury n Reliable system for dose reassurance n Quiet and user controlled to reduce pain
click
remove needle guard
“I like that it’s very little fine finger manipulations. All simple, easy to hold, easy to administer.” RA patient
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West Pharmaceutical Services, Inc. North America +1 800-345-9800
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530 Herman O. West Drive, Exton, PA 19341 Europe +49 2403 7960
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www.selfdose.com
Asia Pacific +64 6862 3400
West seeks partners for its SelfDose injector technology platform. This platform is intended to be used as an integrated system with drug filling and final assembly completed by the pharmaceutical/biotechnology company. West and the diamond logo, SelfDose® and By your side for a healthier world™ are registered trademarks or trademarks of West Pharmaceutical Services, Inc., in the United States and other jurisdictions. West markets SelfDose® as a multi-component system only. Final assembly of the prefilled component is completed by the pharmaceutical company. Copyright ©2017 West Pharmaceutical Services, Inc. #10368 • 0717
| drug delivery |
| BIOSCIENCE TODAY AUTUMN 2017 |
Nemera receives Drug Manufacturing Authorization for its Neuenburg plant, in Germany Important achievement for Nemera, now able to handle, assemble, sterilize and store pharmaceutical drugs and medicinal products for autoinjectors. On 4th September, Nemera received from the German Government Drug Administration (Government Presidium, Tübingen) the Pharmaceutical Drug Manufacturing Authorization according to §13 AMG (German Drug & Medicinal Product Law) at its Neuenburg manufacturing facility in Germany. The certification gives the manufacturing plant the approval to handle, assemble, sterilize and store pharmaceutical drugs and medicinal products for autoinjectors. This approval reflects Nemera’s commitment to quality in developing and manufacturing drug delivery devices.
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The Authorization is an important achievement. It confirms that Nemera meets the highest standards required to ensure the manufacturing and testing of the above-mentioned drug, as well as medicinal and medical products. The pharmaceutical drug manufacturing certification is a required regulatory step, in order to allow Nemera to provide a complete set of services and additional support, for the development and manufacturing of pharmaceutical combination products and drug delivery devices to our customers “Achieving this pharmaceutical drug manufacturing approval is highlighting our commitment to ensure the safety of our drug delivery devices for the benefit of patients. It is also the confirmation that our quality systems and processes are meeting consistently regulatory requirements and patient expectations.” commented Christian Meusinger, Quality Vice-President of Nemera.
| BIOSCIENCE TODAY AUTUMN 2017 |
| drug delivery |
“Achieving this pharmaceutical drug manufacturing approval is highlighting our commitment to ensure the safety of our drug delivery devices for the benefit of patients. It is also the confirmation that our quality systems and processes are meeting consistently regulatory requirements and patient expectations.” Christian Meusinger
Quality Vice-President of Nemera
THE NEUENBURG PLANT Neuenburg plant has been manufacturing high quality products since 1953.
Drug Delivery Devices Innovative developments Customized solutions GMP contract manufacturing
With more than 20,000 sqm of built up area, the plant has Class 8 clean rooms and more than 400 employees, to guarantee a 7/7 and 24h/24 production. Neunburg plant produces billions of Injection molded parts and assembled devices every year. Neuenburg quality management key achievements are: • Short reaction times • Detailed and comprehensive root cause analysis • Elimination of quality problems • Reduction of scrap rates • Elimination of inefficiencies
ABOUT NEMERA www.nemera.net information@nemera.net
Nemera is a world leader in the design, development and manufacturing of drug delivery devices for the pharmaceutical, biotechnology & generics industries. Nemera’s services and products cover several key delivery routes: Parenteral, Ophthalmic, Nasal, Buccal, Auricular, Inhalation, Dermal, Transdermal. Nemera always puts patients first, providing the most comprehensive range of devices in the industry, including off-theshelf innovative systems, customized design development and contract manufacturing. For more information, please visit www.nemera.net If you want to contact us: information@nemera.net
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| gene editing |
| BIOSCIENCE TODAY AUTUMN 2017 |
Gene editing
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| BIOSCIENCE TODAY AUTUMN 2017 |
| gene editing |
success
holds promise for preventing inherited diseases
Scientists have, for the first time, corrected a disease-causing mutation in early stage human embryos using gene editing.
Not only were a high percentage of embryonic cells repaired, but also gene correction didn’t induce any detectable off-target mutations and genome instability— major concerns for gene editing.
The technique, which uses the CRISPR-Cas9 system, corrected the mutation for a heart condition at the earliest stage of embryonic development so that the defect would not be passed on to future generations.
Jun Wu, a Salk staff scientist and one of the paper’s authors, said: “Even though the success rate in patient cells cultured in a dish was low, we saw that the gene correction seems to be very robust in embryos of which one copy of the MYBPC3 gene is mutated.
The work, a collaboration between the Salk Institute, Oregon Health and Science University and Korea’s Institute for Basic Science, could pave the way for improved in vitro fertilization (IVF) techniques as well as eventual cures for some of the diseases caused by mutations in single genes. Gene editing remains in its early stages of development but holds much promise, according to Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory and a corresponding author on the paper outlining the development. He said: “Thanks to advances in stem cell technologies and gene editing, we are finally starting to address diseasecausing mutations that impact potentially millions of people. “Gene editing is still in its infancy so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations.”
“Our technology successfully repairs the disease-causing gene mutation by taking advantage of a DNA repair response unique to early embryos.” The team emphasises that, although promising, these are preliminary results and more research will need to be done to ensure no unintended effects occur. Juan Carlos Izpisua Belmonte said: “Our results demonstrate the great potential of embryonic gene editing, but we must continue to realistically assess the risks as well as the benefits.” Future work will continue to assess the safety and effectiveness of the procedure and efficacy of the technique with other mutations. The work was funded by Oregon Health and Science University, the Institute for Basic Science, the G. Harold and Leila Y. Mathers Charitable Foundation, the Moxie Foundation, the Leona M. and Harry B. Helmsley Charitable Trust and Shenzhen Municipal Government of China.
The work focused on hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in otherwise healthy young athletes, which affects approximately one in 500 people overall. It is caused by a dominant mutation in the MYBPC3 gene, but often goes undetected until it is too late. Since people with a mutant copy of the MYBPC3 gene have a 50% chance of passing it on to their own children, being able to correct the mutation in embryos would prevent the disease not only in affected children, but also in their descendants, say the researchers. The researchers generated induced pluripotent stem cells from a skin biopsy donated by a male with HCM and developed a gene-editing strategy based on CRISPR-Cas9 that would specifically target the mutated copy of the MYBPC3 gene for repair. Using IVF techniques, the researchers injected the bestperforming gene-editing components into healthy donor eggs newly fertilised with the donor’s sperm.
“Gene editing is still in its infancy so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations.” 29
| advertorial |
| BIOSCIENCE TODAY AUTUMN 2017 |
Innovation and investment at worldleading life science campus creates environment for bio businesses to grow Agri-food, biorenewables and bioscience are key UK growth sectors, as scientists seek solutions to challenges of limited natural resources, a growing population and climate change. Much of this work is taking place in the north of England, where Yorkshire and the Humber accounts for 10 per cent of the UK’s bioeconomy. Over 100,000 people work in the sector in the region, contributing £8.7bn to the regional economy. The York, North Yorkshire and East Riding LEP has made this sector one of its key priorities, launching a £10m bioeconomy growth fund last year. Based near York at the heart of the North’s bioeconomy, the National Agri-Food Innovation Campus (NAFIC) is a key centre for innovation and has earned a world-class reputation as a life science campus. Situated in 80 acres of parkland, NAFIC offers sophisticated science laboratory and office accommodation for over 700 employees working at the interface of government, academia and industry. The 17 businesses and organisations at the campus work at the leading edge of applied life sciences, strengthening the region’s capability and reputation in scientific research and innovation. Originally built by the Ministry of Agriculture, Fisheries and Food (MAFF) the evolution of the campus as a multi-tenanted science park began with the bringing together of MAFF’s food scientists to create The Central Science Laboratory. Over time this became the Food and Environment Research Agency, transitioning into the site’s private sector anchor tenant, Fera Science Ltd (Fera). With over 400 staff on site, Fera combines rare and specialist expertise (e.g. in nematology, ecology and entomology) with cutting-edge new technologies (such as portable DNA testing) to provide a range of expert services to the public and private sectors that is unique in the UK. It’s a highly entrepreneurial organisation deploying translational science to convert the best research ideas into tractable services, products and solutions. One of its latest projects is aimed at tackling the looming global protein shortage, converting agricultural residues into high value animal feed via insect bioconversion. NAFIC is also home to several public sector science organisations, including Public Health England, The Medicines and Healthcare Products Regulatory Agency and Department for Environment, Food & Rural Affairs (Defra) Plant Health Policy unit, as well as the UK’s Chief Plant Health Officer. NAFIC is home to the Centre for Crop Health and Protection (CHAP), one of the Government’s four national Centres for Agricultural Innovation. As part of a £22.9m investment, CHAP is currently creating a seven-acre real world test ecosystem on site to conduct world-leading research into
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the impact of agro-chemicals and other interventions upon the natural environment. While there is already a sophisticated blend of science accommodation, including 4km of lab benching, the largest single mass spectrometry facility in the UK, a range of laboratory spaces, cold stores and office space, NAFIC is undertaking a five-year plan to make further strategic investments in the facilities and infrastructure to attract more life science and agri-tech organisations. Companies including Abingdon Health, Innovenn, Mologic and, most recently, Covance - which expanded its BioPharmCMC capabilities onto the site earlier this year have seen the advantage of being close to others working at the forefront of bioscience. Successes have included Innovenn’s creation of Labskin, which replicates living skin for non-animal testing and research, and Mologic’s new research programme improving diagnostic test technology for the detection of protein biomarkers. It also has CE-mark approval for a device that patients on peritoneal dialysis can use to test for infection in their own homes. With this much expertise on site there is a strong ethos of collaboration, with tenants never more than a couple of conversations away from someone who can help solve a problem. For example, Birdstrike Management, which works to protect the safety of aircraft, airports and aircraft passengers, often calls upon expertise from the Animal and Plant Health Agency wildlife team on site for species identification and, for DNA analysis, commissions work from Fera. With organisations working to standards as wide as UKAS, GMP, GLP, FDA, CE Mark ISO9001, ISO14001 someone on site will have experience to share. If your business wants to join our community get in touch with Annette Gamston, Campus Partner Manager, t: 01904 406667, e: annette.gamston@nafic.co.uk , www.nafic.co.uk
An environment in which to grow Based at Sand Hutton, near York, in the heart of the North’s bioeconomy, NAFIC’s unique scientific community provides the ideal environment for businesses to grow. It offers high-grade laboratory and office space, a range of support services and opportunities to interact with world-class scientists and businesses, all working at the interface of government, academia and industry. Call the campus team on 01904 406667 or email enquiries@nafic.co.uk www.nafic.co.uk
The National Agri-Food Innovation Campus, Sand Hutton, York, YO41 1LZ
| fighting malaria |
| BIOSCIENCE TODAY AUTUMN 2017 |
Fighting the battle against
malaria 32
| BIOSCIENCE TODAY AUTUMN 2017 |
Despite major breakthroughs in medicine over the years, some diseases remain mass killers and few cast a longer shadow than malaria, particularly in Africa where it has claimed millions of lives. Key to tackling the disease has been prevention and now the world’s first vaccine against malaria will be introduced in three countries - Ghana, Kenya and Malawi - starting in 2018. The RTS,S vaccine trains the immune system to attack the malaria parasite, which is spread by mosquito bites, and needs to be given four times - once a month for three months and then a fourth dose 18 months later. One of the big challenges is that the breakthrough has been achieved in clinical trials but it is not yet clear if it can be replicated in countries where access to healthcare is limited. That is why the World Health Organisation (WHO) is running pilots in the three countries to see if a full malaria vaccine programme could be started. Dr Matshidiso Moeti, the WHO regional director for Africa, said: “The prospect of a malaria vaccine is great news. Information gathered in the pilot programme will help us make decisions on the wider use of this vaccine.
| fighting malaria |
“Combined with existing malaria interventions, such a vaccine would have the potential to save tens of thousands of lives in Africa.” The pilot will involve more than 750,000 children aged between five and 17 months. About half will get the vaccine in order to compare the jab’s effectiveness. In this age group, the four doses have been shown to prevent nearly four in ten cases of malaria, much lower than approved vaccines for other conditions. It also cuts the most severe cases by a third and reduces the number of children needing hospital treatment or blood transfusions but the benefits fall off significantly without the fourth dose. Ghana, Kenya and Malawi were chosen because they already run large programmes to tackle malaria but despite huge progress, there are still 212 million new cases each year and 429,000 deaths. Most of the deaths are in children. The pilots are being funded by Gavi, the Vaccine Alliance, the Global Fund to Fight Aids, Tuberculosis and Malaria, Unitaid, the WHO and GSK. Dr Seth Berkley, the chief executive of Gavi, said: “The world’s first malaria vaccine is a real achievement that has been 30 years in the making. Malaria places a terrible burden on many of the world’s poorest countries, claiming thousands of lives and holding back economies. These
Continues on page 34
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| fighting malaria |
Continued from page 33
| BIOSCIENCE TODAY AUTUMN 2017 |
pilots are crucial to determining the impact this vaccine could have on reducing this toll.” Kenya is an example of what can be achieved but also of what challenges remain in a country where 70% of the 46 million people are at significant risk from the disease. The preventive measures are led by the country’s Ministry of Health. In the coastal areas near the Indian Ocean and the Lake Victoria region, for example, malaria prevalence hovers around 8% and 27% respectively. Here insecticide-treated bednets are the primary preventive tool whereas indoor spraying with insecticides is targeted towards selected areas with high transmission around Lake Victoria. In the capital city of Nairobi, fewer than 1% of people harbour the parasite that causes malaria. The presence of the parasite is also low in the country’s arid regions, where it can peak at around 3% following heavy rains.
GHANA, KENYA AND MALAWI WERE CHOSEN BECAUSE THEY ALREADY RUN LARGE PROGRAMMES TO TACKLE MALARIA BUT DESPITE HUGE PROGRESS, THERE ARE STILL 212 MILLION NEW CASES EACH YEAR AND 429,000 DEATHS. MOST OF THE DEATHS ARE IN CHILDREN.
Kenya’s malaria response in these areas focuses primarily on effective diagnosis and treatment. Beginning in 2006, the distribution of insecticide-treated bednets in high-risk areas was carried out initially for pregnant women and children under the age of five years, who are at the highest risk of contracting the disease. In 2011, distribution was widened. Another preventive measure targets pregnant women near Lake Victoria and along the coast by giving them preventive doses of an antimalarial drug. Taking a national approach is seen as crucial. Many Kenyans live in areas with low malaria transmission, such as Nairobi, so have little or no immunity to the disease and can easily become infected when they travel to high transmission areas. Often, they start to develop symptoms after returning home to low-transmission areas so health promotion messages
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are broadcast nationally so that residents can learn how to limit their exposure and, if they do fall sick, recognise the symptoms so that they can be diagnosed and treated. Such efforts have had an impact. Countrywide, malaria prevalence dropped from 11% to 8% between 2010 and 2015. Progress has not been uniform. In 2015, the 8% prevalence in the endemic coastal region of the Indian Ocean was twice what it had been in 2010 although the reasons are unclear. And in western Kenya, around Lake Victoria, malaria mosquitoes have started to develop resistance to the pyrethroid insecticides used in the two biggest malaria prevention tools, bednets and indoor spraying. The World Health Organisation conducted research to see if mosquito resistance was undermining the preventative work. Carried out with the support of the Bill & Melinda Gates Foundation, the five- country study, including Kenya, provided reassuring results. Dr Tessa Knox, a scientist working in the WHO Global Malaria Programme, said: “The significant reductions in malaria in the past decade and a half can be largely attributed to massive scale-up of interventions using insecticides. “The overall conclusion was that treated bednets continue to be effective against malaria in areas where we have witnessed development of moderate levels of resistance to pyrethroids, the insecticide class used in nets.” Currently, other new tools are being investigated and new classes of insecticides for use in bednets and sprays are being developed.
| BIOSCIENCE TODAY AUTUMN 2017 |
| fighting malaria |
Research deepens understanding of malaria parasite Science carried out in Nottingham helped to form the foundation for the latest breakthrough in the global fight against malaria. Researchers in the University of Nottingham’s School of Life Sciences were responsible for the identification of the molecular switches that control the three key stages of the malaria parasite’s life cycle – work which has underpinned a new discovery about the way in which the growth of the parasite is controlled. Now, a team of international scientists led by Portuguese academics has discovered that one of the proteins identified by the Nottingham experts plays a vital role in modulating the parasite’s rate of replication. Rita Tewari, Professor of Parasite Cell Biology in the University’s School of Life Sciences said: “This work comes as a result of major work which we undertook to further our understanding of how the protein signalling molecules called kinases control the malaria parasite development in the host body and the gut of the mosquito. “As a result of our research, we produced a big resource of proteins called kinases and enzymes which work in tandem with them called phosphatases, which are very good potential targets for drugs. This is a valuable resource for the scientific community working on malaria.” The research centres on the role of one kinase called pbKIN, which allows the infectious agent responsible for malaria, the Plasmodium parasite, to sense how many calories are being taken in by the host and tailor its replication accordingly. Plasmodium parasites reproduce inside red blood cells every 48 hours but the study has shown for the first time that the parasite’s rate of replication depends on the calories ingested by the host. The study showed that mice who ate 30% fewer calories had a significantly lower parasite infection. Maria M. Mota, from the Instituto de Medicina Molecular in Lisbon, who led the research, said: “This finding alters our understanding of the dynamics of malaria infections in the field.” Dr Oliver Billker, a collaborator on the research from the Wellcome Trust Sanger Institute, said: “This is the first time that anyone has seen that a parasite can actively restrict its growth to the environment and completely changes the way we look at parasite growth. While future research is still necessary to understand the full extent of these findings, it may well have implications not just for malaria, but also for other infectious diseases.”
The ultimate aim of malaria research is to disrupt the three main stages of the parasite’s lifecycle - whether it be in the liver, in the mosquito gut or in the blood. Professor Tewari, whose laboratory is working on understanding which signals are needed for the parasite to divide and reproduce, said: “If we can understand the unique molecular machinery that allows the parasite to replicate then we can find strategies to prevent it. Parasite proliferation is more like an abnormal cancer cell in which the cell divides many times, very quickly and without many checks. “We have shown in the past that many proteins called cyclins or usual switches like phosphatases that are in present humans cells and regulate cell division are either absent or very different in malaria parasite cell.That means that the Plasmodium – the malaria – is not using the usual machinery which other normal cells use. “Now we are trying to understand what the parasite does differently that is not present in the host, the human cell, as that would be the best target for drugs. If we can kill the parasite using those targets, then it won’t affect the human and would reduce side effects of malarial medication.” The work is a collaboration between scientists at Instituto de Medicina Molecular and Instituto Gulbenkian de Ciência in Portugal, Institut Pasteur in Paris, the Wellcome Trust Sanger Institute, University of Nottingham in the UK and The Pennsylvania State University in the US.
“As a result of our research, we produced a big resource of proteins called kinases and enzymes which work in tandem with them called phosphatases, which are very good potential targets for drugs. This is a valuable resource for the scientific community working on malaria.” 35
| Gastroenterology Research |
| BIOSCIENCE TODAY AUTUMN 2017 |
Impact of latest innovative gastroenterology research for patient benefit According to the British Society of Gastroenterology, the burden of gastrointestinal and liver disease is heavy for patients, the NHS, and the economy. Gastrointestinal disease is the third most common cause of death, and the most common cause of hospital admission. The National Institute for Health Research (NIHR) Clinical Research Network is at the forefront of developing cutting edge advances in gastroenterology research that are enabling access to enhanced care and treatment. Obesity levels in the UK have more than trebled in the last 30 years and, on current estimates, more than half the population could be obese by 2050. Strongly associated with obesity, is the increased susceptibility of developing type 2 diabetes, which currently affects 3.2 million of the UK population and costs the NHS £11 billion a year. Gastric bypass can lead to 60% remission in diabetes but with demand for bariatric surgery outstripping supply there is a greater need to develop non-surgical alternatives to combat the ever rising obesity and diabetes epidemic. One promising alternative comes in the form of an innovative endoscopic implant: EndoBarrier® by GI Dynamics® Inc. EndoBarrier is a 60cm duodenal bypass sleeve that is endoscopically implanted for a period of up to 12 months into patients who have been diagnosed with type 2 diabetes and obesity. It does not involve any surgery and sometimes patients may go home within hours of the procedure. The NIHR Clinical Research Network has funded the multi-centred trial being conducted at Imperial College NHS Trust. The NIHR Clinical Research Network has been supporting the recruitment of patients into the EndoBarrier Gastrointestinal Liner Diabetes research from primary care trusts across North West London. This has included liaising with 462 GP practices in order to identify patients who might benefit from this innovative study. There was a strong interest from participants for the study with 225 patients recruited between two sites; Imperial NHS Trust and Southampton University. The study continues until February 2019 but recruitment has closed, as it follows the patients for a year after removal of the device to see how durable the effect is. Half of those included in the study have had the device implanted and will be removed after a year. Early observations indicate a positive impact on the health of those enrolled in the study with positive changes to their diabetes control and weight loss. Julian Teare, Professor of Gastroenterology at Imperial Healthcare NHS Trust and the study’s principal investigator, says: “We know that both obesity and diabetes pose a huge burden on our health service, and we were pleased to receive a huge response from the general public when recruitment for the trial commenced. Patients were
attracted to the study as the intervention is a removable minimally invasive device that does not require any surgery but that has the potential to improve their diabetes and reduce their weight dramatically.” The NIHR Clinical Research Network makes it possible for patients and health professionals across England to participate in clinical research studies within the NHS. It provides the infrastructure that allows high quality clinical research funded by clients, research funders and life-sciences industry to be undertaken throughout the NHS. The NIHR Clinical Research Network works with patients and the public to make sure their needs are placed at the heart of all research and providing opportunities for patients to gain earlier access to new and innovative treatments through research participation. A commercial research project is the MORDIS study - A Multicentre, Open, Prospective Study on Modified Resect and Discard Strategy of Small Colonic lesions. Utilising the latest technology from SpectraScience, the WavSTAT4 Optical Biopsy System is used in the study to predict whether polyps are non-suspect or suspect during a colonoscopy. Polyps (small new tissue growths) in the colon (lower bowel) are quite common and may be benign (normal or ‘non-suspect’) or adenomatous (cancerous/pre-cancerous or ‘suspect’). Non-suspect polyps would generally not be removed but suspect polyps do require removal. During screening by colonoscopy for diseases of the colon, it can be difficult to tell the difference between the two types, which leads to the removal and subsequent laboratory testing of many tissue samples. This extensive sampling is often impractical, time-consuming and costly. Preliminary results of studies at St James University Hospital, Leeds, using the Wavstat4 system have found a high sensitivity and negative predictive value of around 96% in predicting the nature of removed polyps. This would mean that the optical biopsy forceps is highly accurate in predicting when a polyp is non-suspect. The use of this device during screening for bowel cancer could reduce the number of polyps removed thereby reducing the time taken for the procedure and subsequent cost savings in laboratory testing of tissue.
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OBESITY LEVELS IN THE UK HAVE MORE THAN TREBLED IN THE LAST 30 YEARS AND, ON CURRENT ESTIMATES, MORE THAN HALF THE POPULATION COULD BE OBESE BY 2050.
| BIOSCIENCE TODAY AUTUMN 2017 |
| Gastroenterology Research |
In this study, the device was used during routine screening colonoscopy and the predictive results (suspect or nonsuspect) were also made using the device. The NIHR Clinical Research Network supported the study at St James’ University Hospital, Leeds, which resulted in the study achieving 122% recruitment to time and target. Delivery of studies to time and target is a key focus for the NIHR Clinical Research Network and is an important factor to the life sciences industry. Our support to this study was vital in achieving this timely result for the sponsor. Final results of the study are now being finalised for publication. Chief investigator of the study, Dr Venkat Subramanian and Clinical Associate Professor and Honorary Consultant Gastroenterologist at the University of Leeds added: “Further work will be needed to assess potential cost savings for the NHS and how well this technology enables
clinicians and endoscopists in diverse settings to set appropriate follow up schedules for patients with colorectal polyps detected during colonoscopy. Further UK trials are also likely to be required to ensure the technology can be used effectively by the different kinds of endoscopy centres that exist in the UK.” In 2016/17 in England there were 20,792 participants recruited into studies that were Gastroenterology related this is nearly a 5% increase from last year; improved feasibility assessment at sites and monitoring of performance has driven an improvement at delivering studies to time and target. The NIHR Clinical Research Network has played an important part in advances in gastroenterology to ensure that NHS patients in the UK remain at the heart of future research developments.
“We know that both obesity and diabetes pose a huge burden on our health service, and we were pleased to receive a huge response from the general public when recruitment for the trial commenced.” 37
| Anti Microbial Solutions |
| BIOSCIENCE TODAY AUTUMN 2017 |
Why we need to tackle resistant diseases Crisis can be an over-used word but in the case of antimicrobial resistance it is entirely apt. According to health organisations the world over, the need to come up with new solutions to illnesses that are unaffected by drugs is an urgent global priority and companies are being urged to invest in the research. The need for such work is illustrated in the case of what has so far been an easily treated sexually transmitted disease. Data from 77 countries show that antibiotic resistance is making gonorrhoea much harder, and sometimes impossible, to treat. The World Health Organisation (WHO) reports widespread resistance to older and cheaper antibiotics. Some countries are finding cases of the infection that are untreatable by all known antibiotics. Dr Teodora Wi, Medical Officer, Human Reproduction, at WHO, said: “The bacteria that cause gonorrhoea are particularly smart. Every time we use a new class of antibiotics to treat the infection, the bacteria evolve to resist them. “These cases may just be the tip of the iceberg, since systems to diagnose and report untreatable infections are lacking in lower-income countries where gonorrhoea is actually more common.” Each year, an estimated 78 million people are infected with gonorrhoea and complications disproportionally affect women, including pelvic inflammatory disease, ectopic pregnancy and infertility, as well as an increased risk of HIV. Decreasing condom use, increased urbanisation and travel, poor infection detection rates, and inadequate or failed treatment all contribute to the increase. The WHO Global Gonococcal Antimicrobial Surveillance Programme (WHO GASP), which monitors trends in drugresistant gonorrhoea, analysed data from 2009 to 2014 and found widespread resistance to a number of well-known and widely used drugs. Now, the Drugs for Neglected Diseases initiative (DNDi) and WHO have launched the Global Antibiotic Research and Development Partnership (GARDP), a not-for-profit research and development organisation to develop new antibiotic treatments. Dr Manica Balasegaram, GARDP Director, said: “To address the pressing need for new treatments for gonorrhoea, we urgently need to seize the opportunities we have with existing drugs and candidates in the pipeline. “In the short term, we aim to accelerate the development and introduction of at least one of these pipeline drugs, and will evaluate the possible development of combination treatments for public health use. Any new treatment developed should be accessible to everyone who needs it, while ensuring it’s used appropriately, so that drug resistance is slowed as much as possible.”
Dr Marc Sprenger, Director of Antimicrobial Resistance at WHO, said. “To control gonorrhoea, we need new tools and systems for better prevention, treatment, earlier diagnosis, and more complete tracking and reporting of new infections, antibiotic use, resistance and treatment failures. specifically, we need new antibiotics, as well as rapid, accurate, point-of-care diagnostic tests – ideally, ones that can predict which antibiotics will work on that particular infection – and longer term, a vaccine to prevent gonorrhoea.”
“The bacteria that cause gonorrhoea are particularly smart. Every time we use a new class of antibiotics to treat the infection, the bacteria evolve to resist them.” 38
| BIOSCIENCE TODAY AUTUMN 2017 |
| Anti Microbial Solutions |
Research offers hope There is hope in the battle against drug-resistant drugs, though. For example, a newly discovered antibiotic, produced by bacteria from a cystic fibrosis patient, could be used to treat cases of drugresistant tuberculosis (TB), according to a team of scientists from Cardiff University’s School of Biosciences and the University of Warwick. The problem of antibiotic-resistant infections is pronounced in the treatment of TB; it is estimated that by 2040, more than a third of all TB cases in Russia, for example, could show resistance to the drugs currently used to fight the disease. Among potential new drug sources is a group of the bacteria called Burkholderia that thrive in a wide range of natural habitats, but occasionally cause infection such as those within the lungs of people with cystic fibrosis. The microbes have adapted to these diverse environments in part by making potent antibiotics. A team led by Professor Gregory L. Challis from the University of Warwick and Professor Eshwar Mahenthiralingam from Cardiff University set out to determine whether Burkholderia could potentially produce new antibiotics that could treat diseases such as drugresistant TB. They were assisted by Professor Julian Parkhill (Wellcome Trust Sanger Institute, Cambridge, UK) and Professor Stewart Cole (Global Health Institute, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland). The team discovered that one particular species, Burkholderia gladioli, which was isolated from the sputum of a child with cystic fibrosis, produces an antibiotic they called gladiolin.
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This compound is similar in structure to another antibiotic that has been investigated for its ability to jam bacterial cell machinery, but gladiolin is much more stable and could potentially be a better drug candidate. Further testing showed that the antibiotic blocked the growth of four drugresistant TB strains. Professor Mahenthiralingam said: “This work is a continuation of our research on Burkholderia bacteria as a new source of antibiotics, and it has shown that Burkholderia gladioli, which we have historically studied as lung infections in people with cystic fibrosis, can also produce potent drugs for global infectious diseases such as antibiotic resistant tuberculosis. “Since this clinical testing process can take over a decade, it is vital we keep screening sources such as Burkholderia for other new antibiotics, and we hope that further research funding is made available to do this.” The research was funded by Biotechnology and Biological Sciences Research Council (U.K.), the Wales Life Sciences Bridging Fund and a Marie Sklodowska-Curie Actions Fellowship.
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