BioScience Journal 7

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Syringe technologies Advances open up new opportunities


Regenerative Medicine & Stem Cells

Crop Resistance

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Pre-filled syringes driving a new approach to an old technology Welcome to the latest edition of Bioscience Journal, with the articles including a look at the growing interest in pre-filled syringes, which some commentators are suggesting will largely replace the traditional syringe in medical care. As our report shows, the technology has been around for decades but it is gaining popularity with the medical profession because it is seen as a safe, convenient and cost-effective solution. The growth in its importance shows that science is never too advanced that it cannot go back to ‘old’ technologies to develop them for a new age.

John Dean

Editor in chief

Traditionally, most of the responsibility for administering medicines at a patient’s home has fallen on the patients themselves; they have had to make sure that the dose is correctly measured out to ensure the maximum result. The same is true in many hospitals and doctors’ surgeries as well. The idea of the pre-filled syringe turns that idea on its head with the amount of medicine already measured out and anaesthetics, vaccines, insulin and biologicals for treatment of inflammatory varieties of arthritis and psoriasis are just some of the areas in which the technology is increasingly being used. The big advantages of pre-filled syringes include the fact that they virtually eliminate waste, seen as crucial at a time when there is so much concern about the world’s rising pharmaceutical bill, that they minimise the opportunities for mistakes and that they also decrease potential for contamination. In addition to which they are much easier for patients to manage. No surprise then that they are becoming so popular. This edition of Bioscience Journal also examines developments in the area of stem cell research and regenerative medicine, one of the most exciting areas of medical research at the moment. The pace of change is absolutely staggering with scientists making breakthroughs virtually


every day in treatments for a range of health conditions, with each development harnessing the power of the body’s natural defences to fight back against illness. Few areas offer so much potential for truly breathtaking discoveries in the years to come. This edition also examines work under way to tackle arthritis, a debilitating condition that makes life miserable and painful for millions of people. Again, bioscience is playing its part in coming up with a deepening understanding of the condition which is, in turn, leading to new therapies. It’s another example of the way in which work in the sanitised environment of the laboratory brings about drama in the very real word of the patient. Bioscience is not restricted to the area of health research, of course, so we also take a look at work that is under way to tackle the impact of climate change on the production of food. Increasing awareness of the threat posed by flood, pestilence, heat and drought as the planet warms has led to massive investment into solving some of the problems, with everyone from big business and governments to community groups working on possible solutions. The work is crucial because changes in climate are wreaking havoc on parts of the world and that, in turn, is damaging not just communities but agricultural areas, so the race is on to develop crops that are better equipped to survive as more of their traditional growing areas become too hostile for successful farming. This edition also has plenty of other news as well, with each article emphasising that we live in a golden age of research. Each discovery opens the door for the next one and the sheer abundance of knowledge that our scientists are accruing is offering great hopes for the future.



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UK News


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42-50 Regenerative Medicine & Stem Cells 52-54 Crop Resistance


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Researchers develop catalyst to increase the yield of biodiesel

Researchers from the Cardiff Cataylsis Institute have devised a way of increasing the yield of biodiesel by using waste left over from its production process. Using catalysis, the Cardiff University researchers have been able to recycle an unwanted by-product created when biodiesel is formed from vegetable oil and convert it into an ingredient to produce even more biodiesel. It is believed the new process will have significant environmental benefits by improving the yield of biodiesel in a sustainable way that doesn’t require the use of additional fossil fuels, and could potentially reduce the costs of the biodiesel production process. The work could have international ramifications because, by 2020, the EU alone aims to have ten per cent of the transport fuel of every EU country come from renewable sources such as biofuels. Fuel suppliers are also required to reduce the greenhouse gas intensity of the EU fuel mix by six per cent by 2020 in comparison to 2010. At present, biodiesel is produced by combining fats and oils with methanol, which is usually derived from fossil fuels. A waste product from this process is crude glycerol, which is formed

on a large scale and contains many impurities that make it costly to purify and re-use in other areas.

a growing part of the EU fuel pool, with statutory amounts being required to be added to diesel that is derived from fossil fuels.

In their study, the researchers developed a way of turning the crude glycerol back into methanol, which could then be used as a starting reactant to create more biodiesel.

“We’ve provided unprecedented chemistry that highlights the potential to manufacture biodiesel in a much more environmentally friendly, and potentially cheaper, way, by converting an undesired by-product into a valuable chemical that can be reused in the process.”

To achieve this, they reacted glycerol with water, to provide the element hydrogen, and a magnesium oxide (MgO) catalyst. The reaction involved a simple one-step process and could be performed using mild conditions. Using the recycled methanol, the researchers estimate up to a ten per cent increase in biodiesel production, which they claim would be very helpful to industry. The work is currently in its early stages and in future studies the researchers will look to optimise the design of the catalyst and significantly increase its activity and selectivity. Lead author of the study Professor Graham Hutchings, Director of the Cardiff Catalysis Institute, said: “Biodiesel manufacture is


Co-author of the study Professor Stuart Taylor, Deputy Director of the Cardiff Catalysis Institute, said: “We set out to establish ways in which the waste product glycerol could be used to form other useful compounds, but we were surprised when we found that feeding glycerol and water over such a simple catalyst gave such valuable products and interesting chemistry. “This research has the potential to transform the way in which waste is dealt with, and seriously improve the quality of life by reducing carbon emissions from fossil fuels and encourage efficient use of resources.”



Gene editing research bid overcomes crucial hurdle

Research into effect of salt

The role of salt in the diet of pregnant women is to be examined in new research looking at the causes of preeclampsia, a potentially life-threatening condition to mother and baby. The research team at The University of Nottingham’s Obstetrics and Gynaecology unit at the City Hospital have been awarded more than £470,000 by the British Heart Foundation to examine the condition, which begins with sudden onset of high blood pressure and protein in the urine and affects up to six per cent of pregnant women.

Cancer programme

A new £4.1 million research programme to focus on new ways to prevent and predict cancer development and progression has been launched by Cancer Research UK and the University of Bristol. The five-year Integrative Cancer Epidemiology Programme, funded by Cancer Research UK, will use advances in genetics and molecular technology to understand the causes of the disease and help develop preventative interventions in people at risk of, or diagnosed with, cancer.

The UK is leading the world after the national Human Fertilisation and Embryology Authority (HFEA) approved a research application from the Francis Crick Institute to use new gene editing techniques on human embryos.

important for understanding how a healthy human embryo develops.

HFEA officials took the ground-breaking decision after considering submissions from the Institute that outlined how the research led by Dr Kathy Niakan, a group leader at the Crick, aims is to understand the genes that human embryos need to develop successfully.

There has been concern that the concept could in time be used to create ‘designer babies’ but in line with HFEA regulations, any donated embryos will be used for research purposes only and cannot be used in treatment.

The gene editing work carried out at the Crick will be for research purposes and will look at the first seven days of a fertilised egg’s development from a single cell to around 250 cells. The HFEA and the Crick say that the knowledge acquired from the research will be

Midge research

They say that the knowledge may also improve embryo development after in vitro fertilisation (IVF) and might provide better clinical treatments for infertility, using conventional medical methods. Paul Nurse, director of the Crick, said: “I am delighted that the HFEA has approved Dr Niakan’s application. Dr Niakan’s proposed research is important for understanding how a healthy human embryo develops and will enhance our understanding of IVF success rates, by looking at the very earliest stage of human development - one to seven days.”

The embryos will be donated by patients who have given their informed consent to the donation of embryos which are surplus to their IVF treatment. Subject to ethical approval, the research programme will begin within the next few months.


University of Liverpool fellow Dr Stefanos Siozios has been awarded £140,000 from the EU’s Horizon 2020 programme to investigate ways of preventing midges transmitting viruses to livestock. Professor Greg Hurst, from the University’s Institute of Integrative Biology and a collaborator in the research, said: “A better understanding of this immensely complicated relationship between symbionts, insect and virus could help us prevent the spread of viruses to our livestock.”



Research deepens understanding of eczema A research programme into genetics has identified new forms of the skin condition eczema and provided useful information that may lead to new treatments. The work involves 16 researchers across four schools at the University of Bristol, investigators from the International Agency for Research on Cancer and the Universities of Manchester and Oxford.

The team used a technique called genomewide association analysis to look at the genomes of the 377,000 people and to identify small changes in the genes commonly found in people with eczema.

Eczema – an itchy dry-skin condition – affects one in five children and one in 12 adults in the UK and research has shown that genes play an important role in determining how likely we are to develop it.

They found ten new variants, bringing the total number of variants known to be related to eczema to 31.

However, the majority of the genes that cause the condition have yet to be detected. Now, in the largest genetic study of eczema in the world to date, the group of international researchers led by Dr Lavinia Paternoster from the MRC Integrative Epidemiology Unit at the University of Bristol, has combined data on 377,000 participants involved in 40 research studies worldwide, including the Bristol-based Children of the 90s.

What all the new genetic variants have in common is that they all play a role in regulating the immune system, which the team says highlights potential new targets for therapeutic research for eczema. The researchers also found some evidence of genetic overlap between eczema and other diseases like inflammatory bowel disease. This finding suggests that studying these diseases together could give important insights into the mechanisms of disease and


potentially identify new treatments. Dr Paternoster said: “Though the genetic variants identified in this current study represent only a small proportion of the risk for developing eczema and are in no way deterministic, rather they slightly increase your risk, they do give new insights into important disease mechanisms and through on-going research in this area these findings could be turned into treatments of the future.” Dr Sara Brown, an academic dermatologist who contributed to the research from the University of Dundee, said: “Eczema runs in families so we know that genetic factors are an important part of the cause. “The very large numbers of participants in this research has allowed us to fine tune our understanding of eczema genetic risk, providing more detail on how the skin immune system can go wrong in eczema.”



Team observes super-fast process

Gel research

Research by chemists at the University of York has revealed new information about bacterial gels. The research in the Department of Chemistry demonstrated that alginate gels, which can be produced as biofilms by bacteria, are more dynamic than previously thought. Understanding the dynamics may ultimately suggest new ways of helping prevent or better control such bacterial infections, which can be particularly critical in the lungs of cystic fibrosis patients. Dr Victor Chechik and Professor David Smith worked with visiting Romanian scientist Dr Gabriela Ionita on the research.

Hope for sufferers

Researchers at the University of Liverpool have found that a well-established antiepileptic drug could also be a treatment for neurodegenerative diseases.

A team of researchers have observed how a lightactivated compound alters the structure of DNA, which could lead to new cancer treatments. Photo-dynamic therapy, a form of treatment for conditions including several cancers and psoriasis, uses light to activate a drug in a specific area of the body and can reduce the side effects observed in conventional anticancer treatments. Now, scientists working in Reading and Dublin have identified a new way of finding out how such compounds work. It is difficult to observe such fast processes in living cells but the much simpler environment of a DNA crystal has enabled the team to watch the process in great detail. The crystals contain a ruthenium compound which is bound to a short piece of DNA. This class of compound is used in DNA-sensing and is of interest to the pharmaceutical industry for cancer treatment. The researchers found that by using infrared radiation, they could get a snapshot of the process – which occurs in half a billionth of a second – that takes place when light is shone

on the crystals. This activates the compound, making it cause damage to DNA. This research was carried out using two UK central research facilities: the laser facilities in the Central Laser laboratory of the Science and Technology Facilities Council and Diamond Light Source, the UK national synchrotron facility. Dr Susan Quinn, from the School of Chemistry at University College Dublin, the lead author of the study, said: “These results are very exciting as they demonstrate the ability to follow the flow of electrons from DNA to a molecule whose exact position is known and this is an enormous advantage in the study of the early events that lead to DNA damage.” Professor Christine Cardin, from the University of Reading, a nucleic acid crystallographer, led the UK team, which has received major funding from the Biotechnology and Biological Sciences Research Council to support the work, which included co-author Dr James Hall. Prof Cardin said: “Among other things, the insights from this study will feed into the development of new drugs that target cancerous tissue, without damaging healthy tissue around it.” A key element of the funding for the collaboration has been provided by the Royal Irish Academy-Royal Society exchange programme, running since 2008 between Trinity College Dublin and the University of Reading.


Neurodegeneration, which involves the progressive loss of nerve structure and function, is a common characteristic of conditions, including Parkinson’s, Alzheimer’s and Huntington’s. Researchers from the University’s Institute of Translational Medicine have found that the anti-epileptic drug ethosuximide has protective effects in certain models relating to neurodegenerative diseases.

New deal

North-East based Cambridge Research Biochemicals (CRB) will continue to supply The Medical Research Council with custom-synthesised peptides and bespoke polyclonal and monoclonal antibodies for 12 months as a valued preferred supplier under a new pricing agreement. CRB has been operating in the life sciences field for 35 years and is based in Billingham on Teesside.



Skin odour could lead to early diagnosis of Parkinson’s

A study has been launched to identify small molecules secreted by the skin that are believed to emit a unique scent in people in the early stages of Parkinson’s Disease. Researchers believe that Parkinson’s may affect a change in the sebum – an oily substance in the skin – of people with the condition that results in a unique and subtle odour on the skin only detectable by people with an acute sense of smell. The study was prompted by a “super-smeller” from Scotland who was able to identify people with Parkinson’s just from t-shirts they had slept in. The charity Parkinson’s UK is now funding researchers at Manchester, Edinburgh and London to study 200 people with and without Parkinson’s. They hope to confirm findings from a pilot study by the Universities of Manchester and Edinburgh involving 24 people, which suggested that Parkinson’s can be identified by odour alone. One in 500 people in the UK have Parkinson’s, which can leave people struggling to walk, speak and sleep, and has no cure or definitive diagnostic test; 127,000 people in the UK live

with the condition and 7.5 million worldwide. Professor Perdita Barran and her team at the Manchester Institute of Biotechnology (MIB), based at The University of Manchester, will use mass spectrometry technology to analyse skin swabs taken from people with and without Parkinson’s. The research team will extract, analyse and identify small molecule components taken from the skin to identify specific biomarkers found in Parkinson’s. The team will also be using ‘human detectors’people with exceptional smelling abilities. Both the analytical and the human approach will be used to grade identical samples in an attempt to pinpoint which molecular changes in the skin might be producing the unique odour found in people with Parkinson’s. Professor Barran, leading the research at the MIB and working with neurologist Dr Monty Silverdale on the study, said: “The sampling of the skin surface will provide a rich source of metabolites which we can mine to distinguish


healthy patients from those in the early stages of Parkinson’s. “We are excited to embark on this biomarker discovery project. It is hoped that these results could lead to the development of a noninvasive diagnostic test that may have the ability to diagnose early Parkinson’s – possibly even before physical symptoms occur.” Dr Arthur Roach, Director of Research at Parkinson’s UK, which is funding the study, said: “Funding pioneering studies like this has the potential to throw Parkinson’s into a completely new light. “It’s very early days in the research, but if it’s proved there is a unique odour associated with Parkinson’s, particularly early on in the condition, it could have a huge impact, not just on early diagnosis, but it would also make it a lot easier to identify people to test drugs that may have the potential to slow, or even stop Parkinson’s, something no current drug can achieve.”

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Patients join project Cancer patients have joined those with rare diseases as part of the 100,000 Genomes Project, which aims to sequence 100,000 complete sets of DNA from 70,000 NHS patients. By recruiting cancer patients, scientists will be able to build more detailed understanding of how their DNA affects their susceptibility to disease and response to treatment. As well as the potential to benefit patients in the UK, this could also help in the global fight against cancer. Life Sciences Minister George Freeman MP said: “The recruitment of cancer patients is a significant milestone in the revolutionary 100,000 Genomes Project. It will help to unlock our understanding of the causes of this devastating condition, make the UK a leader in genetic research, and provide better diagnosis and more targeted treatment for thousands of NHS patients across the UK. In the programme, a test is performed on a cancer patient’s tumour, which is compared to healthy cells from a sample of blood and saliva. The testing happens alongside the normal care and involves a small sample of the tumour being analysed in much more detail by scientists. As part of the project, scientists are conducting pioneering work to overcome the challenge of extracting enough DNA from the tumour that is of the right quality to be sequenced.

This is a problem that no country has solved and underlines the UK’s position as a worldleader in research and cutting-edge medical technology. As a whole, the 100,000 Genomes Project can give potentially vital information about some of the world’s rarest and most devastating diseases, which not only benefits patients but also their families. Secretary of State for Health Jeremy Hunt said: “Genomics is the future of medicine and the sequencing of cancer DNA confirms why the UK is a global leader in this field. Over half a billion pounds has been invested in genomics to ensure that NHS patients continue to benefit from the prospect of better diagnosis and better treatments.

George Freeman also announced that: • there will be a £250 million commitment to genomics, which ensures the continued role of Genomics England to deliver the project, beyond the life of the project and up to 2021 • the number of genomes sequenced as part of the project has now reached over 6,000 The project has already delivered its first successes, with children at Great Ormond Street Hospital in London recently receiving life-changing diagnoses. The 100,000 Genomes Project, which was launched by the Prime Minister in 2012, aims to better understand DNA and how it can predict and prevent disease, and launch a genomic medicines service in the NHS.

Genomics is the future of medicine and the sequencing of cancer DNA confirms why the UK is a global leader in this field. Over half a billion pounds has been invested in genomics to ensure that NHS patients continue to benefit from the prospect of better diagnosis and better treatments. Jeremy Hunt

Secretary of State for Health




Chemical probe

Scientists have created a chemical probe which can switch off two proteins implicated in cancer, shedding new light on the role they play in cell proliferation. The probe will allow more precise analysis of the biological the roles of CDK8 and CDK19 in cancer and other cells and was developed through a research partnership between The Institute of Cancer Research, London, the University of Cardiff, pharmaceutical company Merck Serono, and Cancer Research Technology, the commercial arm of Cancer Research UK.

Home-produced compost ‘can rival big industry’ Research carried out in Manchester suggests that home-produced composts can provide nutrient-rich growing material that rivals industrial-scale production. A Manchester Metropolitan University team researched compost produced from green and food waste to establish its quality in comparison to large-scale manufacture. The team found that small-scale home and community-produced composts were a highquality plant growth medium rich in nitrogen and phosphorus, decomposing bacteria and fungi, as well as being home to a large range of microscopic animals such as beetles and mites. Marcos Vázquez, a former Manchester Met student and lead author, said: “We were very

pleased to learn from the detailed physical, chemical and microbiological testing that our low-maintenance local composters are producing safe, high-quality nutrient-rich composts.” The collaborative research was established to inform the ecological and environmental association of Galiza, North-West Spain about the quality of mature compost from local community and university canteen composting programmes. Marcos spent three months at Manchester Met as a PhD scholarship student from the University of A Coruña, Galiza, Spain. He has since been working as an anaerobic digestion process engineer at Viridor, Stockport. Dr Robin Sen, Reader in Soil Microbial Ecology and Biotechnology at Manchester Met, said: “Local composting makes a significant contribution to safe cropping in degraded or contaminated soils and can critically replace endangered Sphagnum peat moss-based composts.”

Expanded plant opens BASF has opened an expanded Littlehampton production site to meet the growing global demand for biological solutions for agriculture and horticulture. The move means that BASF can increases its production volumes of beneficial nematodes and inoculants, moving ahead with its strategy to develop beyond conventional crop protection. Philipp Rosendorfer, Vice President R&D Functional Crop Care, said: “We are making significant investments in innovating and delivering the best in biological and chemical solutions.” The expansion will allow BASF to double production capacities for beneficial nematodes, which are microscopic organisms that can control a diverse range of insect and slug pests.

Graeme Gowling, Global Biologicals Marketing, Functional Crop Care, said: “The demand for our beneficial nematodes has increased significantly over the past five years. Our customers see an increasingly important role in using beneficial nematodes in Integrated Pest Management programs, as they are easy to apply, have a longer window of activity and can effectively control yield-robbing pests.” Additionally, the newly expanded site in Littlehampton will increase the supply of inoculants from BASF worldwide and especially to Europe and Africa. Inoculants are rhizobia bacteria that, in a symbiotic relationship with their host legume plants, produce root nodules to conduct nitrogen fixation. BASF produces biological inoculants as an ingredient for seed treatments.


Project collaboration

The University of Manchester and The Centre for Process Innovation, based in North East England, are collaborating in a biochemical project. Succinic Acid is a 4-Carbon platform chemical that can be used for the manufacture of bio-chemicals and bioplastics. Currently, it is manufactured from fossil oil and more recently production has been demonstrated by fermentation of sugar. The project will investigate the feasibility for producing Succinic Acid from a low cost industrial waste stream, glycerol, a byproduct of the production of biodiesel transport fuel.

Drug research

The Sussex Drug Discovery Centre - part of the School of Life Sciences at the University of Sussex - has been awarded £1.8 million by the Medical Research Council to use biology and chemistry to combat the side effects of anxiety drugs like Valium. Led by Professors John Atack, Simon Ward and Martin Gosling, the team at the centre will use biological and medicinal chemistry methods to develop nextgeneration drugs. Their aim is to identify a non-sedating anxiolytic – in other words, Valium without the side effects.



Ebola breakthrough is announced

Researchers at Albert Einstein College of Medicine in New York and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) have engineered the first antibodies that can potentially neutralise the two deadliest strains of the virus that causes Ebola hemorrhagic fever. The findings, made in mice, are seen as a significant step toward immunotherapies that are effective against all strains of Ebola virus that cause human disease. Study co-leader Jonathan Lai, Ph.D., associate professor of biochemistry at Einstein, said: “A broadly effective immunotherapy for Ebola virus would be a tremendous advance, since it’s impossible to predict which strain of the virus will cause the next outbreak.” Zaire Ebola virus (EBOV) was responsible for the 2014 Ebola outbreak in West Africa, the largest in history. The next-most pathogenic strain of Ebola virus is Sudan Ebola virus (SUDV). Study co-leader John M. Dye, Ph.D., branch chief of viral immunology at USAMRIID, said: “This strain is also a concern because outbreaks are occurring more frequently, and it has been responsible for large outbreaks in the past.”

Although a Zaire-specific vaccine is in clinical trials, no vaccine has yet been approved for preventing infection from any strain of Ebola virus and therapies for people who become infected are very limited. ZMapp, a cocktail of three monoclonal antibodies, is the most promising of several experimental immunotherapies for Ebola virus now in development. However, say the study team, ZMapp’s antibodies are specific for EBOV and would not work against the other two Ebola strains that have caused major outbreaks. In addition to Zaire and Sudan, the third major strain is Bundibugyo. In previous work, Dr Jonathan Lai and his colleagues used a technique called synthetic antibody engineering to create the first humanized antibodies against SUDV. For the latest study, Dr Lai, Ph.D. student Julia Frei and postdoctoral fellow Elisabeth


Nyakatura engineered “bispecific” antibodies that contain key glycoprotein-binding sequences from both the EBOV and SUDV antibodies. The antibodies effectively neutralised both EBOV and SUDV in tissue culture studies. In addition, the antibodies provided high levels of protection for mice that had been exposed to lethal doses of either of the viruses. The antibodies must still be tested in larger animals and in humans to know whether they will be effective. Dr Lai said: “It might best be suited for preventing local outbreaks from getting out of hand, as happened in the recent West Africa Ebola virus epidemic. “It’s also possible that a therapy like this could be used prophylactically, to protect health workers or family members who come into contact with Ebola virus patients



Cluster recognised

The US Small Business Administration has awarded a grant to BioSTL and a group of regional partners to further its work in St Louis. Funding from the Regional Innovation Cluster Initiative will support work on the BioGenerator, which supports support to entrepreneurs and small businesses in the region’s bioscience cluster. “It is a huge vote of confidence in St. Louis’ progress as a thriving bioscience community,” said Donn Rubin, president and CEO of BioSTL.

Wheat patent is granted American agricultural technology company Arcadia Biosciences has been granted a US Patent for technology that will increase the resilience of wheat.

Study challenges views on spread of diseases A study into the way plague spreads through prairie dog colonies in the western United States has yielded insights that could help explain outbreaks of plague, Ebola, and other diseases that can be transmitted by animals to humans. The study, led by Dan Salkeld and Mike Antolin of Colorado State University in the United States, suggests that even deadly diseases may persist unnoticed in a population for years as infections, rather than jumping from another species immediately before an outbreak. In addition, the team says that investigations commonly launched after a human outbreak can yield misleading information about which host species were responsible. For instance, it seems that grasshopper mice and coyotes, which scavenge plaguekilled black-tailed prairie dogs, may speed transmission of the plague-causing bacterium by acquiring and spreading the flea vectors.

Thus, fleas can transmit plague faster than was once thought. According to the team, the disease can persist in wider prairie dog populations through repeated dispersal and reinvasion despite local outbreaks that can kill 95%-100% of the members of affected colonies.

Arcadia’s project is developing nongenetically modified Resistant Starch (RS) wheat which has been linked to improved insulin sensitivity and lower blood glucose levels and benefits people with diabetes, pre-diabetes and obesity.

We’ll drink to that

Researchers at the University of Bologna in Italy have developed a biorefinery model that would produce polyphenols, fatty acids, biopolymers, and biomethane from the skins and seeds left over from wine production.

The authors state that this ’slow, smouldering, cryptic disease transmission in animal populations prior to outbreaks in humans is... a hypothetical explanation for the persistence of pathogens.’ They say that oversimplification of the ways animal-borne diseases spread may lead to serious scientific errors, saying: “If disease outbreaks are sporadic and difficult to predict, a bias toward studies of the pathogen’s ecology during the peaks or aftermaths of the outbreaks will naturally arise.” In the case of Ebola virus, they argue, sampling of ‘fruit bats after human outbreaks may have biased subsequent investigations toward batEbola virus ecology’, resulting in researchers’ possibly overlooking other species that could be involved, including nonhuman primates and ungulates. According to the authors: “A misplaced focus on a single animal host species may nullify efforts to create useful early warning monitoring programmes.”


The country produces about five million metric tons of the feedstock annually that currently has little value and the new model combines supercritical carbon dioxide with anaerobic digestion, microbial treatment, and anaerobic fermentation to produce the chemical products.



Pioneering cells work leads to Nobel Prize

The Nobel Prize in Chemistry for 2015 has been awarded to three scientists whose work is adding add immensely to the understanding of human cells. Members of the judging panel awarded the prize jointly to Tomas Lindahl, Paul Modrich and Aziz Sancar for having mapped, at a molecular level, how cells repair damaged DNA and safeguard genetic information. Their work has provided fundamental knowledge of how a living cell functions and is already being used for the development of new cancer treatments. Tomas Lindahl works at the Francis Crick Institute and Clare Hall Laboratory, Hertfordshire, UK, Paul Modrich at the Howard Hughes Medical Institute and Duke University School of Medicine, Durham, NC, USA, and Aziz Sancar, at the University of North Carolina, Chapel Hill, NC, USA. All three have carried out work which examined the nature of changes in human cells and their relationships to diseases such as cancer. Each day our DNA is damaged by UV radiation, free radicals and other carcinogenic substances, but even without such external attacks, a DNA molecule is inherently unstable. Thousands of spontaneous changes to a cell’s genome occur on a daily basis and defects can also arise when DNA is copied during cell

division, a process that occurs several million times every day in the human body. The reason our genetic material does not disintegrate into complete chemical chaos is that a host of molecular systems continuously monitor and repair DNA. The Nobel Prize in Chemistry 2015 awards three pioneering scientists who have mapped how several of these repair systems function at a detailed molecular level. Tomas Lindahl demonstrated that DNA decays at a rate that ought to have made the development of life on Earth impossible. This insight led him to discover a molecular machinery, base excision repair, which constantly counteracts the collapse of our DNA. Aziz Sancar has mapped nucleotide excision repair, the mechanism that cells use to repair UV damage to DNA. People born with defects in this repair system will develop skin cancer if they are exposed to sunlight. The cell also utilises nucleotide excision repair to correct defects caused by mutagenic substances, among other things Paul Modrich has demonstrated how the cell corrects errors that occur when DNA is replicated during cell division.


This mechanism, mismatch repair, reduces the error frequency during DNA replication by about a thousandfold. Congenital defects in mismatch repair are known, for example, to cause a hereditary variant of colon cancer. According to the judging panel from Royal Swedish Academy of Sciences, the Nobel Laureates in Chemistry 2015 have provided fundamental insights into how cells function, knowledge that can be used, for instance, in the development of new cancer treatments. Tomas Lindahl was born 1938 in Stockholm, Sweden and was Professor of Medical and Physiological Chemistry at University of Gothenburg between 1978–82 before becoming Emeritus group leader at Francis Crick Institute and Emeritus director of Cancer Research UK. American Paul Modrich is an Investigator at Howard Hughes Medical Institute and James B. Duke Professor of Biochemistry at Duke University School of Medicine, Durham, NC, USA. Aziz Sancar, a US and Turkish citizen, is Sarah Graham Kenan Professor of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.



Advancements may lead to new treatments for Parkinson’s

Scientists in Detroit in the United States have come up with findings that could lead to new treatments for Parkinson’s disease. The team at Wayne State University have investigated the hallmark sign of Parkinson’s disease, the intraneuronal accumulation and progressive spreading of clumps in certain areas of the brain, known as Lewy bodies. The team led by Assia Shisheva, Ph.D., professor of physiology, has made advancements on a new molecular mechanism that may ‘melt’ the clumps.

Sparking solution to a dental problem

New laboratory

Malvern Instruments has set up a new biopharmaceutical applications laboratory in the heart of San Diego’s biotechnology cluster.

Diamonds could turn out to be a dentist’s best friend, according to research carried out in the United States.

treatment. To prevent this from happening, researchers have been exploring other fillers, including nanodiamonds.

Gold, silver and porcelain are among the many materials dentists can use to fix damaged teeth but the research suggests that microscopic diamonds could have a role to play as well, according to the American Chemical Society.

Laboratory testing showed it was stronger than gutta-percha by itself and was effective at killing Staphylococcus aureus, which is one of the bacteria responsible for root canal reinfections.

The scientists have developed a new material with nanodiamonds that has the potential to improve current root canal therapies and help prevent future infection. Millions of people undergo root canal procedures every year to clear out damaged or infected pulp, the soft part in the middle of a tooth. Dentists tend to use a rubber compound called gutta-percha to fill the gaps. In some cases, however, a patient’s tooth can get re-infected, which calls for another

Researcher Dean Ho and his colleagues combined nanodiamonds, gutta-percha and amoxicillin, a broad-spectrum antibiotic, into a new material.

The scientists say future studies will check whether the composite works in clinical practice. Funding for the research came from the National Science Foundation, the Center for Scalable and Integrated NanoManufacturing, the V Foundation for Cancer Research, the Wallace H. Coulter Foundation, the National Cancer Institute, the Society for the Laboratory Automation and Screening and Beckman Coulter Life Sciences.


The laboratory has been developed in partnership with Sevion Therapeutics, a San Diego-based biopharmaceutical company that discovers, develops and acquires next-generation biologics. Sevion Therapeutics will host the laboratory for which Malvern will provide analytical instrumentation, training and continuing support.

Cancer advance

Researchers at the Translational Genomics Research Institute (TGen) in Arizona, in the United States, joined an international team of scientists to explore how a protein from malaria could help stop cancer. Collaborators at the University of Copenhagen found that the mosquitoborne parasite that causes malaria produces a protein that binds to a particular type of sugar molecule in the placenta. Researchers found the same type of molecule in many types of cancer. TGen scientists helped test the theory and concluded that the link was feasible.



Spider glue research could lead to new materials Bioscientists at Virginia Tech in the United States have investigated the glue used by orb spiders as part of a project to invent new materials. The glue – created when glycoproteins are secreted from a spider’s abdomen and interact with the atmosphere – has been studied by Brent Opell, a professor of biological sciences in the College of Science and a Fralin Life Science Institute affiliate. Prof Opell’s research team, which included Sarah Stellwagen, a 2015 biological sciences

doctoral graduate, and Mary Clouse of Fairfax Station, Virginia, a senior majoring in biological sciences, determined that ultraviolet rays, specifically UVB rays, are an important environmental factor in the performance of spider glue. They tested the webs of five local spider species – three that catch prey in broad daylight and two that hunt at night or in deep forest shade shaded areas. They found that the webs of sun-soaked spiders were far more resistant to UVB rays than the webs of those that hunt in the dark or shade, perhaps indicating an important adaptive trait. Prof Odell said: “Our study adds UVB irradiation to the list of factors known to affect the performance of spider glycoprotein glue, which

includes humidity, temperature, and strain rate. “It is important to more fully understand these effects as material science moves toward producing environmentally non-toxic and energy conservative adhesives inspired by spider thread glycoprotein.” Ali Dhinojwala, H.A. Morton Professor in Polymer Science at the University of Akron, said: “Inspired by this study we can learn from the chemistry of spider glue to design new molecules to improve resistance to UVB light.” Ali Dhinjowala was not involved in this study but has collaborated with Prof Opell on other spider glue projects, such as a study on humidity’s effect on spider glue supported by the National Science Foundation.

China links with UK to drive forward research A collaboration between organisations in the UK and China has been agreed to further research into human and agricultural medicine. The Medical Research Council (MRC), the Biotechnology and Biological Sciences Research Council and the Economic and Social Research Council have joined forces with the National Natural Science Foundation of China (NSFC) to establish a joint fund of £9M to support research on antimicrobial resistance (AMR). The UK contribution (£4.5m) will be channelled through the Newton Fund, an initiative launched in April 2014 to strengthen research and innovation partnerships between the UK and emerging knowledge economies. The Chinese government will provide

matched funding to support internationally competitive projects between researchers from China and the UK. Antimicrobial Resistance is a big problem for healthcare and agriculture. Antibiotic overuse and misuse in agriculture and human medicine has led to a growing number of bacteria in humans, animals and the environment that are resistant to them. Drug resistant infections will kill an extra 10 million people a year worldwide – more than currently die from cancer – and cost the global economy up to $100Tn (£64Tn) by 2050, unless action is taken. In China alone, by 2050 as many as one million people a year could be dying because of AMR. The cumulative economic cost would be $20Tn – equivalent to two years of current Chinese output.


UK Life Sciences Minister George Freeman MP said: “Antimicrobial Resistance is a major threat to millions of lives around the world. This £9m joint investment will help leading scientists in the UK and China share expertise and innovations to develop new treatments that could help eradicate this threat to global public health.” Professor Lu Rongkai, Deputy Director General of the Bureau of International Cooperation, NSFC, said: “The increasing threat posed by antimicrobial resistance is an international issue that requires much deeper understanding, which will only be achieved through an interdisciplinary approach.” Dr Mark Palmer MRC Director of International Strategy said: “We know diseases don’t recognise international borders and that addressing health problems around the world demands a global response.”



The West SmartDose® electronic wearable injector, designed for patient convenience, incorporates a Daikyo Crystal Zenith® cartridge and can deliver a dose of up to 3.5mL, which may allow for viscous biologics that are sensitive to glass, metal ions and/or silicone oil to be administered over longer periods of time

Modern Biologics require modern packaging By Dr. Nicolas Brandes West Pharmaceutical Services, Inc.

Some biologic drug products do not react well with glass, requiring drug manufacturers to look at other options for containment and delivery. For example, modern biologic formulations sensitive to silicone oil or tungsten may require alternative packaging. Silicone oil, used as a lubricant in glass containers to obtain plunger gliding functionality, has been strongly connected to protein aggregation as well as the presence of subvisible particles in the suspension. Other undesirable effects in combination with glass primary packaging include potential breakage, delamination, heavy metal release, low dimension control and lack of design flexibility. Challenges with glass, as well as a sharpened focus on safety since patients with chronic diseases are treating themselves at home more frequently, drives pharmaceutical companies’ demand for increased quality from drug containment and delivery system manufacturers. While glass remains the standard for injectable drug containment for the prefilled syringe market, the material’s higher dimensional variability in manufacturing could be a concern when evaluating the functionality of the syringe or cartridge in conjunction with the delivery system.

High-quality polymers, such as cyclic olefin polymers (COP), help maintain the quality of sensitive biologics through enhanced cleanliness and decreased interaction with the drug product. Primary containers made from materials such as the Daikyo Crystal® Zenith (CZ) COP can help contain higher dose volumes or provide delivery options for viscous drug products. Cartridges and syringes molded from the CZ® polymer are free of silicone oil und tungsten, and exhibit break resistance as well as consistent and predictable gliding forces. The rubber components that are used in the CZ systems are laminated with Flurotec® film, which functions as an effective barrier against extractables and provides lubrication at the same time.


Some patients either do not want to inject themselves with medications in prefilled syringes, or their conditions make it difficult. Some drugs, including biologics, might require large volumes of viscous solutions, making a single-dose option either difficult or impossible. While there are numerous auto-injector devices on the market, pharmaceutical companies need innovative and responsive packaging partners that can keep up with the


requirements these biologics create. Some glass-sensitive biologics must be housed in polymers because of potential breakage or protein aggregation with glass. Others are more suited to injectors that can control the delivery of large doses over time when the drug is too much for a single injection. An example is the West SmartDose® electronic wearable injector system, which incorporates a CZ polymer-based drug container and is designed to enhance the experience of patients required to self-inject a larger volume biologic drug at home. Choosing the correct packaging and delivery system can not only make medication adherence easier on the patients, but also can encourage brand preference among patients and practitioners. By making the right choices early on in the development process, packaging and pharmaceutical manufacturing can mitigate risk and deliver a high-quality product to patients. SmartDose® is a registered trademark of Medimop Medical Projects Ltd., a subsidiary of West Pharmaceutical Services, Inc. West and the diamond logo and By your side for a healthier world™ are registered trademarks or trademarks of West Pharmaceutical Services, Inc. Daikyo Crystal Zenith® is a registered trademark of Daikyo Seiko, Ltd. Crystal Zenith and FluroTec® technologies are licensed from Daikyo Seiko, Ltd.



Major steps being taken in battle against


Researchers from many disciplines are working together to ease the pain of rheumatoid arthritis patients and potentially save the NHS millions of pounds on ineffective drugs. Doctors can waste a long time prescribing different therapies to patients while trying to find one which provides effective relief but there is currently no short cut, no way of telling which person will respond to which medicine. Until the correct drug is discovered by trial and error the patient goes on suffering and the NHS spends money on drugs which don’t work and handles increased numbers of appointments. Last year researchers from various institutions came together under the umbrella of the MATURA Consortium to try to shed light on this problem.

With £5 million funding from the Medical Research Council and Arthritis Research UK eleven academic groups and nine commercial concerns will be looking at two approaches to the issue - better tests and techniques to improve diagnosis, and ways to predict which patient will respond to which treatment. One of the treatments which has unpredictable results in patients is anti-TNF therapy, an approach which blocks the effects of a protein called tumour necrosis factor which, when overproduced by the body, can damage bones and cartilage. Forty percent of patients do not respond to anti-TNF therapy.

A similar number fail to respond to methotrexate, one of a group of medicines known as disease-modifying anti-rheumatic drugs (DMARDs) Four drugs will form the focus of the research, which will attempt to discover precisely how each affects the body because it is known they each use different mechanisms. They are methotrexate, etanercept, rituximab and tocilizumab. Two main projects will run alongside one another. The first will examine knee biopsies of rheumatoid asrthritis patients to test whether biomarkers can predict response to biological therapies. This research will include a year-long clinical trial involving 200 patients. A second research programme will look at blood-based biomarkers in patients under treatment to predict response to methotrexate and biological therapies. The MATURA Consortium is headed by Prof. Constantino Pizalis of Queen Mary University in London and Prof. Anne Barton from the University of Manchester. Each will head up one of the research streams. Prof. Pizalis told Arthritis Research UK: “We can’t continue to use biological therapy on a trial-and-error basis. We need to find biological markers to identify patients who are likely to respond to the first drug they are given. As well as improving diagnostics and finding better outcome measures, we can accelerate the discovery of new targets and develop new drugs. “This is the beginning of a new journey to improve treatment for people with rheumatoid arthritis and to make an enormous difference to people’s lives.”

Arthritis research by Frances Griss 20



We can’t continue to use biological therapy on a trial-and-error basis. We need to find biological markers to identify patients who are likely to respond to the first drug they are given. Prof. Constantino Pizalis

Queen Mary University in London






Companies bring forward new treatments Despite mixed results for the therapy, drug companies are continuing to seek approval for new drugs in this field. In November 2015 Samsung Bioepis announced that the European Medicines Agency’s committee for medicinal products in human use (CHMP) had expressed a positive opinion on Benepali, a biosimilar version of the biologic etanercept. The final decision on whether or not to approve the drug lies with the European Commission and, if marketing authorisation is granted, it will be the first etanercept biosimilar to be approved in the EU. The positive opinion was based on Phase 1 and Phase 3 clinical studies which tested Benepali against Enbrel. The company reported: “In the 52-week phase 3 clinical study, which involved 596 patients randomized across 70 sites in 10 countries, Benepali demonstrated comparable safety and equivalent efficacy to Enbrel, as evidenced in ACR20 response rate of 80.8% in the Benepali arm versus 81.5% in the Enbrel arm.” Samsung Bioepis is also at an advanced stage of development for two other biosimilar drugs for the treatment of rheumatoid arthritis and announced clinical trial results for both at the annual meeting of the American College of Rheumatology and the Association for Rheumatology Health Professionals in San Francisco in November 2015. Known as SB2 and SB5, the compounds are biosimilar to the approved biologics infliximab and adalimumab respectively. The SB2 study randomized 584 patients with moderate to severe rheumatoid arthritis despite methotrexate therapy across 73 sites in 11 countries and showed comparable efficacy over 54 weeks.

The SB5 study randomized 544 patients with moderate to severe rheumatoid arthritis despite methotrexate therapy across 52 sites in seven countries over 24 weeks again showed comparable safety and equivalent efficacy to adalimumab, the company has announced. Christopher Hansung Ko, CEO of Samsung Bioepis, said: “By leveraging our strengths in product development and quality assurance, we will continue to focus on developing affordable, high-quality biologic treatment options for patients in Europe who need these life-enhancing medications.” Also in November 2015 American company Amgen went public on its Phase 3 trial of

its biosimilar ABP 501 against adalimumab. Their figures claimed at week 24, 74.6 percent of patients in the ABP 501 group and 72.4 percent in the adalimumab group met the ACR20 response criteria. Sean E. Harper, M.D., executive vice president of Research and Development at Amgen, said: “Demonstrating biosimilarity is scientifically complex, but Amgen’s 35 years of proven biologic R&D experience is facilitating the advancement of exciting programmesas like ABP 501. Our long-term commitment to advancing care in inflammation is as strong as ever, with a portfolio of novel and biosimilar compounds that have the potential to benefit patients worldwide.”

By leveraging our strengths in product development and quality assurance, we will continue to focus on developing affordable, high-quality biologic treatment options for patients in Europe who need these life-enhancing medications. Christopher Hansung Ko CEO of Samsung Bioepis




Bacteria research offers encouragement Other fields of research are looking at an interesting and long-suggested proposition that the bacteria which inhabit human digestive systems, live on our skin and even in our mouths have an impact on the inflammatory forms of arthritis and related conditions. The suggestion is that changes in the environment in which live personal microbes, your microbiome, caused by pregnancy, a course of antibiotics, weight loss or anything else can cause changes which can affect the immune system. These changes may lead to disease which can be alleviated or avoided, possibly by simply changing what you eat. Arthritis research UK is funding £2 million of research into the role of the microbiome, specifically gut bacteria, on conditions as diverse as established rheumatoid arthritis, childhood arthritis and ankylosing spondylitis. The grant, announced in January this year, follows a cluster of smaller awards made public last year and includes cash for researchers as far afield as Harvard and New York universities in the USA and at Oxford and Birmingham universities and University College London in the UK.

Group leader Prof. Fiona Powrie from the University of Oxford said: “This funding will allow our consortium to push forward with its goal of bridging the gap between microbiome description and function. It’s a key first step in unlocking the potential of the microbiome to yield therapies for inflammatory diseases.” Previously published studies have found convincing correlations between differences in the levels of certain bacteria in patients suffering from a number of immune-related diseases and healthy control populations. For example, Dr Jose Scher of New York University School of Medicine and Hospital for Joint Diseases, published research in 2013 which suggested that in animals gut bacteria had a role to play in the immune response required for joint inflamation. The team had also found a strong correlation between increased levels of Prevotella copri in human inflammatory arthritis patients.


A team led by Xuan Zhang of the Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, published results in July 2015 showing depleted levels of Haemophilus species in patients with rheumatoid arthritis and an over representation of Lactobacillus salivarius. Dr Stephen Simpson, director of research programmes for Arthritis Research UK, said: “We hope that the £2 million award will help us understand the relationship between the bacteria in our gut and human health, specifically arthritis. This knowledge is absolutely essential if we’re to develop new treatments that could one day revolutionise the way we prevent and treat painful and debilitating conditions like inflammatory arthritis.”




Goldilocks Effect Advances in the delivery of precision medicine trials in the UK have sparked interest in the commercial world. The concept of precision medicine is not new, but generating the scientific evidence to drive the concept into everyday clinical practice is challenging, to say the least. Traditional approaches, involving multiple phase trials in different hospitals and at different times, are reliable but take time, even more so when the biomarker that predicts good response is rare. A new, more efficient approach to testing stratified novel therapeutics is underway in the UK which also has the potential to achieve a faster route to drug registration. Molecular oncology has seen an explosion of biologic knowledge over the last 10-15 years and is widely recognised as being in the vanguard of precision medicine research. Professor Rick Kaplan is a global innovator when it comes to cancer research. A medical oncologist with over 40 years’ experience in clinical research, he’s currently a senior leader at the Medical Research Council Clinical Trials Unit and also works as Honorary Consultant in Oncology at University College London Hospital: “The ‘hit and miss’ process which led to perhaps a dozen potential treatments per year being taken into clinical trials has been replaced by a conveyer belt of targeted,

experimental cancer drugs - there are literally hundreds in the pipeline. The chances of those drugs targeting the intended cancers are much higher than anything that we could manage in the past. What we need now is a logical, systematic way to quickly and efficiently find out which drugs target which tumours in which patients.” According to Professor Kaplan the UK is the ideal place to do this. Having worked in the USA for 30 years before settling in the UK in 2004, and having also served on advisory committees and panels for multiple government agencies, professional organisations and clinical trials organisations in North America, Europe and Australia, he’s well placed to describe what he calls ‘The Goldilocks Effect’: “Firstly, the UK is large enough to have adequate pools of patients. But it’s also

small enough to foster a real motivation and necessity for people to work together; clinicians, academics, life-science companies and charities. This is in contrast to, say, the US, which is so large and so decentralised that it discourages such wide ranging collaboration. “Secondly, in the UK brand new drugs are not automatically available in the National Health Service (NHS) which presents us with a window of opportunity during which we can begin to unpick which drugs actually work in which patients. By comparison, in the US patient demand combined with commercial forces mean that drugs are used in a wider patient population than the original intended target and subsequent information on effectiveness can be skewed. “Another reason is the research infrastructure provided by the Government-funded National Institute for Health Research (NIHR),

It’s not too big, not too small, and the regulatory environment is just right. It’s a bit like Goldilocks getting her hands on the perfect bowl of porridge – the UK is fertile ground for delivering precision medicine.




particularly the NIHR Clinical Research Network and the Experimental Cancer Medicine Centres - key components in facilitating fast and efficient clinical research. The reality is that precision medicines increasingly need to draw upon smaller and smaller proportions of a particular disease population. So to get the recruitment levels the net needs to be cast wider. “The Clinical Research Network, which is the research delivery arm of the National Health Service, can facilitate a hub and spoke approach which allows patients who are keen to participate in a trial to be referred on to the trial site at a specialist centre such as one of the 18 Experimental Cancer Medicine Centres. Again this doesn’t happen easily somewhere like the US because of the commercial market. “So to summarise, it’s not too big, not too small, and the regulatory environment is just right. It’s a bit like Goldilocks getting her hands on the perfect bowl of porridge – the UK is fertile ground for delivering precision medicine research.” And the green shoots of multiple-arm prospective stratified medicine trials are beginning to show. Two pioneering projects are now underway in the UK. “Focus4 and The Lung Matrix are both ‘platform’ trials”, Professor Kaplan explains. “By this we mean a framework of trials in a specific disease area. Focus4 looks at colon cancer and The Lung Matrix targets lung cancer. “Starting a new trial is usually a two year process but in our approach, when a new drug/ biomarker combination is developed, we don’t start a new trial, we simply add a new arm to the existing platform by means of a protocol amendment and avoid the two year delay.” Professor Gary Middleton is a Consultant Medical Oncologist and Chief Investigator for The Lung Matrix. He’s also a member of the trials management group and Chief Investigator for one biomarker arm of Focus4. He explains how the platform approach

tips the screening versus eligibility balance favourably: “The Lung Matrix is intrinsically linked to Cancer Research UK’s Stratified Medicine Programme 2 which is genetically screening up to 2,000 lung cancer patients a year. Pharma companies seeking a biomarker in a rare patient cohort can add the study to our platform and tap into our screening programme and we will be able to identify that rare two or three per cent in the 2000 plus patients we are screening. Pfizer and AstraZeneca are firmly on board and we have a whole host of other companies interested.” Another common thread of both platform programmes is flexibility. Professor Kaplan continues: “Focus4 is essentially a first line treatment study. There are currently three biomarker specific arms and a non-biomarker chemotherapy arm meaning that every single patient screened is eligible to join the trial. Four more biomarker arms are in the pipeline, and if any drug fails to suggest benefit in a cohort, other new drugs can then be tested for new patients with that biomarker. “Also, there is built-in flexibility that allows us to refine the biomarker definitions. So if we find that a patient with biomarker A is not going to respond to a particular drug unless they also have biomarker B, we can change that biomarker definition. The trial will adapt as the science evolves.” There is optimism across the clinical community that this new adaptive approach will accelerate the discovery of a targeted therapy for bowel cancer. In lung cancer, where attributable targeted therapies already exist, Professor Middleton is also optimistic that The Lung Matrix - which currently has 20 arms and another two due to launch - will yield new targeted therapies and may even herald a shift away from the traditional four phase model of clinical trials: “The general belief is that the only way you can get drugs to market is by doing large phase three style studies. But in lung cancer


we have seen drugs successfully registered on the basis of 50 patients taking part in a phase two study. The Lung Matrix aims to amplify that success by conducting many small studies simultaneously. Each arm will recruit around 30 patients. Naturally, some drugs will not show any activity. But where we see good levels of positive activity we are hoping that with compelling biology evidence we may, in some cases, have a faster route to registration.” Professor Tim Maughan is Chief Investigator of Focus4. He was one of the architects of the first clinical research network (in Wales in 1998) and subsequently helped develop clinical research networks across the UK. As interest in the platform approach grows in the commercial world Professor Maughan echoes the words of Professor Kaplan - that the collaborative mind-set of the UK underpins its ability to conduct complex programmes of precision medicine trials: “Under the auspices of the National Cancer Research Institute Clinical Studies Groups a number of groups and individuals have worked closely together for the last decade; Cancer Research UK, the National Institute for Health Research, the Clinical Research Network and the Experimental Cancer Research Centres, Biomarker Pathology Genetics Group, not forgetting the Clinical Trials Units. This collaborative framework of experienced clinical researchers has created a positive environment and given us the confidence, and the track record, to develop the platform approach and engage companies like AstraZeneca, GSK, Novartis, Bayer and Amgen. “As clinicians this new direction is important. It enables us to get more molecular profiling of tumours and gain access to new drugs. The concept of one treatment for all patients of a particular disease is out-dated. These platform trials provide a flexible and rapid way of evaluating the activity of new approaches and testing them rigorously to demonstrate benefit.” Find out more about the NIHR Study Support Service:



Advances in

syringe technologies open up new opportunities

Interest in the convenience and safety of pre-filled syringes is growing to the extent that some commentators are suggesting they will largely replace the traditional syringe for standard medical care. The technology has been around for decades and is slowly gaining popularity with the medical profession as a safe, convenient and cost-effective solution. More than 50 drugs and vaccines are available in this way with more companies providing the product and more countries and health services adopting this option all the time. Anaesthetics, vaccines, insulin, biologicals for treatment of inflammatory varieties of arthritis and psoriasis are just some of the applications of this technology. Pre-filled syringes virtually eliminate waste, minimise the opportunities for mistakes and decrease potential for contamination, in addition to which they are much easier for patients to manage in a home environment. Issues around their use involve shelf life and the safety of the plastic packaging against proven glass receptacles but studies have shown they are certainly capable of meeting the required standard. Elimination of waste is a major argument in their favour because standard glass phials are routinely overfilled by as much as 25% to ensure there is enough drug in the phial to

allow for ease of filling an ordinary syringe - right down to the last dose. This can be very expensive, particularly with compounds which are difficult to produce. By pre-filling the syringe over-filling is virtually eliminated. Repeated use of the same phial to draw doses also involves a risk of contamination, which is eliminated by using a pre-filled syringe. Increased safety and speed of access are arguments in the favour of ready-prepared dosage in an emergency context and for patients administering their own doses at home, when they are more comfortable not having to draw up their own medicines. In February 2015 a Smithers Rapra market report into pre-filled syringes predicted continued growth in this market to $6.6 billion by 2020, accounting for 6.7 billion units. New developments include the two-chamber syringe for mixing dried compounds with water prior to injection. The mixing used to have to carried out by hand but it can now be done with pre-measured quantities in a sealed environment further reducing opportunities for error and contamination. Announcing their joint development with Arte Corporation, ProJect Pharmaceutics described the manufacturing process of the two-chamber product: “The diluent is filled first and can be autoclaved as required by international guidelines. The drug solution is filled into the second chamber and completely sealed on the filling line before entering the freeze drier. Due to its special design, the system opens by itself within the freeze drier enabling lyophilization of the drug solution in presence of the diluent.�









Market place becoming more competitive Popular as this technology is, there are others vying for a niche in the same markets with equal claims on convenience and popularity with patients and clinicians alike. In 2011/12 Garcia-Diaz et al studied patient satisfaction and fear levels for both prefilled syringes and a pen. The 30 long-term arthritis patients at Hospital Moises Broggi in Barcelona had been using the syringe before being switched to the pen after suitable training. Results showed no significant difference with management of the device or with post-injection pain; satisfaction levels of 90% for the syringe and 93.3% for the pen were recorded but patents showed statistically significant increased levels of fear with the syringe. In diabetes patients, pen use is very common and many patients re-use the needles on their pens, although these needles are designed to be used ideally only once. Mismikova et al studied three groups using insulin pens in Moscow in 2011 and found that patients using a single needle for seven days had more pain, increased bacterial contamination than those using a needle for four those only using the needle once had the lowest levels. Hyperemic foci at injection sites were found only in the groups using needles multiple times. Used correctly, pens are very popular and suppliers are constantly working to improve their designs based on feedback from patients and practitioners, whose concerns were particularly needle-stick injuries. For example in April 2015 Oxfordshire company Owen Mumford announced their latest product called Autoject Micro. Business development manager George I’ons said: “Autoject Micro has been developed to make it easier for patients and healthcare professionals to deliver single dose injectable treatments while also addressing cold store

and logistics costs with its smaller form factor. Its intuitive design and safety features have been created to address key patient concerns such as needle-stick anxiety and adherence, while providing advanced drug delivery capabilities.” Earlier in the same year the same company’s Unifine Pentips Plus pen needle won a Red Dot Award. At that time Richard Walker, global product manager for the company, said: “The initial concept behind Unifine Pentips Plus was to make the injection process as easy and comfortable for the end user as possible, which plays an integral part in encouraging good self-management practices. “The research and design team went back to the drawing board to create a completely new solution for the long-established standard insulin pen. [The product] is proven to encourage better needle change behaviour and for our design to be recognised by the judging panel at Red Dot is great news.” In situations where many injections need to be carried out or where patients are very fearful of needles, science fiction has become reality to offer the hypospray. Although not universally accepted as the terminology for needle-free injection devices, the Star Trek word does seem to have entered the lexicon. Using compressed air or a spring system to inject a thin stream of fluid either subcutaneously or intramuscularly in 0.1second or less, there is no needle and therefore no risks associated with needle reuse or needle-stick injuries. In September 2015 Pharmajet, one of the manufacturers of such devices, announced that its equipment would be used across the USA for seasonal flu vaccinations through a pharmaceutical supply company. CEO Ron Lowy said: “Entering the market, the Pharmajet needle-free injector has been well received by patients and health care providers alike. Based on our post-market surveys with patients receiving a needle-free flu shot, 93 per cent of patients and 87 per cent of health care providers reported that they would choose the Pharmajet needle-free option again for the upcoming flu season.” The previous year the company announced that it was the only needle-free injection


company to receive a performance, quality and safety pre-qualification certificate from the World Health Organisation (WHO), allowing its Stratis jet injectors to be used for mass immunisation campaigns. Diabetes patients are another major potential user group for this technology, especially those individuals with a needle phobia. In early 2016 Glide Technologies announced progress with its solid dose needle-free system and exenatide, a GLP-1 antagonist for the treatment of type 2 diabetes, showing no statistical difference between the solid product and Byetta, the current liquid product. Glide technology uses a spring-loaded mechanical device to introduce tiny solid pellet of a drug or vaccine which quickly dissipates into the body. The company announced: “The technology has multiple advantages over currently marketed liquid peptide products, which are needle administered and require cold chain logistics and refrigeration in the home. In particular, the technology has the potential to significantly improve patient compliance, which is important where self-administered injections are required, such as in diabetes. The results follow previously announced successful proof-of-concept studies with Glide’s novel solid dose formulations of currently marketed liquid products teriparatide and octreotide. Consequently Glide’s solid dose formulation technology has now achieved equivalence across a series of peptide products, demonstrating the flexibility of the platform to deliver this important class of therapeutics.” The variety of injection technologies and range of manufacturers available is testament to the importance place on having the right tool for the job by millions of patients and medical practitioners. Market forces are driving innovation at a staggering rate, although different solutions are being adopted in different places at different rates and some prove unsuccessful in the long term. There is certainly no shortage of imagination or ingenuity being brought to bear on this fastmoving field.



Human factors and prefilled syringes Human factors is now firmly established at the heart of medical device development, and that includes prefilled syringes. Regulators, and in particular the US Food and Drug Administration (FDA) have recently published guidance on human factors testing for manufacturers (UCM259760 ‘Human Factors for Medical Devices, published February 6th 2016). FDA have also just published a list of medical devices that they regard as top priority for human factors, and autoinjectors are on the list. The message from the FDA is very clear; if you are intending to apply for pre-market approval in the US for any type of medical device, you will need to demonstrate that you comply with these requirements. And if you are developing an autoinjector, human factors (HF) validation is mandatory. In essence, manufacturers are being asked to integrate human factors into their new product development, and to demonstrate that they understand the use-related risks for their device. Where to start? Three aspects are important; the intended uses, the intended users and the anticipated use environment. Have you clearly stated who the intended users are, and for what specific use your PFS is intended? Have you understood the environment in which your product is likely to be used? The recommended approach is to adopt a systematic method for analysing and evaluating the usability of your product through early, small-scale formative testing. Product designers will recognise this phase as ‘design verification’. Once you have verified that the design of your product meets the needs of its intended users, you will then need to validate that it can be used safely and

effectively. Typically this will mean running a human factors validation study in which you test the final ‘go-to-market’ version of your product. The validation study will need to use ‘simulated use’ scenarios in which a sample of patients will inject into a skin pad. The root cause of any use error or difficulty will need to be investigated so that you can demonstrate that you understand the causes of potential failures. Validation for products intended for the US will need to be carried out in the US with representative samples of the intended users. So for example, if your product is intended to treat rheumatoid arthritis (RA), your test sample must include people in the US with the right severity of RA, and with a mix of prior experience of injecting. Increasingly, PFS are being used for complex molecules and biologics, and in many cases the first injection might be performed by a healthcare professional in a clinical setting. This effectively means that HCPs are now an additional user group and should be included in the validation study. On completion of your validation study, the results will need to be fed back into your userelated risk assessment. After a further review of the risks, you will need to demonstrate that you have reduced the level of use-related risk to the minimum possible level, and that it is not practical to reduce risk further. But what if you plan to use an existing PFS, perhaps one that has been used for a


Richard Featherstone Richard Featherstone is founder and Managing Director of Medical Device Usability. He has over 10 years of experience as a human factors and usability practitioner for pharmaceutical and medical devices, with a further 20 years of experience in the pharmaceutical industry. Richard advises some of the world’s largest medical device and pharmaceutical companies on their HF strategies, and leads the MDU team in their global summative and formative testing programmes.

considerable time in one therapy area, but which you intend to develop for a different type of treatment? Do you need to go right back to square one and re-verify the design? Well, like the whole HF process, you are managing use-related risk. You may be aware of known use problems with the PFS (for example by reviewing customer complaints, or by reviewing the published literature). You may also perform an expert review to identify whether there are any ways in which risk could be reduced. But one thing is clear; if you are switching patient types to a very different therapy area, it is highly likely that FDA will ask you to revalidate the PFS in the new user group. Here at MDU we have built up considerable experience in human factors testing of medical devices, including PFS, pen injectors and autoinjectors. We test extensively in the US and EU and we work with some of the world’s leading pharmaceutical and medical device companies.



Auto Injectors: Customer needs and future trends

Pharmaceutical industry might well be one of the most exacting industries on the market. In order to satisfy a very broad range of stakeholders, including patients, prescribers, payers, patient-care providers and other healthcare professionals, both pharma companies and product manufacturers must work in partnership and bring everything that they have to the table. To say the least, the success of a product depends to a great extent on the cooperation between the pharmaceutical company and the device manufacturer. Understanding this, SHL Group offers innovative solutions which differentiate customer products from a sea of parenteral drug options.


As a successful and sustainable device manufacturer, SHL must generate high value functionality to satisfy the increasing demand for devices and services.. Given the challenges and market differentiation needs pharmaceutical companies face today, it is crucial for them to identify a device partner that will be able to deliver. The partner should be able to offer a range of proven device solutions that are adaptable to a number of different therapeutic areas and drug formulations. The partner should also be well positioned to guide their pharmaceutical customer in selecting the most appropriate design for their project, so that they can identify the functions that will create value

for the patients and help the product to stand out against competition. By staying innovative, providing economical solutions, and always ensuring product quality, SHL maintains its status as one of the top device manufacturers on pharmaceutical companies’ list.


With current generation of large molecule biotech drugs, biopharmaceutical industry faces growing need for new device solutions that deliver higher viscosity drugs in larger volumes. Moreover, due to a number of originator drugs coming off patent in a few years, their biosimilars will soon be entering the market, some of which have higher viscosity or cannot be formulated into a single 1 mL dose. In light of this, SHL has developed Molly® 2.25 – a new device based on Molly® 1.0, which is also able to effectively deliver more viscous drugs at a higher volume. The Molly® 2.25 auto injector, while accommodating a larger 2.25 mL pre-filled syringe, maintains all the strengths of previous devices made on this platform. These include the same simple two-step operation, quick-to-market timeline, ergonomic engineering, and customization according to customer-specific requirements. At the same time, Molly® 2.25 builds on those strengths by introducing some new features. In contrast to Molly® 1.0, the larger version has an ergonomic cap that is pull or twist-


off (for rheumatoid arthritis patients who need firmer grasp). The cap also prevents the device from rolling, whilst also sporting arrow-shaped cut-outs to further clarify handling directions. The backend is improved to appear more user-friendly. The result is a robust device that is extremely easy to handle and highly functional at the same time. As a preconfigured device, Molly® 2.25 retains all the timeline, business model and cost advantages of its predecessor.


The beauty of a ready-made platform is that it can be reinvented again and again, always keeping in mind how it can improve user experience. With the advancement of the Internet of Things, connectivity is the next feature to be added to auto injectors, with the purpose of increasing patient compliance and quality of life for patients and caretakers. Device companies, such as SHL, who hold a greater understanding of the core functions of a drug delivery system and the related stakeholders’ needs, will have the advantage when looking to add connectivity. If connectivity-added drug delivery devices bring real value to the stakeholders involved, there is a real opportunity to completely change the landscape for self-treatment of chronic diseases.




Safe’n’Sound®, a customizable platform of add-on passive safety devices for prefilled syringes In the parenteral industry, Needlestick injuries remain a global concern with over 3 million exposures to blood occurring every year according to the World Health Organization (WHO). Sharps injuries result in not only health issues but also psychological and costs issues. In order to overcome those problematic, regulation and recommendations have been established in order to improve patients and health workers conditions. Within those texts, safety devices for prefilled syringes (more precisely automated engineered safety devices) have been highlighted as a key route of improvement.

From a pharmaceutical perspective, Safe’n’Sound has been designed to give flexibility to the laboratories being an open and customizable platform. Indeed, Safe’n’Sound is compatible with syringes of different filling volume (1ml & 2.25ml), flange type and suppliers. Safe’n’Sound is compatible with marketed ISO standard syringes allowing pharmaceuticals to use syringe from multiple suppliers and de-risk their supply. In order to respond to pharmaceuticals needs, Safe’n’Sound has also been designed to accommodate several flange types.

Nemera has developed Safe’n’Sound®, a customizable platform of add-on passive safety devices for prefilled, which not only responds to the recommendations of the US Federal Needle stick Prevention Act, 2000 and the Council Directive 2010/32/EU (aiding in the protection from potential Needlestick injuries), but also provide pharmaceuticals with innovative solutions responding to the new problematic of the parenteral segment.

Safe’n’Sound is a customizable platform of add-on passive safety devices for prefilled syringes to aid in the protection from accidental needlestick. Safe’n’Sound is a single use device designed for naïve users and healthcare professionals. Safe’n’Sound is a patented product, 510(k) cleared which can be sold worldwide Safe’n’Sound is an open, adaptable and customizable platform to give flexibility to pharmaceuticals, and respond to user needs.

Indeed, the rise of biologic drugs and the increasing trend towards home-care setting are raising new concerns. Even though selfadministration is reducing treatment cost and intended to improve patient compliance, Needlestick injuries remain a concern. Biologics are also adding more complexity to the parenteral segment. Unlike typical drugs made from synthetic chemicals, biologics are produced from a living organism making them more complex drugs on size, complexity and value. Combining those two factors, it results in patients suffering mainly from chronic diseases with / without impairment who have to self-inject large volume drugs, highly concentrated, more viscous, sensitive and expensive. As a result, to overcome those problematic, innovative safety devices as Safe’n’Sound are required.

From a user perspective, as a passive safety device, no extra gesture is required by the user with Safe’n’Sound compared to a naked syringe. The safety feature activates automatically at the end of the injection, easing the use. User interface has been integrated since the beginning in the design and development of the device, integrating many ergonomic features: a large thumb pad surface to smooth the injection; large built-in finger flange to facilitate handling; a round shape for easy and comfortable handling; a spring located at the syringe flange position to provide good visibility of the tip of syringe and able inspection of the drug even with low filling volume drugs. An optional add-on ergonomic extended finger flange has also been developed to improve the handling, gripping and comfort for the user.


To accommodate larger filling volume drugs and responds to biologics problematic, Nemera has also developed a 2.25ml version of Safe’n’Sound®. It provides pharmaceuticals flexibility on their dosage formulation, and an innovative safety device solution to equip their large volume drugs while responding to patients needs in terms of ease of use and safety. In a more and more competitive environment, customization is critical. Flexibility is part of Nemera’s customer focus culture. Pharmaceuticals can leverage Nemera’s strong experience in manufacturing and development experience in the parenteral device segment to differentiate from competition with the utmost services and lead times. Potential customization of Safe’n’Sound are to color the add-on Extended finger flange and plunger rod, while improving brand imagery or facilitate drug dosage recognition. Many other customizations are possible. Please consult us your specific drug delivery requirements.











dermal/ transdermal

Nemera provides solutions for the pharmaceutical industry, including standard innovative products, development of custom devices and contract manufacturing. nasal/ buccal/ auricular Phone: +33 (0)4 74 94 06 54



Contributing to the success of injectable drugs In an increasingly competitive landscape, pharma companies need to focus on their core competence of drug development. Hence, device manufacturers need to support their customers with a range of services beyond the development and manufacturing of the injection device. This article provides some in-depth insights into the Extended Services provided by Ypsomed and how these help pharma companies to stay one step ahead of their competition. With the large number of new biologics and the surge in biosimilar product launches, the demand for self-injection devices continues to grow. As the number of devices reaching the market increases, pharmaceutical and biotech companies are looking to source state-of-the-art devices that are available quickly and at low risk. Responding to these emerging requirements, Ypsomed has built up a comprehensive range of platform products including their manufacturing infrastructure allowing faster and simpler customization projects while shortening time-to-market and minimizing project risks.


One of the key criteria for minimizing risks is a profound understanding of the injection device IP landscape to ensure that all device solutions are covered by appropriate intellectual property protection and do not infringe third party patents.

FREEDOM BY DESIGN - DIFFERENTIATION Pharma companies strive to differentiate their self-injection devices through individual design options. Ypsomed either modifies the

look and feel of its ergonomically proven and tested platforms or offers an entirely new outer shape implemented by using an outer shell structure that allows freedom to generate a unique design (see YpsoMate® and YpsoMate® Design). The final design of the device does not interfere with the 2-step handling concept of the underlying platform.


In order to ensure that the expectations of the patients are met it is essential that human factors engineering is part of the development process. Ypsomed conducts early and late-stage formative studies as part of each platform development. This further supports patient specific studies once the platform is customized for a specific patient group. Ypsomed fully supports its customers during these human factor studies, thus contributing significantly to the success of the submission process.

SUCCESSFUL REGISTRATION SUBMISSIONS In order to streamline the registration process and allow pharma companies to

YpsoMate® Design is a version of the proven YpsoMate® platform autoinjector, with a fully customizable, individual industrial design concentrate on the drug-related part of the dossier, Ypsomed provides all device-related documentation. With dossier support being an integral part of customer projects, Ypsomed employs a dedicated team of regulatory experts that provides dossier support for each project, following either the Common Technical Document (CTD) or the Master File (MAF) approach. Ypsomed makes a crucial contribution to the successful submission of the overall combination product.


Many pharma companies decide to perform final drug and device assembly at the filling site of the drug to reduce time, risk and transportation costs. Ypsomed works closely with reputable equipment manufacturers to provide state-of-the-art and ready to order final assembly solutions. Assembly systems for high (>1 million p.a.), mid (<1 million p.a.) and low (<150’000 p.a.) demands are readily available.


The trend to longer acting formulations and less frequent injections means that some patients may not be used to the routine of their therapy. This is where reusable trainer devices allow patients to practice in a clinical or home environment before performing their injections. Ypsomed offers trainer devices for the successful instruction of clinicians and patients.


Shorter time-to-market and reduced project risks with Ypsomed Custom Products


Ypsomed not only provides innovative, reliable and easy to use injection devices, but also a range of extended device services, tailored to the needs of each project: From industrial design, human factors engineering and IP landscape management to trainer devices, final assembly infrastructure and registration support. With this offering Ypsomed contributes to the success of the drug by allowing its customers to focus on their core competence of drug development.


Go for proven solutions.

Speed up time-to-market with customized platform products. Modular and proven platform technologies reducing time-to-clinic and time-to-market Clearly differentiated products based on innovative and patented technical solutions Human factor engineered designs to guarantee safe and effective use Customized products from automated large-scale manufacturing Designed and manufactured in Switzerland

For more information visit Ypsomed AG // Brunnmattstrasse 6 // 3401 Burgdorf // Switzerland T +41 34 424 41 11 //



Pre-filled Syringe Technology and Injection Devices The product development process for pre-filled syringes and injection devices is a little different from that of a ‘traditional’ pharmaceutical. There are essentially five steps (figure 1), and for many, the commencement of clinical testing (stage 4) is regarded as the critical milestone. Hence, in this article we focus on the ways in which analytical testing services can support the process, in stages 1-3.

By Caroline Coupar


Technical Specialist, RSSL

Once a lead design has been generated, it is necessary to develop and evaluate a prototype.


Physico-chemical Properties The EU Directive on medical devices (93/42/ EEC) and its amendments, backed by various guidelines (MEDDEVs), deal with general requirements for marketing medical devices within the EU.

Chemical Characterisation It is sensible to start assessing potential device materials, including lubricants, at the earliest point. Chemical characterisation can be carried out in accordance with pharmacopoeial test methods using a combination of wet chemistry, chromatography, spectroscopy and differential scanning calorimetry.

Once a prototype has been created there is often a need to develop and validate analytical methods specific to the product. Functional tests on the device alone may be performed by


the manufacturer, though the functionality of the device will inevitably require evaluation in conjunction with the Active Pharmaceutical Ingredient (API) or drug product (DP). Once validated, these methods can support the development through the pre-clinical, clinical and commercialisation stages. There is also scope to commence performance testing during the prototype phase, questioning whether a device might be exposed to impacts and forces during manufacturing, filling, device integration, shipping, and operation by the end user – all of which might result in product



Figure 1: Combination Device Product Development Process

Stability Release Testing: Extractables and Leachables Method Development

Extractables and Leachables Chemical Characterisation Physical Properties

Chemical Characterisation Method Development Physical Properties Sub-visible Particle Analysis

Extractables and Leachables

Method Validation

Method Development

Performance Testing

Method Validation





Microbiological Integrity

Release Testing

Release Testing



Physical Chemical Microbiology

Performance Testing

Concept and Design


defects. The construction can be assessed non-destructively using techniques as simple as visual observation to the more advanced X-ray tomography. The physical characterisation methods outlined by ISO11040-8 will determine the ease of syringe plunger movement through measurements of break loose and extrusion forces, dead space determination and freedom from air/ liquid leakage. Amongst others, a potentially critical performance parameter such as dosage accuracy could also be assessed. Extractables and Leachables An extractables profile needs to be determined for all the materials used in the prototype and then the therapeutic drug must be analysed for leachables from the medical device. Techniques used to create the extractables profile include LC-MS, GC-MS, ICP-MS, NMR and ion chromatography (Dionex). Sub-visible Particle Analysis Some drugs can be sensitive to hydrophobic syringe surfaces, shear forces and the presence of lubricants. Such unfavourable interactions can lead to increased sub-visible particles which may cause harm to patients. Hence it is useful to determine the numbers of particles shed by a medical device, and this is usually performed according to pharmacopoeial methods such as light obscuration and microscopy. The light obscuration method is preferred by the pharmacopoeias, as it is objective and can be used to count particles down to 2Âľm. The microscope method is more labour intensive, but is more suitable for coloured, viscous or protein based biological drug products and gives an initial indication of the nature of any particles. In addition, sub-visible particles can

Commercialisation and Manufacturing

be further characterised using a combination of microscopy, FTIR, X-ray microanalysis and NMR techniques.

preserving the conformity of the medical device product during internal processing and delivery to the intended destination.

Biopharmaceutical Quantification Host cell DNA determination by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) techniques can be utilised for biopharmaceuticals. It is necessary to validate the removal of both protein and nucleic acid derived from the production host. Host protein detection is mediated through the development of specific antibodies allowing the development of sensitive ELISA’s. The degree of coverage is usually assessed by Western Blotting. The detection and quantitation of host cell DNA can be achieved through nucleotide binding assays such as Picogreen or specific assays based on real-time PCR. The greater sensitivity and specificity of qPCR lends itself to the later stages of pharmaceutical clinical development.

A combination of real-time and accelerated stability studies will establish stability and it is essential to have robust stability-indicating methods to determine the chemical and physical stability of the pack/device and its contents. It may also be necessary to develop methods for the determination of preservative levels in the product.


The purpose of pre-clinical studies is to establish medical device safety and to enable a robust design of the full clinical trial. Hence, upon entering the pre-clinical phase, consideration needs to be given to the potential toxicity of medical device materials. Biocompatibility A range of systematic biological based (i.e. biocompatibility) tests need to be done in accordance with ISO 10993. Stability Testing ISO 13485:2003 requires a medical device developer to establish documented procedures or documented work instructions for


One aspect that is often overlooked is the need to ensure that enough spare devices are setdown to analyse additional time points during development, and fund out of specification/ out of trend (OOS/OOT) investigations.


The medical device product development cycle is necessarily complex to ensure safe and efficacious products. Analytical testing can commence at different stages within the product development cycle and careful planning can contribute to a timely launch. Few medical device developers have all of the analytical resources they require in-house for regulatory submission, which makes outsourcing an attractive proposition, provided they can find a contract laboratory with the latest analytical equipment, knowledge of the standards and experience in problem solving, method development and validation. Reading Scientific Services Ltd (RSSL) offers a range of services to support your product development. For more information please contact Caroline Coupar, email or visit

Expert Pharmaceutical Analytical Services RSSL provides analytical testing, consultancy and training for the global pharmaceutical, biopharmaceutical and healthcare industries. RSSL is GMP approved and is inspected by both the MHRA and FDA. Our services include: • Analytical Services for Drug Formulation

• Method Development and Validation

• Biopharmaceutical Product Analysis

• Microbiological Analysis

• Contamination – Chemical and Physical

• Pharmaceutical Training

• Cleaning Validation

• Pharmacopoeial Testing to USP, EP, JP and CP

• Extractables and Leachables

• Physical and Structural Properties

• Impurity Isolation and Sample Purification

• Stability Storage, Management and Testing

• Medical Devices

Customer Focused, Science Driven, Results Led For further details contact Customer Services on: +44 (0) 118 918 4076 or email: or visit Web:



High purity and excellent chemical resistance for syringes the adsorption of proteins or other biomolecules to ZEONEX® and ZEONOR® surface is very small compared to glass. Such adsorption can change the API concentration in the drug formulation. The trend towards new protein based pharmaceuticals, produced by modern biopharmaceutical methods, pushes the use of alternative packaging materials like ZEONEX® and ZEONOR® as first choice. ZEONEX® and ZEONOR® can be sterilised utilising steam autoclave, electron beam, gamma radiation and ethylene-oxide gas. Other handling benefits of ZEONEX® and ZEONOR® versus glass include their low specific weight and excellent shatter resistance.

Actual Medical COP Grades

ZEONEX® 5000

Tg: 69 °C MFI: 9 g /10 min @ ( 230 ºC / 21,8 N )

Type III DMF Number: 27657


Tg: 102 °C MFI: 20 g /10 min @ ( 280 ºC / 21,8 N )

Type III DMF Number: 13885


Tg: 136 °C MFI: 20 g /10 min @ ( 280 ºC / 21,8 N )

Type III DMF Number: 14084


Tg: 163 °C MFI: 6 g /10 min @ ( 280 ºC / 21,8 N )

Type III DMF Number: 17236

A number of leading syringe and vial suppliers offer fully commercial RTU or RTF standard container designs made from ZEONEX® and ZEONOR®. A recent development is the introduction of multilayer vials to market. These constructions combine the excellent water barrier of ZEONEX® and ZEONOR® with high oxygen barrier and additional mechanical strength from other polymers like polyamides. Another big benefit of plastics containers versus glass containers is the freedom of design. Therefore ZEONEX® and ZEONOR® is very well suited for the development of fully customized drug cartridges in auto-injectors , pens and other injection devices.

All grades above meet the test requirements for plastic containers in EU-­Pharmacopoeia (8th) US-­Pharmacopoeia (37th) JP-­Pharmacopoeia (16th) ZEONEX® 690R meets biocompatibility requirements of ISO 10993-­4 , -­5 , -­6 , -­10(a) , -­10(b) and -­11 ZEONOR® 1020R and ZEONEX® 790R meet biocompatibility requirements of ISO 10993-­4 and -­5 (Chapter 10a , 10b and 11 n ot conducted in accordance with animal welfare )

Regulatory status of medical grade ZEONEX® and ZEONOR® In the past decade, Cyclo Olefin Polymer (COP) and Cyclo Olefin Copolymer (COC) based syringes, cartridges, and vials have attracted ever increasing attention from the pharma industry as a valid transparent plastic alternative to glass made primary drug containers. The main application focus is with injectable parenteral drugs, especially modern biopharmaceuticals. With ZEONEX® and ZEONOR®, ZEON offers fully amorphous and highly transparent thermoplastic resins. The balance of outstanding water barrier properties in combination with high purity, excellent chemical resistance, high transparency and no interaction with drugs, put ZEONEX® and ZEONOR® as a perfect alternative to glass or other plastics solutions for vials, syringes and other customer designed drug containers.


High transparency in UV-wavelength range and very low autofluorescence of ZEONEX® and ZEONOR®, makes them highly desirable for cuvettes, High Throughput Screening (HTS) microplates or biochips in analytical/diagnostics applications. Microfluidic arrays benefit from the excellent mouldability and precise transcription of microscopic structures, achieved with ZEONEX® and ZEONOR®.


ZEON Corporation, headquartered in Tokyo/Japan, is a leading and globally operating, Specialty Polymer company. As part of its Specialty Materials operations, Zeon manufactures and sells Cyclo Olefin Polymers under the brand names ZEONEX® and ZEONOR®. Since the establishment of ZEON Corporation in 1950, the company has consistently taken advantage of its original technologies and created numerous unique products. Based on own C4 and C5 extraction technologies ZEON developed an integrated production system and is striving to create new products and new business areas by utilizing these core technologies. ZEONEX® and ZEONOR® polymers are prominent examples of how Zeon core competencies has established leadership in both major and niche markets around the world. ZEON Europe GmbH in Düsseldorf/Germany is the European marketing/sales organisation.


ZEON have four certified COP grades with medical/pharmaceutical approvals. Each grade has its own Type III Drug Master File registration, passes actual EU-, US- and JP-Pharmacopoeia requirements and selected chapters of ISO 10993 Biocompatibility. ZEONEX® and ZEONOR® provide the extremely low extractables and leachables levels needed for containers like prefilled syringes or cartridges (carpoules).


Due to the non-polar, hydrophobic and non-reactive surface nature of ZEONEX® and ZEONOR®, there will be no interaction with the pharmaceutical drugs inside the prefilled container. Typically,

More detailed information about ZEONEX® and ZEONOR® properties and applications is available at

Commercial prefillable ZEONEX® syringes of various sizes

Various microfluidic assay designs, UV cuvettes and microslide




Biosimilars: should they have a ‘similar’ system to the originator?

By Dr Brian Edwards Principal Consultant NDA Group

The safety of any medicine such as biosimilar is as dependent as much on the system that supports it as the biological properties of the medicine itself. Part of this system rests as proprietary information within a company, while part rests within healthcare system that uses the product. This raises the question of how and by using which metrics can we measure system safety to ensure system similarity? It is hard showing there’s nothing to worry about, so should similarity between the innovator and the biosimilar systems be standardised? Measuring adverse reaction frequencies indicate harm rather than safety

which depends on human performance. Even if we were to rely on spontaneous reports, the delayed onset of adverse reactions and overlapping of therapies hinders causality assessment especially when comparing different products using spontaneous evidence. This makes it even more important that licence holders work with healthcare providers to ensure processes are in place to ensure traceability their products in case they need to demonstrate safe use. Hospital IT (information technology) systems are an essential source for recording and retrieving information about adverse events and suspect medicines. So, it is of concern to find evidence from the Netherlands showing that very low frequencies of recording of brand names and batch numbers for biologicals in pharmacy datasets (1). Thus the presence of multiple IT systems within healthcare that lack integration may be an obstacle to efficient adverse event reporting weakening traceability especially, as has also been shown in the US, many IT systems do not capture drug identifiers other than brand and/or INN. In the US, lack of system integration was cited as a significant reason for not reporting ADEs. NHS England provide the following guidance about switching to biosimilars ‘Doctors reserve the right to switch a patient’s medicine provided there are appropriate monitoring arrangements in place’. So without adequate arrangements for traceability healthcare professionals could reasonably argue against switching to a biosimilar. Biosimilar biologicals are entering a market where there is considerable uncertainty about how to manage risk and thus their


systems need to be at least of equivalent quality to that of the innovator. Unfortunately, we only use a few metrics for measuring system performance which are not shared publically. Industry associations would be strongly advised to convene a working group to recommend and agree upon system metrics and performance indicators. This means it is even more important to adhere to the high standards of non-clinical and clinical quality criteria for similarity that have been established by WHO, EMA and FDA and continue discussions about how they can be more precisely defined. Meanwhile at all steps of the prescribing and dispensing chain, every feasible form of identifier should be strongly encouraged to aid traceability. Pharmacy software providers need to be engaged so that current IT systems are updated to capture all such identifier information, in particular, batch number. I agree no biosimilar safety concerns have been demonstrated so far from those biosimilars that have been marketed but we must not allow complacency to deter us from striving to improve our systems. (1) Klein K, Scholl JHG Vermeer NS et al Traceability of Biologics in The Netherlands: An Analysis of Information-Recording Systems in Clinical Practice and Spontaneous ADR Reports Drug Safety February 2016, Volume 39, Issue 2, pp 185-192




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Upcoming Topics Developments in Biobanking Biosensors – applications and benefits Drug Discovery and Development Molecular Diagnostics Biosimilars To advertise contact: David Lancaster on 0845 887 3829



Hope for the future

Few areas of medical research are exciting as much interest as the potential offered by stem cell research and regenerative medicine. Every day sees scientists making breakthroughs in a range of health conditions, each one driven by the prospect of using the human body to trigger defences. One of the most exciting recent developments has seen University of Cambridge researchers in the UK discover the strongest evidence to date that human pluripotent stem cells -- cells that can give rise to all tissues of the body -- will develop normally once transplanted into an embryo. Human pluripotent stem cells for use in regenerative medicine or biomedical research come from two sources: embryonic stem cells, derived from fertilised egg cells discarded from IVF procedures; and induced pluripotent stem cells, where skin cells are ‘reset’ to their original, pluripotent form. They are seen as having promising therapeutic uses in regenerative medicine to treat conditions that affect various organs and tissues, particularly those that have poor regenerative capacity, such as the heart, brain and pancreas. However, some scientists have been concerned that the cells may not incorporate properly into the body, resulting in tumours. The latest study suggests that this will not be the case and that stem cells, when transplanted appropriately, are likely to be safe for use in regenerative medicine. They have now published a paper on the subject and Professor Roger Pedersen from the Anne McLaren Laboratory for

Regenerative Medicine at the University of Cambridge, commenting on co-author Victoria Mascetti’s findings, said: “Our study provides strong evidence to suggest that human stem cells will develop in a normal -- and importantly, safe -- way. This could be the news that the field of regenerative medicine has been waiting for.” Previous research has not succeeded in getting human pluripotent stem cells to incorporate into embryos. However, in research funded by the British Heart Foundation, Victoria Mascetti and Professor Pedersen showed that it is possible to successfully transplant human pluripotent stem cells into the mouse embryo and that they then develop and grow normally. Professor Pederson said: “Stem cells hold great promise for treating serious conditions such as heart disease and Parkinson’s disease, but until now there has been a big question mark over how safe and effective they will be.” Ms Mascetti’s research showed that when transplanted at the correct stage, the stem cells went on to grow and proliferate normally, to integrate into the embryo and to distribute themselves correctly across relevant tissues. She said: “Our finding that human stem cells integrate and develop normally in the mouse embryo will allow us to study aspects of human development during a window in time that would otherwise be inaccessible.” Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which helped fund the study, said: “These results substantially strengthen the view that induced pluripotent stem cells from adult tissue are suitable for use in regenerative medicine -- for example in attempts to repair damaged heart muscle after a heart attack.”




Our study provides strong evidence to suggest that human stem cells will develop in a normal – and importantly, safe – way. This could be the news that the field of regenerative medicine has been waiting for. Professor Roger Pedersen

Anne McLaren Laboratory for Regenerative Medicine at the University of Cambridge CONTINUED ON PAGE 44





New treatments now possible Another breakthrough, in the transformation of human cells by an international team led by researchers at the University of Bristol, could open the door to a new range of treatments for a variety of medical conditions. Their paper demonstrates the creation of a system that predicts how to create any human cell type from another cell type directly, without the need for experimental trial and error. Julian Gough, professor of bioinformatics at the University of Bristol, said: ‘The barrier to progress in this field is the very limited types of cells scientists are able to produce. Our system, Mogrify, is a bioinformatics resource that will allow experimental biologists to bypass the need to create stem cells.” The first human artificial pluripotent stem cells were created by Japanese researcher Shinya Yamanaka in 2007, through a process of educated trial and error that took a long time. In the nine years since, scientists have only been able to discover further conversions for human cells a handful of times.

Professor Gough said: “Mogrify predicts how to create any human cell type from any other cell type directly. With Professor Jose Polo at Monash University in Australia, we tested it on two new human cell conversions, and succeeded first time for both.

‘This represents a significant breakthrough in regenerative medicine, and paves the way for life-changing medical advances within a few years from now, and the possibility in the longer term of improving the quality of longer lives, as well as making them longer.”

“The speed with which this was achieved suggests Mogrify will enable the creation of a great number of human cell types in the lab.

To achieve the result, Professor Gough worked with then-PhD student Dr Owen Rackham, who now works at Duke-NUS Medical School in Singapore, for five years to develop a computational algorithm to predict the cellular factors for cell conversions. The research team comprised collaborators from Bristol, Australia, Singapore, and Japan.

“The ability to produce numerous types of human cells will lead directly to tissue therapies of all kinds, to treat conditions from arthritis to macular degeneration, to heart disease. The fuller understanding, at the molecular level of cell production leading on from this, may allow us to grow whole organs from somebody’s own cells.

Scottish research project secures funding

Exciting work is under way in Scotland where Keisuke Kaji, researcher at the University of Edinburgh’s MRC Centre for Regenerative Medicine (CRM), has been awarded a £4m Fellowship Award by the Medical Research Council. The seven year project will focus on a further understanding of the reprogramming technique whereby specialised tissue cells in the body are manipulated in such a way that they become induced pluripotent stem cells (iPS cells), cells that can go on to form any specialised type of cell in the body. Dr Kaji and his laboratory team at CRM will aim to understand the underlying molecular mechanisms of reprogramming using molecular biology techniques such as CRISPR/Cas9 and DamID.

reprogramming technique. At the end of our project we hope to be able to generate iPS cells with a much higher efficiency and in a much shorter time period. “We have about 300 different cell types in our body, but can generate only a few of them in the laboratory today. We have evidence that some of the molecular manipulations used to generate iPS cells can also be used to make specialised cells more efficiently. We aim to understand how to control cell characteristics and make useful cell types for medical applications.”

Dr Kaji said: “The funding helps us to unravel the mechanisms underpinning the




Investment supports American projects The potential offered by the field has also seen increasing levels of investment in the United States. Stem cell agency, The California Institute for Regenerative Medicine (CIRM) has awarded $19.9 million to ImmunoCellular Therapeutics to carry out a Phase 3 clinical trial in people with newly diagnosed glioblastoma using a kind of vaccine made from the patient’s own immune system. Every year, an estimated 13,000 Americans alone die from glioblastoma. Around 50 percent of people die within 15 months of diagnosis, and fewer than 10 per cent survive five years. C. Randal Mills, Ph.D., CIRM’s President and CEO, said: “This kind of deadly disease is precisely why we created CIRM 2.0, our new approval process to accelerate the development of therapies for patients with unmet medical needs. “People battling glioblastoma cannot afford to wait years for us to agree to fund a treatment when their survival can often be measured in just months. “We wanted a process that was more responsive to the needs of patients, and that could help companies like ImmunoCellular get their potentially life-saving therapies into clinical trials as quickly as possible.” In a healthy individual, the body’s immune system usually spots and destroys foreign

threats, such as viruses, bacteria and cancer cells, that have infiltrated our bodies.

collected after birth from healthy newborns provided by CBR.

In glioblastoma, patients typically undergo surgery, chemotherapy and radiation to destroy the tumor but such treatments only temporarily halt tumor progression, and the cancer usually returns within months due to the presence of cancer stem cells that can elude these treatments. The surviving cancer stem cells can make new cancer cells which eventually spread throughout the brain.

NYSCF CEO and Co-founder Susan L. Solomon said: “Umbilical cord tissue is a largely untapped source of rich cells to be used in medical research and cell therapies.”

In attacking this disease, the ImmunoCellular therapy targets six cell surface proteins that are found on glioblastoma cancer stem cells. Cells from the patient’s own immune system are exposed to fragments of these cancer cell surface proteins in the lab. When returned to the patient’s body, the immune system cells can now help detect, and hopefully kill, the cancer stem cells responsible for the tumor’s recurrence and growth. ImmunoCellular plans to recruit about 400 patients at 120 clinical trial sites around the US, Canada and Europe. Results from ImmunoCellular’s earlier Phase 2 trial showed that patients given this therapy lived longer than those who received the standard treatment. It also showed minimal side effects. Also in America, the New York Stem Cell Foundation (NYSCF) and Cbr Systems has announced a collaboration to customise the creation of high-quality stem cell lines, part of work to make the technology commercially scaleable. NYSCF will create induced pluripotent stem (iPS) cell lines from umbilical cord tissue


Geoffrey Crouse, President of Cord Blood Registry and Executive Vice President of AMAG Pharmaceuticals, said: “We are excited by the efforts of NYSCF to further improve reprogramming technologies for induced pluripotent stem cells.”

People battling glioblastoma cannot afford to wait years for us to agree to fund a treatment when their survival can often be measured in just months C. Randal Mills, Ph.D CIRM’s President and CEO



Stem cells Imagine that I have a daughter who at an early age develops type 1 diabetes. The beta cells of the islets of Langerhans are being destroyed by her own immune system. She will be dependent on insulin injections all her life. Now imagine I have a friend who while playing rugby suffers a broken neck and loses all use of his limbs – he will be a wheelchair user for the rest of his life. Finally, imagine a friend who has a new baby boy. Following a heel-prick blood test he is told that his son has Duchene’s muscular dystrophy – his son will be a wheelchair user by 12-13, and will probably die of pneumonia in his early twenties. These stories are all tragedies, but all could be cured by stem cell technology – we would just need to grow a new pancreas, a new spinal cord, or build new muscle. If we were like plants this would be easy – plant cells are totipotent - a leaf, stem or root cell can be isolated and cultured to form a whole new plant. Unfortunately our cells do not have this ability. Once human cells have differentiated to be a beta cell or a muscle cell, or any terminal differentiation state then they are very reluctant to de-differentiate.

The discovery of stem cells, or at least pluripotent stem cells, gave hope that the dream of manufacturing cells and tissues to cure many conditions, such as those above, could be realised. If we have a totipotent cell then the situation would be relatively simple – we simply need to find the cocktail of growth factors and cytokines which drive a particular differentiation pathway. This type of approach has been successful with the cells listed in Table 1. Some of the therapies resulting have been used to treat burn victims. Keratinocytes isolated from fresh human epidermis can be grown for weeks and, when combined with a supporting matrix such as a fibrin matrix, can be used to successfully treat severe burn victims. More recently cells isolated from the dermal papillae have shown potential for persuading bulge stem cells to regenerate hair follicles. Mesenchymal stem cells (MSCs) have been used in a variety of studies by staff in Chester. Prof. Johnson has been investigating the potential use of clinically relevant MSC populations for the development of new cell therapies, particularly for patients with spinal

Table 1 – Types of stem cell Name




Embryonic stem cell



derivatives of the three primary germ layers: ectoderm, endoderm & mesoderm

Haematopoietic stem cells


Bone marrow

All types of blood cells – red blood cells, B & T lymphocytes, natural killer cells, neutrophils, basophils, eosinophils, monocytes

Mesenchymal stem cells


Bone marrow

Osteoblasts, osteocytes, chondrocytes, adipocytes and stromal cells.

Neural stem cells



Neurons, astrocytes & oligodendrocytes


cord injury and for cartilage repair. Dr Wilson has been using MSCs and HUVECs to derive osteoblasts and adipocytes that enable her to study the secretome as a means to understand how these cells influence bone erosion. The adipocytes have the added potential to investigate metabolic rate in type 2 diabetes – an approach being taken by Dr Ireland and Prof. Williams. Although successful approaches have been described, the various stem cells are not present in large numbers and the generation of large numbers can be a problem. The real potential for stem cells will come if we can successfully de-differentiate (or transdifferentiate) adult stem cells. Two organisms that are capable of this are the Salamanda, which is capable of re-growing excised limbs, and Planaria, a flat worm which is capable of re-growing any body part that is excised – including the head. These and other organisms provide useful models to understand differentiation, as it is hoped that these will indicate the types of switches that need to be flipped to reverse differentiation. Recently blood monocytes have been successfully persuaded to form chondrocytes. Monocytes are in plentiful supply so this is hopefully a significant step assuming it can be confirmed. However, this conversion required insertion of a variety of genes known to be involved in differentiation using a viral vector. The ability to perform this re-wiring without a virus would reduce concerns on safety when considering for the clinic. This short piece has just touched the surface of this exciting area. There are problems to be overcome. However, we should expect to see significant strides made to deal with the tragedies highlighted in the first paragraph over the next 10 years.

By Professor John HH Williams

Interested in Medical Research? The University of Chester’s Institute of Medicine aspires to become a leading centre for first-class medical research, building on existing strengths in biomedical research, cardiovascular physiology, cancer biology, isolation and utilisation of stem cells and inflammatory diseases. Taught Postgraduate Courses MSc Biomedical Science MSc Diabetes MSc Gastroenterology MSc Haematology MSc Infection and Immunity MSc Medical Genetics MSc Oncology MSc Stem Cells and Regenerative Medicine Research Degrees We offer research degrees in a wide range of topics, and our MRes in Medical Science is designed to prepare you for PhD study. If you are interested in undertaking an MPhil or PhD with the Institute of Medicine, our current research areas include: • Novel cancer therapies • Wound healing • Microbial epitopes and inflammation • Microparticles and rheumatoid arthritis • Danger signals • Monocyte differentiation patterns • Stress protein biology • Proteomics

Institute of Medicine For a full list of the courses available, as well as information about the Institute of Medicine, visit:



Centre for Human Development, Stem Cells and Regeneration “Translating pioneering developmental and stem cell science for patient benefit” Medical advances have led to a welcome increase in life expectancy, indeed, it is estimated that by 2020, 20% of the UK population will be over 65. However, longevity introduces new challenges: increases in age related diseases and associated reductions in quality of life. The clinical problem is significant, for example in the musculoskeletal arena, skeletal fractures alone cost the European economy €17 billion and the US economy $20 billion annually; the numbers of hip fractures worldwide will increase from 1.7 million in 1990 to 6.3 million in 2050. Stem cell science and regenerative medicine are currently some of the most exciting and promising areas for reparative medicine with the opportunity to enhance our understanding of tissue development and therefore the generation

Labelled viable human skeletal stem cells growing on human bone of specifiable tissues, thus improving the quality of life of an ageing demographic. The Centre for Human Development, Stem Cells and Regeneration (CHDSCR) ( ), University of Southampton, part of the £10M Institute of Developmental Sciences, was founded in 2004 as a cross-disciplinary research and translational programme within the Faculty of Medicine at the University of Southampton. CHDSCR Vision: Translating pioneering developmental and stem cell science for patient benefit. CHDSCR Mission: Our aim is to understand early human development and fundamental stem cell biology to inform and aid our translation and development of cell therapies for regenerative medicine. The Centre comprises over 15 multi-disciplinary groups working on fundamental and clinical

research encompassing human development, across the spectrum of stem cell research, through to translational delivery for patient benefit, applying tissue engineering and regenerative medicine strategies. The Centre has pioneered the collection and use of human embryonic and fetal tissues for the investigation of normal and abnormal development that informed our work on human embryonic stem cells, human embryonic germ cells and human embryonic/early fetal development, as well as our translational agenda. We were one of the first groups in the world to demonstrate the importance of epigenetics in Osteoarthritis and, in 2014, we undertook the first 3D titanium-bone stem cell impaction bone graft operation in the UK. Our world-leading research programmes harness the translational strength of the Faculty together with an innovative Stem Cell PhD programme to train the next generation of stem cell and regenerative medicine scientists, able to work across boundaries and between multiple disciplines.

the new £55M Institute for Life Sciences (IfLS) at the engineering and life science interface, utilising unique world-leading approaches to develop interdisciplinary interactions (linking with physical sciences, mathematics and social sciences) across the Faculties

The CHDSCR has a strong Outreach programme with a desire not only to train the next generation but to foster an understanding and awareness of stem cell biology and regenerative medicine to the general public. We have developed in collaboration with Winchester Science Centre an extremely successful interactive exhibit entitled Stem Cell Pinball, now on permanent display at Winchester Science Centre and presented to public audiences at Science festivals throughout the country.

of Medicine, Engineering and the Physical Sciences to address the challenge of Repair and Replacement and to aid the development of new approaches to tissue regeneration across the cell spectrum from embryonic to adult and induced pluripotent stem cells. FortisNet exemplifies this approach to address musculoskeletal challenges working from the cellular level and fabricated biocompatible structures for stem cell growth using disruptive technologies to advance repair and regeneration.

The CHDSCR has excellent research facilities including a UK Government licensed human tissue bank and outstanding translational capacity as a consequence of close proximity to over £75M clinical translational infrastructure including the Wellcome Trust Clinical Research Facility, NIHR Biomedical Research Centre and Unit, MRC Lifecourse Epidemiology Unit and the soon to be completed £25M Centre for Cancer Immunology all at the Southampton General Hospital. The CHDSCR collaborates closely with

Matrix protein (type I collagen) in human fetal skeletal stem cell populations

The CHDCSR is also addressing some of the issues associated with increases in age related diseases through shared translational research programmes between Southampton and Australasia Universities, as well as linkages across Europe and S. America through shared distinctive world leading expertise combined to take forward nanotechnology, additive manufacturing and stem cell science to address the needs of an ageing population.

“The Centre provides a vibrant and thriving multidisciplinary research environment that enables the translation of pioneering developmental and stem cell science for patient benefit.”

Professor Richard OC Oreffo

Professor of Musculoskeletal Science and Director, Centre for Human Development, Stem Cells and Regeneration


Translating pioneering developmental and stem cell science for patient benefit. Centre for Human Development, Stem Cells and Regeneration Interdisciplinary Research Excellence in Basic and Translational Stem Cell Science −− Institute−for−Developmental−Sciences −− Institute−for−Life−Sciences

Translational Clinical Research Platforms and Programmes


−− Wellcome−Trust−Clinical−Research−Facility−

−− NIHR−Biomedical−Research−Centre−and−Unit− −− MRC−Lifecourse−Epidemiology−Unit −− Centre−for−Cancer−Immunology

Integrated PhD and MRes. Programmes in Stem Cells / Regenerative Medicine −− Training−the−next−generation−of−stem−cell−scientists

Public Understanding of Science Programmes −− Including−LIFELAB−schools−outreach:−

Date−|−Time Venue text

Product development and research for stronger, active bodies. FortisNet For more information about FortisNet, please contact the Institute for Life Sciences Collaboration Manager, Dr Alexandra Mant:



FortisNet: strength through collaboration An interdisciplinary hub of expertise in regenerative medicine, orthopaedics, prosthetics and assistive technologies. The musculoskeletal challenges described above form part of a wider landscape, where diabetic amputations have increased to 7,000 per year in the UK, an estimated 40,000 in India and over 70,000 in the USA. Almost 300 Service personnel suffered traumatic limb loss in recent UK military operations in the Middle East, with over a third involving significant multiple amputations. Amputees will require sophisticated rehabilitation and, even with modern medicine, specialised care for years to come. Meanwhile, in large parts of the developing world, few have access to orthopaedic surgery, modern prosthetics or assistive technologies, so we must develop intelligent, low-cost solutions to meet those needs. At the Institute for Life Sciences (IfLS),

No single group or research team has all the expertise. The problems users face are so complex and multifaceted that we really need to pull in all the expertise for the delivery of new technology.”

Dr David Moser

Head of Research, Chas. A. Blatchford & Sons our response to these challenges is to launch FortisNet (‘Fortis’ meaning ‘strong’): an interdisciplinary, collaborative network in hard and soft tissue research. Led by the IfLS Director, Professor Peter JS Smith, FortisNet focuses on three interwoven themes at the engineering-life sciences interface: Components: Growing and replacing hard and soft tissues (e.g. stem cell therapy for fractures; novel scaffold materials for seeding stem cells; retrieval and analysis of failed implants; understanding the biology of implant failure; design of better joint replacements) Limbs: Prosthetics and augmentation (e.g. optimised fit of prosthetic limbs; smart prosthetic liner materials; device design and usability; energetics of gait; user-reported outcomes data and analytics) Individual: Assistive technology and rehabilitation (e.g. neurorehabilitation after

HRH The Duchess of Cornwall discusses musculoskeletal research challenges at the Institute for Life Sciences, after receiving an Honorary Doctorate from the University of Southampton in recognition of her work supporting osteoporosis research, management and prevention. Photo credit: Jon Banfield stroke; robotics; better clinical trial design; reducing complications from rheumatoid arthritis; managing frailty) The aim of the network is to develop products and processes that will improve lives, attract new businesses and create jobs for our skilled graduates. Importantly, we want to do this by connecting clinicians, enterprise, end-users and academic researchers, so that our research challenges clearly serve clinical, end-user and market needs. An internal platform network of over 40 leading researchers and clinicians at the University of Southampton and University Hospital Southampton NHS Trust have

joined experts from UK universities, hospitals, industry, local government, defence organisations, health networks and the endusers of research to begin shaping the research priorities for FortisNet. At a launch event in January, new collaborative projects received pump-priming support from an EPSRC Institutional Award, while foundations were laid for large, industry-driven initiatives. We welcome new members. If you share our collegiate, interdisciplinary vision and want to help shape the future of musculoskeletal research, please contact the IfLS Collaboration Manager, Dr Alexandra Mant (

“My own career providing insights into musculoskeletal disease, notably osteoporosis, has taught me the value of interdisciplinary endeavour. FortisNet offers this and more, putting our specialised and broad-based expertise in the UK firmly on the map.”

Professor Cyrus Cooper

Professor of Rheumatology and Director, MRC Lifecourse Epidemiology Unit, University of Southampton and Professor of Epidemiology at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford



Setting up a Bio Science Business – putting together the Team This is the second short article in our series on setting up a new business in the bio science space Beyond the confines of a very small consultancy it is difficult to run a business all by yourself however in the early days you may be unsure of the sort of people you will need to help you and the extent to which you will want to use them and may well have concerns about your ability to pay regular salaries. The answer will generally be to buy in services as you need them from other organisations or the self employed. This is usually very cost effective as you only buy the hours you need but is also very flexible allowing you to buy more hours as business expands and to engage specialists who can do the work in a fraction of the time that you could do it yourself or have it done by a junior employee who seems the best you can afford. This principle can be used not just to access technical, business or scientific advice to help with a particular project but also to provide professional administrative support. Having someone answer your phones in the company name while you are off doing the actual work or still doing the “day job” will avoid missed opportunities and make your operation look much more substantial and professional. You can also engage “virtual PAs” or bookkeepers all of whom have different skills that can ensure the business runs efficiently while you concentrate on building it. As you grow you may well want to raise finance for the business which for most

companies in this space will mean equity investment. One of the first things the investor will want to know is whether you have the team to deliver on your business plan. Again this does not mean that you have to have hired everyone that you need to carry out the work but you will have to explain how you intend to access the necessary expertise. Where you only need someone for a short period of time or for occasional advice a consultancy contract whereby you pay for work done is ideal but there will be some people who you are going to need regularly and will inevitably have to join the payroll. If the investment money is going to be used to hire them you may be able to set up conditional contracts with them whereby you agree to hire them if you raise the money. One of the benefits of this is that the investor can see the terms of the hire and also the cv of the individual which may make them feel a lot more confident. You should expect to offer shares to senior hires coming in at this point in addition to salary - this ensures they share your interest in the success of the company but may also be necessary to persuade them to take a lower salary than they might otherwise expect and in a riskier business.

you will benefit from having non executive directors who are not involved in the running of the company on a day to day basis but who have business expertise and contacts that can help you see the bigger picture and grow the business. They are generally engaged on a consultancy contract for the equivalent of so many days a year. Another approach while the company is in an early scientific mode is to create a scientific advisory board of senior scientists in the field with whom you can bounce around ideas. This can be very inexpensive and although they do not take on the responsibilities of directors their involvement may encourage potential partners and investors to take you more seriously than they might otherwise have done.

By Patricia Barclay Bonaccord

Finally as you grow you should expect to build a board of directors. Initially this may just be you or you and other senior staff but over time

Bonaccord – UK Life Science Law Firm of the Year



Producing crops that can resist the ravages of

climate change Amid all the talk about the impact of climate change, one of the areas sometimes overlooked is the potentially severe effect on the production of food. However, increasing awareness of the threat posed by flood, pestilence, heat and drought has led to massive investment into solving some of the problems, with everyone from big business and governments to community groups working on possible solutions. That investment is needed if you look, for example, at recent research into wheat, one of the world’s stable foods. The research suggested that moving wheat production to different regions in Europe to avoid the increasing effects of climate change may not be possible.

The international study, including scientists at UK-based Rothamsted Research and funded by the Biotechnology and Biological Sciences Research Council (BBSRC), suggested that the probability of adverse weather events with the potential to significantly reduce wheat yield will increase markedly across Europe, including higher temperatures and severe droughts. One of the strategies for reducing the risk of wheat yield losses due to adverse weather is changing the time when crops flower or mature. However, the report says if this strategy was to be adopted with the current varieties available, it would lead to a lower level of global radiation to which the crop is exposed and this, in turn, would result in lower yield potential. That means that the only remaining alternative is to move growing areas but the report says that the spreading effects of climate change in Europe, for example, will make it more difficult to find areas that are not currently used for wheat and are also free of adverse weather.

In 2015, average global temperature increase exceeded 1oC for the first time; this is halfway towards 2oC threshold that could result in potentially dangerous climate change. Dr Mikhail Semenov Rothamsted Research


Dr Mikhail Semenov at Rothamsted Research and one of the lead scientists of the study said: “In 2015, average global temperature increase exceeded 1oC for the first time; this is halfway towards 2oC threshold that could result in potentially dangerous climate change. “Understanding future risks to wheat production in Europe is critically important for development of robust adaptation strategies. Our research showed that adaptation options for wheat could be limited due to a substantial increase in probability and magnitude of adverse weather events in Europe under climate change.” Dr Malcolm Hawkesford, who is leading the 20:20



Wheat strategic programme of research at Rothamsted Research, added: “It is critical that we use the best available to us resources to model impacts of climate change on wheat and explore adaptation strategies. “These studies are essential to inform us with regards to the type of cultivars that will be required in the future in order to ensure that yield potential losses are avoided whilst the nutritional value of the crops cultivated is maintained and potentially further enhanced.” The research forms part of the MACSUR Knowledge Hub, co-funded by BBSRC under the Joint Programming Initiative for Agriculture, Food Security and Climate Change. MACSUR brings together research from 71 institutes in 18 countries.






Research into potatoes could hold key to better understanding In Africa, the humble potato is one of the focuses of work designed to find out how this staple food will cope with dramatic changes in the climate. According to the International Potato Center (CIP), change is already a reality for farmers in many parts of the world, warming temperatures manifested in everything from more frequent droughts and floods to an expanding distribution of crop pests and diseases. Jürgen Kroschel, Team Leader for Agroecology and Integrated Pest Management at the CIP, said: “A crop pest that currently produces three or four generations per year may produce as many as six or seven generations per year once average temperatures rise by 2ºC—3ºC. “Pests and diseases already pose major threats to the food security and livelihoods of smallholders in developing countries, yet there is a shortage of information about how much and where climate change will transform those threats.” To help answer some of the questions, he is co-ordinating a CIP-led collaboration with several other international research centres

and national programmes to predict how global warming will affect some of the most destructive crop pests and diseases in East Africa. The goal is to help local government agencies and farmers better confront pests and diseases as the climate changes. Funded by the CGIAR Research Program on Roots, Tubers and Bananas (RTB), the initiative focuses on pests and diseases affecting potato, sweet potato, banana and cassava in Africa’s Great Lakes Region. It involves researchers from CIP, Bioversity International, the International Center for Tropical Agriculture, the International Institute of Tropical Agriculture, the UK’s Food and Environment Research Agency, the Commonwealth Agriculture Bureau, US universities and national programmes in the region. Some of the tools those researchers are using were developed during a prior CIP project to model climate change’s impact on insect pests in Africa, which was funded by the German

Federal Ministry of Economic Cooperation and Development. Researchers have been working in both the laboratory and in the Ruhengeri area of Rwanda and Burundi’s Rusizi Valley, where banana, cassava, potato and sweet potato are widely grown. More than 400 farms are involved and Jurgen Kroschel said: “We are not only studying the impacts of climate change on pests and diseases, but on the livelihoods of farmers in these areas.” In tandem, scientists on the project have conducted laboratory research to better understand how rising temperatures affect the development of specific pests, data that is being used to predict how climate change will increase the risk they pose. Jürgen said: “You need individual assessments for each species to predict changes under rising temperatures. You can’t generalise.”

Funding awarded for research projects Other work is under way after the BBSRC, along with the Natural Environment Research Council, and 12 industry partners agreed to fund six research projects to improve the sustainability of UK farming. Among the funded studies is work to improve the drought tolerance of wheat, research to determine the best foodstuffs for ruminant animal health and production, and a project focused on optimising the use of buffer strips to enhance water quality. Dr Celia Caulcott, BBSRC Executive Director, Innovation and Skills, said: “These studies will help address important challenges for the UK’s farming industry, which is worth billions to our economy, and help progress towards sustainable agricultural systems for the future.” Iain Gillespie, NERC Director of Science and Innovation, said: “In the 21st Century the global food system faces significant pressures, not least from world population growth and climate change. These projects will help equip the agriculture industry with the knowledge and expertise it needs to find sustainable and affordable ways of meeting these challenges.

“By working with industry to identify big scientific questions and translate research into practical solutions, we can help ensure our world-leading science continues to deliver tangible benefits for our economy and society.” The funded projects are: • Increasing wheat drought tolerance and recovery throughout the life cycle through regulation of plant growth mechanisms – Professor Matthew Paul, Rothamsted Research • Future-proofing our breeding goals Breeding for climate resilience in UK dairy systems – Professor Eileen Wall, Scotland’s Rural College • Magnesium Network (MAG-NET): Integrating Soil-Crop-Animal Pathways to Improve Ruminant Health – Professor Martin Broadley, The University of Nottingham working with colleagues at Aberystwyth


University and NERC British Geological Survey • Impacts of different vegetation in riparian buffer strips on hydrology and water quality – Professor Adrian Collins, Rothamsted Research • Reduced Stomatal Density Wheat: New Prospects for Drought and Pathogen Resistance – Professor Julie Gray, The University of Sheffield working with colleagues at the National Institute of Agricultural Botany • Diverse forage mixtures to optimise ruminant animal production, nutrient use efficiency, environmental impact, biodiversity, and resilience – Professor Chris Reynolds, University of Reading, working with colleagues at Rothamsted Research


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