Eu research 4 digital magazine

EU Research Vol: 2013 Issue 3

COMING TO AMERICA A Focus on the research of the NIH

FP7: SPOTLIGHT ON HEALTH An introduction to the future of transport The Latest Research News

Follow EU Research on www.twitter.com/EU_RESEARCH

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n the late 1970s, when I was working in the press office of the South Western Electricity Board, the board hosted a demonstration of electric cars - described then as the vehicle of the future. The fact this was more than 30 years ago, and the commercial launch of such vehicles is still in the future, albeit the near future, is a good indication of the rather tortured gestation of such a concept.

Things have changed, however, as the electric cars being demonstrated then were battery-electric. Today, the world is preparing for Fuel Cell Electric Vehicles.

That it is 174 years since William Grove, the Welsh physicist, developed the ‘gas voltaic battery’, now known as the fuel cell, means it is still quite a leap to describe fuel cells as a technology whose time has come.

Martin Brodie runs his own media and communications company, after a career in journalism and public relations. After starting his journalist career on the Bristol Evening Post , Martin joined Rolls-Royce plc in Bristol in1980 and held a number of senior communications positions in the defence and civil aerospace businesses before moving to the group’s corporate headquarters in 1991. From then until his retirement in 2009, Martin was responsible for much of the Group’s international communications and was also involved in UK national media relations throughout this period.

His last role was Head of Communications – Europe Middle East and Africa.

His previous roles also included responsibility for engineering and technology, during which he was editor of the first Rolls-Royce environment report, Powering a Better World.

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However, it looks like the technology requirements are now better understood and the major car manufacturers are gearing themselves up for a 2014/15 commercial launch, with public transport vehicles in roughly the same time-scale. Hybrid cars, which combine an electric motor and a conventional engine, either petrol or diesel, have been quite successful in terms of retail sales and there is, or soon will be, a wide range of around 90 different models available worldwide.

To build on the market acceptance of hybrids,what both manufacturers and motorists need is for the cost of fuel cell motoring to be seen as attractive in terms of first cost, and then general upkeep, including fuel, most possibly hydrogen.

Finding fuel may be the big drawback, as countries need to install a widespread network of hydrogen refuelling stations. That requires commitment and determination from both the private and public sectors.

Hope you enjoy the issue.

Martin Brodie

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Contents

4 Research News

EU Research’s Richard Davey takes a look at current events in the scientific news

10 Visual Optics

Professor Pablo Artal tells EU Researcher how adaptive optics instruments could improve the diagnosis and treatment of optical conditions

13 Kreshmoi

Professor Henning Müller talks about his work to develop a search system for biomedical information

16 Funsel Professor Mauro Giacca explains how their research will help identify new biotherapeutics against common degenerative diseases

19 REPSUBREP Scientific coordinator Dr Dana Branzei tells us about her research into the regulatory mechanisms that coordinate DNA replication integrity and intra-S repair

24 National Institutes of Health

EU Research talks to The National Institutes of Health in the US, the world’s single largest source of funding for medical research, supporting research into both wellknown diseases and emerging threats to public health.

30 NanoVirPharm NanoVir, the American drug research company’s cofounders, Dr Chris Fisher and Dr James Bashkin, explain how new DNA-binding compounds will improve treatment of HPV

33 Pre-Clinical

Dr Marc Baum of the Oak Crest Institute of Science in the US writes about his research into developing intravaginal ring technologies which can release drugs to protect women from HIV

36 Non-Clinical Studies

Hynda K. Kleinman, Ph.D tells us about her work in developing new drug candidates using Tβ4, and how it could improve the treatment of cardiovascular conditions in particular

39 Live Smart Live Safe

Dr Jennifer Wells of the TechAid Institute explains how her project will help people with intellectual disabilities prepare for the event of a natural or man-made disaster

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42 Alcohol Research UK Alcohol abuse costs Europe billions of pounds a year in healthcare costs, lost working days, and even crime. Research Manager Dr James Nicholls talks to EU Research about the Governmental examination of the issues

46 MCFC Contex Molten carbonate fuel cells could have a significant role to play in reducing society’s overall carbon footprint. Dr Stephen McPhail tells us about their research into how to prevent the contamination of the fuel cell stack

49 Ice & Lasers

By in-situ analysis of ice from deep within ice sheets the European Research Council Advanced Grant project aims to shed new light on the topic, as principal investigator Dr Jérôme Chappellaz explains

55 Wiserban Wireless body area networks hold real potential across a range of healthcare and lifestyle applications, including cardiac implants, hearing aids, activity monitors and even pedometers. We spoke to Dr Vincent Peiris about their work in miniaturising the communication layer of wireless body area networks

EU Research

EU Research Vol: 2013 Issue 3

COMING TO AMERICA A Focus on the research of the NIH

FP7: SPOTLIGHT ON HEALTH An introduction to the future of transport The Latest Research News

Follow EU Research on www.twitter.com/EU_RESEARCH

58 ISH2UP

We spoke to Professor Aarne Halme and Anders Lundblad of the ISH2SUP project, supported

by Fuel Cell and Hydrogen Joint Undertaking (FCH-JU), about their research into novel solutions for hydrogen storage on both the mobile and portable scale

61 FCH-JU According to some estimates, by the year 2030, there could be 1.6 million electric vehicles powered by fuel cells using Britain’s roads. EU Research talks to the Fuel Cell and Hydrogen Joint Undertaking (FCH JU)

65 Transparency Feedback from end-users is crucial to guiding the development of any product, and the machine tool industry is no exception. Marcus Michen of the Transparency project explains how knowledge-based collaboration will change the way machine tools are designed and operated

68 Stardust

We spoke to Karin Nygård Skalman, Lotten Svensson and Johanna Kilpi-Koski from the project regarding their work to coordinate innovation around the Baltic Sea region in terms of the social and economic challenges

EDITORIAL

71 Party Democracy Over time political parties have transformed themselves into professionalised organisations much closer to the state than civil society, raising important questions about how democracy functions. Professor Ingrid van Biezen of Leiden University tells us about her research into the regulation of political parties, and its effects on democracy

74 Statecap Developed nations are characterised by not only high levels of material prosperity, but also political and institutional stability that encourages development. We spoke to Professor Torsten Persson about his research into the role of state building in the development process

Managing Editor Martin Brodie info@euresearcher.com Deputy Editor Patrick Truss patrick@euresearcher.com Deputy Editor Richard Davey rich@euresearcher.com Science Writer Holly Cave www.hollycave.co.uk Acquisitions Editor Elizabeth Sparks info@euresearcher.com PRODUCTION Production Manager Jenny O’Neill jenny@euresearcher.com Production Assistant Tim Smith info@euresearcher.com Art Director Daniel Hall design@euresearcher.com Design Manager David Patten design@euresearcher.com Designer Susan Clark design@euresearcher.com Illustrator Martin Carr mary@twocatsintheyard.co.uk PUBLISHING Managing Director Edward Taberner etaberner@euresearcher.com Scientific Director Dr Peter Taberner info@euresearcher.com Office Manager Janis Beazley info@euresearcher.com Finance Manager Adrian Hawthorne info@euresearcher.com Account Manager Jane Tareen jane@euresearcher.com EU Research Blazon Publishing and Media Ltd 131 Lydney Road, Bristol, BS10 5JR, United Kingdom T: +44 (0)207 193 9820 F: +44 (0)117 9244 022 E: info@euresearcher.com www.euresearcher.com © Blazon Publishing June 2010

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RESEARCH

NEWS

EU Research’s Richard Davey takes a look at current events in the scientific news

Maire Geoghegan-Quinn

Call to improve gender equality in European Research After ten years of policy initiatives - and despite female graduates outnumbering males – the EU is far from gender equality in R&D. “This is regretful for women researchers and bad for Europe,” says Research, Innovation and Science Commissioner Geoghegan-Quinn.

Earlier this month, the European Commission released its latest information on the representation of women in science. The message that emerges from the report entitled: She Figures 2012: Gender in Research and Innovation, is hardly surprising: Women are still underrepresented in science. The gap appears to be closing—slowly—but more needs to be done if it is to close completely anytime soon. “Some people think that if we just wait, it will get better, and that’s one way in which the She figures are extremely important,” says Curt Rice, vice president for research and development at the University of Tromsø in Norway.

The report’s authors conclude that continued and expanded measures are necessary if progress is to continue.

“There is no evidence of spontaneous reduction of gender inequality over time. All these policies, and many more, are needed to ensure that constant progress is made towards gender-equality in research and scientific careers.”

Make sure you vist us on our website www.euresearcher.com. For more information regarding any of your dissemination needs please contact us on info@euresearcher.com

US Navy to Field Laser Weapons System It has been a thing of science fiction for years, but the US Navy has developed and tested a Laser Weapons System that could be used to shoot down drones and disable ships.

The prototype, which cost around $31 – 32 million, is expected to be installed upon USS Ponce in 2014.

The weapon could revolutionise combat as it runs on electricity and therefore will remain active as long as there is a power source. It will cost less than $1 per shot compared to the many thousands of dollars it would cost to fire a missile.

On the whole, the technology has been praised, however a report from the Congressional Research Service has noted some drawbacks including the potential for civilian airline accidents and the fact that the weather can affect the performance of the laser. (source: http://uk.reuters.com/article/2013/04/08/us-usa-weapons-laser-id UKBRE93716Z20130408?feedType=RSS&feedName=scienceNews)

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US Research Funding No cuts to most sectors President Obama has drawn a line in the sand in his continuing fight with budget-cutting lawmakers when it comes to future federal funding for research and development. He’s calling for reversing recent spending cuts to most sectors of R&D spending and adding additional funds for many areas next year, despite tough fiscal times.

The President has repeatedly called for increasing research funding (with some success); this year is no exception.

The proposal is largely symbolic, however, standing little chance of getting enough support in a divided Congress. The House science committee’s chairman, Republican Lamar Smith of Texas, says that the budget “gets a failing grade,” in part because it boosts spending in a time of mounting debt.

But science advocates are raising the pressure on Congress not to cut research spending. As a group of Nobel laureates said in a recent letter to lawmakers, “Our concern is for the younger generation who will be behind the innovations and earn the Prizes of the future.”

EU Research

Chinese Scientists Unveil World’s Lightest Substance Researchers at Zhejiang University have created carbon aerogel with a mass of 0.16 milligrams per cubic centimetre; this material is so light that it can be supported on a flower’s petals without causing damage.

The practical applications of this record breaking material lie in its absorbency. Carbon aerogel has the ability to absorb up to 900 times it weight in liquid and could be used to combat oil spills.

Professor Chao Gao, who co-authored the study, has also said that it could be utilised for water and air purification purposes.

Carbon aerogel is created when a semi-solid gel of carbon nanotubes and graphene undergoes a freeze-drying process, producing the solid material. (source: http://www.bbc.co.uk/news/scienceenvironment-22079592)

Genetic break Lab-made Rat Kidney Could Help Dialysis Patients

In the future, Ott believes that with the use of different cells to build up the organ, results will improve significantly and the goal of creating human organs will be one step closer. (source: http://uk.reuters.com/article/2013/04/14/us-kidney-manmadeidUKBRE93D08N20130414?feedType=RSS&feedName=healthNews)

Scientists have successfully created a rat kidney. In an online edition of Nature Medicine, Dr. Harald Ott, of the Center for Regenerative Medicine at Massachusetts General Hospital in Boston, spoke about the process used to create the kidney and the possible ramifications it had for patients with kidney failure.

The creation of the rat kidney means that it is theoretically possible to up-scale the procedure to human size; using a patient’s own cells, the organ could be created minimising the chances of rejection.

Ott and his team bioengineered the kidneys and tested them with a dialysis machine; the kidneys had blood passed through them and they filtered waste and created urine. The real test came when they transplanted a kidney into rats which had had a kidney removed.

The new kidneys were not as effective as real kidneys, but were nevertheless did a good job.

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Sir Kenneth Murray: 1930-2013 Sir Kenneth was an international leader of scientific innovation who saved countless lives worldwide by developing the first vaccine against viral hepatitis B. One of the earliest workers in genetic engineering, he was cofounder of the first European-based Biotechnology company, Biogen.

Most of his commercial income was used to found the Darwin Trust in 1983. The trust has supported the education of many young scientists, and helped to found cutting-edge research and improved facilities at the University of Edinburgh.

Sir Kenneth obtained a first-class honours degree in chemistry and aPhD in microbiology from the University of Birmingham, where he met his wife, Noreen, who became a close scientific collaborator.

Noreen died in 2011.

Compulsive Mice Compulsive Mice Compulsive Mice Compulsive Mice Compulsive Mice Compulsive Mice Compulsive Mice Compulsive Mice Two teams of researchers have discovered how to flip a switch in the brain circuits of mice that impels the animals to groom themselves with their paws continuously. The discovery may yield new strategies for reducing compulsive behaviour such as repetitive hand washing in humans who have obsessive-compulsive disorder and other diseases marked by the characteristic such as autism and Tourette syndrome.

He joined the University of Edinburgh in 1967 at what was then the only department of molecular biology in the country.

In one set of experiments, the team stimulated a particular neural pathway, generating repetitive, excessive grooming in the mice.

A second set of experiments with mutant mice used the same pathway to eliminate the compulsive behaviour.

He and his colleagues made the University a leader in the molecular biology revolution. Sir Kenneth was Head of Molecular Biology from 1976 to 1984, and Biogen Professor of Molecular Biology in 1984.

“In tandem, this is really a leap forward towards a refined understanding of the circuitry underlying these behaviours,” says psychiatrist Scott Rauch of McLean Hospital in Belmont, Mass, USA.

Following his retirement in 1998, he continued to come to the laboratory every day, leading further scientific endeavours. Increasingly, he spent more time on his philanthropic support of others.

The two studies not only offer potential for future research and treatments in humans, but they validate that experiments with mice are a legitimate means of investigating compulsive disorders.

NASA to Capture Asteroid for Mars Mission Stepping-stone US President Obama has asked NASA to look into the possibility of capturing an asteroid to be pulled into orbit near the moon.

The asteroid would serve as a stepping-stone for astronauts on eventual Mars missions.

NASA hopes to visit such an asteroid by 2021 and forms part of a wider study to investigate asteroids that could be on a collision course with the planet. Preparation for a mission to Mars could be expected in around 2030.

In a conference call to reporters, NASA administrator Charles Bolden said: “This mission allows us to better develop our technology and systems to explore farther than we’ve ever been before - to an asteroid and to Mars - places that humanity has dreamed about … but has had no hope of ever attaining.” (source: http://uk.reuters.com/article/2013/04/11/us-spaceasteroid-idUKBRE93A00F20130411?feedType=RSS&feedName= scienceNews)

©NASA/JPL-Caltech/ASU

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EU Research

The Future of Offshore Wind Farms SUPRAPOWER is a new four year EU-funded project working on producing a reliable, lightweight superconducting offshore wind turbine. Under the coordination of Tecnalia in Spain, the SUPRAPOWER project comprises of nine partners from industry and science.

The SUPRAPOWER team believes that current turbines do not meet the needs they were designed for; rising operation and maintenance costs are also a factor in why a new type of turbine is needed.

One of the project collaborators, the Cryogenic Engineering Division at Karlsruhe Institute of Technology, believes that superconductivity is one possible answer to increasing the effectiveness of the new turbines. By installing a rotating cryostat that can cool superconducting coils to -253°c, electrical current could flow without resistance meaning that more electricity is conducted by the turbine.

Further to the superconductive elements of the new turbines, the project will look at ways of reducing their size and mass which would then reduce the cost of manufacture. (source: http://cordis.europa.eu/fetch?CALLER=EN_NEWS& ACTION=D&SESSION=&RCN=35671)

LEXNET Project Reducing electromagnetic field exposure There have been public concerns now for many years regarding the health effects surrounding wireless communication masts and their proximity to people’s houses; wireless communication networks and their use of electromagnetic fields (EMF) have become increasingly more prevalent in modern society.

According to a 2010 Eurobarometer poll, some 67% of respondents thought that mobile phones affect our health despite the lack of any clear evidence backing the claim. However, as the desire for faster more effective wireless communication methods increases so too will the need for more of these masts.

The LEXNET Project is made up of a group of 17 leading telecommunication operators, vendors, research centres and academic institutions. Launched in November 2012, LEXNET’s primary goal is to significantly reduce EMF exposure across Europe while at the same time maintaining quality of service.

LEXNET (which stands for Low EMF Exposure Future Networks) is project managed by Dr Joe Wiart; he believes that it is important “to study innovative low RF exposure solutions at many levels, ranging from the radio devices to the network architecture, topologies, management and the provision of services.”

Funded by the European Commission’s Seventh Framework Programme (FP7), the three year project will support the development of future network infrastructures and innovations in enabling future internet access across a wide range of wireless mediums. (source: http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSIO N=&RCN=35615)

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Male Sex Hormones Key to Beating Breast Cancer In a report on the BBC news website, a team of scientists from the University of Colorado has discovered that many breast cancers carry androgen receptors on their surface. These receptors are stimulated by male hormones, such as testosterone, and cause the tumours to grow. According to Dr. Jennifer Richer and her colleagues at the university, around three quarters of all breast cancers have the receptors.

The American Association for Cancer Research believes that a new generation of drugs could effectively block these receptors and curb tumour growth. Such antiandrogen therapy is already used in relation to prostate cancer and there are plans for clinical trials to test the effectiveness on breast cancer. (source: http://www.bbc.co.uk/news/health-22076692)

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ERT and ERC Call for €80 Billion Budget for Research and Innovation In a letter addressing EU leaders, the European Research Council (ERC) and the European Round Table of Industrialists (ERT) have urged decision makers to approve the €80 billion funding programme for research and innovation, known as Horizon 2020. The letter was signed by Leif Johansson, (Chairman of ERT and Ericsson), Helga Nowotny (President ERC), Peter Löscher (Vice-Chairman ERT and President and Chief Executive Officer, Seimens), and Tim Hunt (Member of ERC scientific council and Nobel Laureate).

The budget for the time period covering 2014-2020 will play a pivotal role in how Europe competes on a global level; any reduction in funding could potentially lead to European scientists being lured away to other countries leaving EU research behind in the field. The letter states that Europe should become a magnet for

talent wherever it can be found and goes on to say: “Scientific discovery and technological progress will produce new products, processes and services, and new industries will be created in their wake. If we want Europe to be an attractive place for research investment and entrepreneurship, Europe’s R&D budget must serve this purpose.”

The EU invests 1.9% into research and innovation relative to GDP; this figure compared to the US’s 2.8%, Japan’s 3.3%, and South Korea’s 3.4%, shows that the EU has a long way to go before in order to compete effectively. (source: http://erc.europa.eu/sites/default/files/press_release/files/ Joint_letter_ERT-ERC_to_EU_leaders_in_support_of_R&I.pdf)

Global Climate Change Slowdown Linked to Oceans Global climate change is a real concern worldwide; more and more heat trapping gases are being released into the atmosphere which is significantly affecting the Earth’s surface temperature.

Ten of the hottest years on record have occurred since 1998, however there has been a slowdown in the heating of the surface since 2000.

In a study published by experts from France and Spain in Nature Climate Change, the oceans could be the reason for this slowdown.

Excess heat has been absorbed by the top 700 meters of the ocean; however this heat will not be trapped forever.

Virginie Guemas of the Catalan Institute of Climate Sciences in

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Barcelona, lead author of the study, believes that within the next decade the stored heat will be released back into the atmosphere, triggering global warming again.

The study points to La Nina weather events in the Pacific which brought cool waters to the surface in 2000; this cooler water was then able to absorb more heat from the air. The study also showed that the Atlantic has also been absorbing extra heat. (source: http://uk.reuters.com/article/2013/04/07/us-climate-oceansidUKBRE93608420130407?feedType=RSSVirginie%20Guemas%20 of%20the%20Catalan%20Institute%20of%20Climate%20 Sciences%20in%20Barcelona&feedName=scienceNews)

EU Research

Boson Particle Over-Hyped Peter Higgs, the UK academic whom the particle is named after, stated it is being used by scientific institutions to justify massive research budgets. He is concerned that media interest in the Higgs boson was warping the general public’s understanding of that area of science by dominating publicity.

Professor Higgs especially singled out the CERN research organisation in Switzerland, which runs the £6 billion Large Hadron Collider, for criticism and urged them to spend more time promoting other projects.

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“I think it’s been overhyped ... The way it’s been plugged by organisations like CERN has worried me,” Mr Higgs said at the Cheltenham Science Festival yesterday.

“It worried me that once it was discovered they would be caught out and the perception would be that there was no need for the machine any more.”

The hope is that the collider will find evidence of dark matter, believed to make up around a quarter of the Universe and widely considered to hold the key to understanding its origins.

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Adaptive optics instruments have long been used to correct distortions in telescopic images, now researchers are working to modify the technology and apply it with the human eye.

Professor Pablo Artal of the ADV Visual Optics project tells EU Researcher how adaptive optics instruments could improve the diagnosis and treatment of optical conditions

Using adaptive optics with the human eye The problems involved in imaging in telescopes and imaging in the eye are not dissimilar, despite the clear difference in scale. Adaptive optics instruments have long been used to correct distortions in telescopic images, now researchers from the Advanced Visual Optics project are working to modify the technology and apply it with the human eye. “We have been using a wave-front sensor and a device to modify images. The wave-front sensor is used to basically measure the optical properties, traditionally in telescopes and in the atmosphere, and in our case we’re looking at the eye. It’s like a system to say; ‘well, these optics are good’, or ‘they’re not that good’, and you get real numbers measuring the optical quality,” explains Professor Pablo Artal, the project’s scientific coordinator.

The second part of an adaptive optics instrument is a specialised device which is used to modify the images. “Initially we used a deformable mirror which had some electronics behind it, which would modify the surface through very tiny changes. More recently we have used liquid crystal devices to do similar things, this also reduces cost and increases versatility,” says Prof. Artal.

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Optical defects The first area of application that Prof.

Artal and his colleagues identified for this adaptive optics technology was in opthalmoscopes, devices used in clinics to get images of the retina. Although very important clinically, it can be difficult to get high quality images of the retina. “The quality of the eye’s optics limits this instrument and so we can’t see the retina well. We were interested in incorporating adaptive optics in opthalmoscopes - measuring the optics and then taking images,” continues Prof.

Artal. These advances have in turn inspired a further wave of research, and Prof. Artal says it’s possible to go further using deformable mirrors and liquid crystal devices. “You can not only correct the optics, you can also generate basically any optics you want,” he outlines. This idea was first introduced

by Artal and collegaues and is called the adaptive optics vision analyser. “You can then modify the optics and ask; ‘well, what’s happened? How am I going to see if I put in this? What is going to happen if I have this particular lens?”

EU Research

Retinal images of a point source and of a letter “E” as reconstructed from optical measurements at different angles of visual field.

The adaptive optics instrument allows researchers to pre-set all the possible optics and analyse all the capabilities of the eye in advance. The eye is actually a relatively simple optical instrument, basically comprised of two lenses, the cornea and the crystalline lens; Prof.

Artal says the instrument measures the performance of the whole eye in a standardised way. “We use a range of different devices, but primarily we are using something called the HartmannShack sensor. We illuminate the eye with a small, invisible, infra-red beam from a laser. The light going through the eye is reflected in the retina, comes back and passes through the eye again. We collect this image and record how it is distorted – then analyse it on a computer,” he explains. From this, researchers can then assess the performance of an optical system. “We have a mathematical way to characterise how good the optics are; this is based on a pure optical measurement, from this sensor that we’ve incorporated,” outlines Prof. Artal. “This sensor is critical, because the information from it drives the corrector.”

The project uses a liquid crystal special light reflector in this role, an electro-optical device that reflects the light, which in turn makes small changes to the image. The project’s primary focus is on producing a range of different optical solutions, which Prof. Artal says will help doctors identify the best possible treatment in consultation with the patient. “The beauty of this device is that we can produce any optical change.

This is going to be linked to prescriptions and particular spectacles, contact lenses or laser treatments,” he explains. Deteriorating vision is part of the aging process, with everybody suffering from presbyopia to some degree as they grow older, so this research could have a wide impact. “As you get older you lose the ability to accommodate, your ability to see at different distances,” says Prof. Artal. “If you were previously emmetropic – if you didn’t have any refractive problem – then when you get presbyopia you basically cannot see things that are near to you, so typically you need reading glasses. However, if you were myopic – so near-sighted – then as you get older you can see things that are near to you but you can’t see things in the distance.”

Schematics of an adaptive optics system for the eye.

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Diagnosis and treatment The main cause of presbyopia is thought to be the increasing rigidity of the crystalline lens, which can no longer change shape. Contact lenses or intraocular lenses can be used to address this problem, while another option is laser refractive surgery, which is currently based on removing tissue from the cornea.

“The cornea is around half a millimetre thick; currently when you remove tissue the change is permanent,” outlines Prof. Artal.

This can be a problem if the initial surgery is not totally successful, so Prof. Artal says some researchers are looking at treating the cornea in a different way. “Instead of removing tissue, you’d be able to change the properties of the cornea in a reversible way,” he continues. “Imagine a procedure where we can manipulate the cornea in such a way that the cornea is intact. This would mean not removing tissue or ablating it, but changing its properties in a reversible way. Then the patient could go to our instrument and decide; ‘well, I want to have this optical correction – I’m happy just to see objects at near and intermediate distances. I’m not so worried about seeing things over long distance, or just the opposite.’”

Schematics of an adaptive optics instrument used to study night myopia in a recent experiment.

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At a glance Full Project Title Adv Visual Optics—Advanced Visual Optics. Project number: 256468 Project Objectives The main project objective was to further develop adaptive optics-based instruments for the eye. From laboratory prototypes, allowing for binocular visual testing under full optical control, toward compact and economic systems available for real world applications.

Project Funding Spanish Ministry of Science and Technology • European cohesion funds • Fundacion Seneca (Murcia region) Project Partners • L aboratorio de Optica, Universidad de Murcia (Main) • V optica SL (laboratory spin-off company developing clinical instruments) Contact Details Project Coordinator, Professor Pablo Artal Laboratorio de Optica, Universidad de Murcia (LO·UM) Instituto Universitario de investigación en Óptica y Nanofísica (IUiOyN) Campus de Espinardo (Edificio 34), 30100 Murcia, SPAIN T: +34 868 887 224 E: pablo@um.es W: http://pabloartal.blogspot.com/ “Night Myopia Studied with an Adaptive Optics Visual Analyzer” Artal P, Schwarz C, Cánovas C, Mira-Agudelo A ., PLoS ONE , 7 (7), 40239, (2012)

Dr Pablo Artal

An adaptive optics instrument was used to study the condition of night myopia and to understand for the first time its causes (Artal et al., PLoS One, 7, 2012).

This may of course depend on their occupation. If somebody did move to a job which required good vision over long distances then hypothetically it would be possible to improve their vision in that way. “If this is the case you just select the

different type of device that allows you to measure and correct all the optics. Maybe it could even be worn in the street,” he outlines. “Then there are also light scattering issues which affect all of us. For example, when you are driving in the night

We illuminate the eye with a small, invisible, infra-red beam from a laser. The light going through the eye is reflected in the retina, comes back and passes through the eye again. We collect this image and record how it is distorted – then analyse it on a computer optics that are better in our instrument then you go to the treatment,” says Prof.

Artal. This form of treatment is still a fair way off however, and Prof. Artal’s plans for the future centre more on improving the adaptive optics instrument. “We plan to make the instrument in a kind of open view way, so that it can be incorporated in a

and you see a light from another car in the road, this kind of glare can impair vision.

This is due to the scattering of light – it’s possible to remove this a little bit and develop devices that can, for some particular conditions, try to improve vision in this situation. That is another area that we could potentially look into in future.”

Project Coordinator

Pablo Artal is a professor of optics, with interest in the visual and biomedical fields. He is an inventor of technologies applied in ophthalmology, a fellow of the Optical Society of America and the Association for Research in Vision and Ophthalmology, a recipient of the prestigious Edwin Land medal and is editor of several international journals. He founded Voptica SL and writes a science blog (http://pabloartal.blogspot.com/).

Different schematics views of the most recent5 binocular adaptive optics vision analyzer.

It permits full control of both eyes allowing even for stereo visual testing.

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EU Research

A vast amount of medical information is available on the internet but it is very difficult to judge its quality, particularly for those of us who lack medical knowledge. Professor Henning Müller of the KHRESMOI project tells us about his work to develop a search system for biomedical information

Can you trust medical information on the internet?

A large proportion of internet searches are health-related, with both the general public and physicians using the web to research symptoms, look at previous cases and identify possible treatments and their risks. However, while a vast amount of biomedical information is available on the internet, it is very difficult to judge its quality, an issue the KHRESMOI project is working to address. “The main objective www.euresearcher.com

of the project is to develop a search system for biomedical information for three main target user groups; the general public, General Practitioners and Radiologists,” says Professor Henning Müller, the project’s overall coordinator. It often takes a few years before emerging research is applied by busy GP’s, so supplying them with relevant, up-to-date information faster would be very beneficial; Professor

Müller believes it would also be helpful for radiologists. “They deal with a lot of visual information. This is actually the most quickly growing area of medical information,” he points out. “Each of our partners has a role for either one of the user groups, or for one of the underlying technologies. We aim to build a system for health information research, giving access to health information in a variety of

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Khresmoi system overview

different ways. The goal is to create a community around medical information extraction and analysis.”

Sharing information This work reflects the way the doctorpatient relationship is changing as medical information becomes more widely available. Professor Müller believes that getting patients more involved in their treatment, rather than just being a passive recipient, can encourage them to take more responsibility for their own health.

“Several studies have shown that if people know about a condition then they can adapt to it and change their behaviour,” he says. If they are actively engaged in their treatment patients are also likely to share more information, which can help doctors diagnose the problem and treat it more effectively.

“Often physicians are not 100 per cent sure about the exact condition a patient has. So they may look at the statistics, try to find the most probable diagnosis, and then base the treatment on this. But very often it’s still not fully clear what a patient really has,” continues Professor Müller. “The treatment process is based on experience – a physician will give a certain treatment when people come in with a fever. And then if the first three people come back, because maybe it’s a new strain or a different type of bacteria/ virus, then they will change the treatment and adapt it. But if the physician has more information from his colleagues, then maybe the first three people would not have been treated incorrectly.”

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The project is indexing publicly available web-pages and medical literature to gather information across a wide range of conditions then asking physicians to classify it. The user groups being targeted of course require different kinds of information. “Radiologists are very interested in being able to mark a region in an image and then find visually similar regions in diagnosed images.

They can then find information about the pathologies and look at the evidence to support the diagnosis such as a biopsy,” explains Professor Müller. The general public don’t usually have the same level

of years you might have become quite knowledgeable about it, so would be comfortable with technical language.”

The underlying technology and the basic information are the same for the parts of the system concerning the general public and medical professionals.

However, when users access the website they identify their user group and the interface can be adapted. “We have a back-end, where we have the automatic machine translation. We also have the semantic information extraction, the knowledge base, an image retrieval engine and a text retrieval engine. In all

We aim to build a system for health information research, giving access to health information in a variety of different ways. The

goal is to create a community around medical information extraction and analysis of medical expertise, so are looking for clear, accessible information that they can trust. “They want information that is on their level –they don’t want a scientific article describing a study in very technical language,” stresses Professor Müller. “We’re doing a specific classification on the technical level of the language. So we’re trying to classify how technical the language is on a webpage or an article and how difficult it is to read, in line with patient needs.

Patients who’ve just been diagnosed might need quite basic information on their condition. At the other end of the scale if you’ve had diabetes for a couple

of this, the indices are basically the same information. We can have a very simple, I would say Google-like, interface for the general public, whereas we have something that resembles more a digital library for GPs. Then the interface for radiologists looks more like a radiology viewing station, a tool that they’re used to,” explains Professor Müller. The web pages have to meet certain criteria. “We index medical web pages certified by Health On the Net Foundation (HON). HON is evaluating health websites according to ethical and quality criteria, the HONcode, in order to provide trustworthy and ethical health online information.”

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continues Professor Müller. Medical journals are indexed as well. Both are linked to a knowledge base, the LinkedLifeData. “Then we index the medical literature, such as PubMed, which is maintained by the national library of medicine in the U.S; they also have an index of the open-access literature. So we index all of the open-access literature including the article images.”

Search results The results are ranked based on trustworthiness, complexity of the language and relevance to the search query, while it’s also possible for Doctors to add information. All of the case-based literature the project is working with is fully anonymised, which ensures patient confidentiality, but Doctors have to take care to maintain it when adding information to the system. “Physicians have a kind of personal library where they can store found cases when they log into the system. They can also upload information – they are responsible for ensuring that there is no personally identifying information in that,” says Professor Müller. It is also important to consider where the information came from, any environmental factors and whether the local population might be more likely to suffer from a particular condition.

“If you look at statistics on certain diseases, some ethnicities are more prone to heart infarctions than other ethnicities, so this is something that needs to be taken into account,” acknowledges Professor Müller.

“When we have an anamnesis, the description of a patient’s basic medical history, we analyse information on a

younger patient very differently to how we’d look at an older patient. For example, an image of a young patient’s lung looks very different to an older patient’s, even if they’re both totally healthy.”

Some medical articles include information on age, ethnicity and gender, which allows Professor Müller and his colleagues to filter their results. The system itself is multi-lingual, with the project mainly concentrating on European languages, specifically English, French, German, Spanish and Czech. “We have an automatic translation possibility in the interface – so if you’re typing a query in French, German, Spanish or Czech it will automatically suggest a corresponding English term if needed. So you can type the terms e.g. in French but then make the query in English. Many people are comfortable with reading text in English, but then precisely describing a medical condition in English is much harder,” says Professor Müller. There are often many ways of describing the same condition in one language, but Professor Müller says the system can take account of these kinds of issues. “We use, among other sources, a knowledge base called LinkedLifeData.

This covers medical terminology, including thousands of synonyms of specific terms, as well as the standard or non-standard abbreviations that are used,” he continues. “Many of these terms do not exist only in English, but also in French, Spanish and German. We can extract these semantic terms and then use them in other languages, for example to run the queries. This makes it possible to retrieve documents in several languages.”

At a glance Full Project Title Knowledge Helper for Medical and Other Information users (KHRESMOI) Project Objectives Khresmoi is developing a multilingual multimodal search and access system for biomedical information and documents.

Project Funding EC contribution: €8 Million Project Partners HES-SO (CH) • Vienna University of Technology (AT) • Atos Origin (ES) • ELDA (FR) • Ontotext (BG) • Dublin City University (IE) • University of Duisburg-Essen (DE) • Charles University in Prague (CZ) • University of Sheffield (UK) • Health on the Net (CH) • Medical University of Vienna (AT) • Society of Physicians in Vienna (AT) Contact Details Project Coordinator, Henning Müller, PhD, Prof.

HES-SO Valais TechnoArk 3, 3960 Sierre, Switzerland T: +41 27 606 9036 E: henning.mueller@hevs.ch W: www.khresmoi.eu W: http://medgift.hevs.ch/ Allan Hanbury, Célia Boyer, Manfred Gschwandtner, Henning Müller, KHRESMOI: Towards a Multi-Lingual Search and Access System for Biomedical Information, Med-e-Tel, pages 412-416, Luxembourg, 2011.

Henning Müller, PhD, Prof.

Project Coordinator (left) and Allan Hanbury, PhD, Scientific Coordinator (right)

Project Coordinator Henning Müller and the scientific coordinator Allan Hanbury

Henning Müller studied medical informatics at the University of Heidelberg from 1992 to 1997. He has worked at the medical faculty of the University of Geneva since 2002, becoming a Professor at the HESSO in 2007. He is currently coordinator of the EU-project Khresmoi and scientific coordinator of the VISCERAL project.

Khresmoi screenshot

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New biotherapeutics to treat degenerative diseases

Neonatal rat hearts treated with a control microRNA (left) or two human microRNAs strongly increasing cardiomyocyte proliferation (middle and right). The picture shows the presence of several, replicating (red) cells in the muscular mass of the left ventricles of the middle and right hearts, which appears thicker, with plenty of cells. Green: all cardiomyocytes; red: replicating cardiomyocytes, staining positive for the Edu marker; blue: all nuclei.

As life expectancy increases so the incidence of degenerative conditions, such as heart failure, Alzheimer’s and diabetes, rises too. Professor Mauro Giacca explains how research on the FUNSEL project will help identify new biotherapeutics against common degenerative diseases Degenerative diseases constitute a major health problem across Europe. As life expectancy increases conditions like Alzheimer’s disease, heart failure, blindness and diabetes grow ever more prevalent, intensifying the search for new treatments. “The overall aim of the FUNSEL project is to find new biotherapeutics or biological based products, such as proteins, peptides, and nucleic acids, such as microRNAs, to act against highly prevalent degenerative disorders,” says Professor Mauro Giacca, the project’s scientific coordinator.

Director of the International Centre for Genetic Engineering and Biotechnology (ICGEB) in Trieste, Italy, Professor Giacca says that the project works in a systematic way to find new drugs to treat degenerative diseases. “The idea is to follow two paths, both based on functional selection. We don’t focus on understanding the mechanism first, we just want molecules that work for therapy,” he explains. “One 16

idea is to test all the factors in the human genome that are known to be secreted outside the cells and which circulate in the extra-cellular environment and search, among them, for those that are therapeutically useful against degenerative conditions.”

this genetic information is placed inside a modified virus. In Trieste we specialize in the Adeno Associated Virus (AAV), which is a very small and simple virus, very common in humans. While we are all naturally exposed to this virus no disease is associated with it,” outlines Professor Giacca.

If you treat cardiomyocytes with microRNAs you stimulate their proliferation, and if these microRNAs are given after a myocardial infarction, in vivo, then they promote regeneration of the myocardium. Instead of scarring, a significant portion of the cardiac wall is replaced by the formation of new tissue Secreted proteins There are about 20,000 genes in the human genome, each one coding for a different protein. Approximately 2,000 of these proteins bear a tag that leads to them being secreted outside the cells. “Under our project most of the genes coding for these 2,000 secreted proteins are cloned one-by-one and

The AAV virus can be engineered relatively easily and is also very effective in the exact cell types that degenerate during life, leading to disease. “The AAV virus is a fantastic vector that can transfer exogenous genes very easily into neurons, cardiac myocyte cells, beta cells in the pancreas or in cells in the retina,” continues Professor Giacca.

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Proliferating cardiomyocytes after microRNA treatment in vitro and in vivo. Front and bottom pictures: cultured cardiomyocytes that replicate in response to one of the microRNAs (green: cardiomyocytes, magenta: nuclei of proliferating cells; blue: all nuclei). Picture in the middle: effect of one microRNA in the heart (red: cardiomyocytes, green: nuclei of two proliferating cardiomyocytes; blue: all nuclei).

“The idea here is to establish a collection of several hundred different AAV vectors – one coding for each of the secreted proteins – and to then take pools of these collections. Typically, we take pools of about 100 different vectors and put them into an organ affected by a degenerative disease. In the heart, we induce damage experimentally in mice, typically by ligating the coronary artery and thereby inducing a myocardial infarction, or by administering drugs that damage myocardial cells.”

The project builds on the idea that, after injection, each of these 100 viruses will transfer their genes to a different cell.

When researchers induce damage, cells that contain an irrelevant factor will die in the same way as a normal cell; however, says Professor Giacca, if the cell contains a protective or regenerative factor, then it

will preferentially survive. “Two or three weeks after inducing damage, we go back, take out the surviving cells and see which factor was present,” he explains.

Researchers are thus selecting for protective or pro-regenerative factors in a completely unbiased manner. “This is functional selection in vivo – we have no a priori knowledge of what we will find, nor any knowledge of what the mechanism might be. We just know that it works,” stresses Professor Giacca. “The idea behind using secreted factors is that it will not necessarily depend on delivery using modified vectors. We would like to stay away from this strategy for therapeutic purposes, but secreted factors can be easily produced by genetic engineering as recombinant proteins and then we can consider injecting these, without necessarily using gene therapy.”

The other part of the project’s research deals with microRNAs, which follows similar principles to the work with secreted factors. Researchers know that besides these 20,000 genes encoding from 20,000 different proteins, the human genome also contains the information required to produce about 2,000 small RNA (RiboNucleic Acid) molecules called microRNAs. “This information is encoded by the genome and goes through a complicated process to give rise to small, double-stranded RNAs, about 21-22 nucleotides in length,” explains Professor Giacca. The project is building a collection of these microRNAs, which are powerful regulators of gene expression and are also involved in several biological processes, including differentiation and proliferation.

“The advantage of these microRNAs is that, given their size, they can be produced

Set up of the high throughput screening facility at the ICGEB Trieste, Italy

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At a glance Full Project Title Functional Selection (FUNSEL) Project Objectives The purpose of the FUNSEL project is to develop an innovative procedure for the identification of proteins and microRNAs to be used as therapeutics against highly prevalent degenerative disorders, including heart failure, neurodegeneration, retinal degeneration and diabetes. Selection for these factors is carried out in a systematic manner upon in vivo gene transfer of AAV libraries encoding for the secretome and the miRNome.

Project Partners The project is carried out at the International Centre for Genetic Engineering and Biotechnology in Trieste, Italy through the support of an Advanced Grant of the European Research Council (ERC) to Mauro Giacca.

Contact Details Mauro Giacca, MD PhD Director, ICGEB Trieste Component International Centre for Genetic Engineering and Biotechnology Padriciano 99 34149 Trieste, Italy Office T: +39 040 375 7324 Lab T: +39 040 375 7325 E: giacca@icgeb.org W: http://www.icgeb.org/mauro-giacca.html Eulalio, A., Mano, M., Ferro, M.D., Zentilin, L., Sinagra, G., Zacchigna, S., Giacca, M. 2012.

Functional screening identifies miRNAs inducing cardiac regeneration. Nature 492, 376-81.

Mauro Giacca, MD PhD

Project Coordinator

synthetically,” continues Professor Giacca.

“While performing these selections ex vivo, we obtained and tested about 1,000 of these microRNAs. We are trying to find, again in a completely unbiased way, some microRNAs that could drive cardiac cell proliferation.”

Cell proliferation Researchers have, in fact, already found about 40 of these microRNAs that are able to stimulate proliferation of cardiomyocytes, even when these cells are taken from adult tissues. Cardiomyocytes do not normally proliferate, and are not replaced by the division of other cells after they die, but Professor Giacca says that treating them with microRNAs can have a big impact. “If you treat these cells with microRNAs you stimulate proliferation, and if these microRNAs are administered in vivo after myocardial infarction they promote regeneration of the myocardium.

Instead of scarring, a significant portion of the cardiac wall is replaced by the formation of new tissue. This is really very exciting,” he says. The experiment, published in the December 12 issue of Nature has, so far, been performed only in rodents, but researchers are now ready to scale it up into larger animal models of cardiac disease to then move towards a possible clinical trial in humans.

The ultimate goal of the research is, of course, to improve treatment of degenerative diseases. In all these conditions, the common denominator is cell loss and the incapacity of other cells to overcome this problem by regenerating the lost tissue. “We are thinking of developing the microRNAs that have been

discovered as treatment for people who have suffered an acute myocardial infarction,” says Professor Giacca. “If a patient is admitted to hospital after a myocardial infarction and undergoes normal interventional procedures, a portion of the myocardium undergoes death. Normally this portion is replaced over a few weeks with the formation of scar tissue,” outlines Professor Giacca.

“The idea is to treat the patient around four or five days from the acute episode, when the dead tissue starts to be eliminated and the scarring mechanism has not yet been activated. A few of these microRNAs will be injected to stimulate regeneration of the surviving cardiomyocytes surrounding the lesion. The proliferation of these cells should somehow limit the size of the scar.”

The project focuses on regeneration of the retinal cells using the same principles, and the Group has also established collaborations with others to look at the beta cells in the pancreas. A major difficulty will be to try and use this approach in the brain. “In the heart it is only necessary to construct cells, because they can integrate with the pre-existing cells. The brain is very different; not only do you need cells, you also need them to make the right connections. Sometimes these connections are relatively far away from the cell body,” explains Professor Giacca.

“As for the heart, we aim to find new molecules for all these applications in a systematic manner. At the same time we plan to bring the first molecules – especially the microRNAs for cardiac regeneration – to practical translation towards the clinical end point.”

The seat of the International Centre for Genetic Engineering and Biotechnology in Trieste, Italy.

Mauro Giacca, MD PhD, is the Director of the Italian Component of the International Centre for Genetic Engineering and Biotechnology (ICGEB) in Trieste, Italy since 2004. He is a leading international expert in gene therapy of cardiovascular disorders, with particular emphasis on cardiac regeneration.

Further information: http://www.icgeb.org/mauro-giacca.html

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Unravelling the secrets of DNA repair Damage to DNA often occurs during the replication process; the body responds by activating pathways to repair the damage. Dr Dana Branzei, scientific coordinator of the REPSUBREP project, tells us about her research into the regulatory mechanisms that coordinate DNA replication integrity and intra-S repair As we grow

older our DNA begins to degenerate, a process which is often associated with genetic instability, while it is also regularly exposed to various endogenous and environmentally damaging agents. In order to maintain genome stability, cells are endowed with different DNA repair systems and DNA damage surveillance mechanisms, an area of great interest to Dr Dana Branzei and her colleagues at IFOM, the FIRC Institute of Molecular Oncology. “My lab is interested in how cells are able to repair and tolerate DNA damage, particularly when it arises during DNA replication, and how these different DNA repair mechanisms are coupled with one another and with other cellular process, such as cell-cycle transitions and the establishment of chromatin structure,” she outlines. “In the REPSUBREP project we’re investigating the mechanisms of DNA damage tolerance in eukaryotic cells, and their impact on genome integrity and regulation.”

stress,” explains Dr Branzei. There are several ways to bypass damage or fill in DNA gaps that arise during replication; these mechanisms are generally referred to as DNA damage tolerance pathways.

“Most of the time it is possible to prevent chromosome breaks during replication, but occasionally they do happen,” continues Dr Branzei. “If a replication fork is not properly restored it is likely to lead to collapse and chromosome breaks, that can then lead to aberrant recombination and genome rearrangements.”

There are two main pathways of DNA damage tolerance, one of which is errorfree, while the other is error-prone. The error-free pathway uses recombination to bypass DNA damage, while the error-prone pathway uses specialised translesion DNA polymerases. “My lab is interested in how cells are able to bypass damage in an errorfree manner involving recombination. This

usually happens by switching templates, from the damaged parental DNA to the undamaged, newly synthesized chromatid strand. We have identified that error-free damage tolerance is mediated by the formation of sister chromatid junctions, a type of chromosomal structure,” explains Dr Branzei. Researchers at Dr Branzei’s lab have been able to visualise these structures and show that they not only promote DNA damage bypass, but also that they need to be resolved effectively to prevent problems later on during chromosome segregation.

“One of the major goals of the REPSUBREP project is to characterise this process of template switching and to identify how it influences chromosome structure and integrity,” she says.

The aim in this work is to identify the factors and regulatory pathways involved in the formation and metabolism of the chromosomal intermediates that arise

DNA damage DNA damage tends to occur spontaneously during the replication process. One of the main problems is that replication forks often get blocked; difficulties in fork recovery can lead to chromosome breakage and ultimately genome rearrangements.

“The project is studying the repair pathways that get activated during replication in response to these kinds of endogenous stresses, or when cells are exposed to different types of genotoxic

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2D gel analysis of replication intermediates.

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ChIP-on chip analysis (genome-wide analysis of protein cluster or replication profiles).

during template switching. A number of pathways can be activated in response to DNA damage during replication, one of which is mediated by a process called SUMOylation; the Sgs1/BLM protein, mutated in cancer-prone Bloom syndrome patients, is an important focus of research in this regard. “Sgs1 is a RecQ helicase. We know that this helicase plays a very important role in resolving the sister chromatid junctions that arise during replication and damage tolerance,” says Dr Branzei. SUMOylation affects a number of the targets that participate in this resolution process, while it also has an impact on the functionality of other chromosomal structural proteins, such as the Structural Maintenance of Chromosome complex, Smc5-6. “There’s an important link between Sgs1 activity and SUMOylation, which acts in very intricate ways to promote error-free replication. The exact mechanism of how Sgs1 is regulated via SUMOylation remains unknown, but we do know that several other targets participating in error-free DNA damage tolerance are activated by SUMOylation,” continues Dr Branzei.

SUMOylation The SUMOylation process plays a central role in determining whether damage bypass occurs via an error-free or an errorprone pathway. Alongside its involvement in the resolution of intermediates, Dr Branzei says SUMOylation is also important in terms of how the DNA lesions that occur during replication, primarily DNA gaps, are repaired or filled in. “SUMOylation seems to be the driving force in channeling these lesions into the error-free pathway of template switching,” she explains. Dr Branzei and her team have also found that SUMOylation that occurs during replication

Immunostaining of spindle pole bodies (chicken DT40 cells).

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can also affect the chromatin architecture, although this work has not yet been published. “SUMOylation promotes DNA looping, and this looping plays an important role in channelling lesions towards the error-free pathway, and away from other mutagenic pathways,” she says.

“So it is not the case that just one target gets SUMOylated and activates a whole cascade of events.”

The SUMOylation of certain targets plays a positive role in promoting replication or repair, but hyperSUMOylation can also be toxic to the cell, so the modification process is quite dynamic. The RecQ helicases have a central role in resolving the sister chromatid junctions that arise during

The project’s main interest in these terms is Fanconi-anaemia and certain cohesinopathies, but they are also trying to understand the DNA repair defects associated with various tumours. It is becoming clear that problems in replication, and in resolving the problems that arise during replication, are an important feature of the oncogenic process. “Our work is important for enabling us to establish the molecular mechanisms behind specific or general tumourigenic processes. Not all tumours or cancers have the same type of DNA repair defect. It is important to study what happens in specific cancers – what is the repair defect of that specific cancer cell and how can we target it to achieve efficient therapy?” says Dr Branzei.

My lab is interested in how cells are able to bypass damage in an error-free manner involving recombination. This usually happens by switching templates, from the damaged parental DNA to the undamaged, newly synthesized sister chromatid DNA damage tolerance, but several other helicases are involved. “We are working on several other families of helicases, such as the iron-sulphur cluster helicases, the Fanconi-anaemia associated family of helicases, and the UvrD family of helicases. We are also looking at several other enzymes, such as structure-specific nucleases,” outlines Dr Branzei. This research holds real importance to our understanding of certain types of disease.

“For instance, there is a cluster of diseases called cohesinopathies that are caused by mutations in factors that mediate sister chromatid proximity, or cohesion between sister chromatids,” says Dr Branzei. “We’ve established different cell lines that basically mimic the mutations found in human patients and we are trying to characterise their DNA repair defect. We have evidence that those different cohesinopathies might have a recombination defect in common.”

Over the coming years Dr Branzei expects that her research will focus increasingly on how chromatin structure and architectural changes influence DNA damage tolerance, as well as on the mechanisms behind the activation or adaptation of DNA damage surveillance systems. “I think that there is a connection between chromatin structure and the formation of various recombination structures, and the ability of cells to shut down various safeguard mechanisms that get activated in response to DNA damage.

I would be interested in looking at that in future,” she says. “We have also developed a new approach for visualising chromosomal structures that we can use to identify the roles of various factors to genome integrity. There is still a lot to do in that regard – we have only just started to get the techniques working and to understand what happens in different genetic backgrounds.”

At a glance Full Project Title Regulatory mechanisms coordinating replication integrity and intra-S repair (REPSUBREP) Project Objectives The REPSUBREP project aims at identifying the mechanisms underlying error-free replication and DNA damage tolerance (DDT) when cells are exposed to genotoxic stress. Specific objectives are identifying the genetic pathways and the DNA structures that mediate error-free DDT as well as the regulatory pathways and molecular switches that influence the error-free versus error-prone DDT switch.

Project Funding €1,841,600 over 5 years Contact Details Project Coordinator, Dana Branzei, Ph.D Head of the “DNA repair” lab F.I.R.C. Institute of Molecular Oncology Via Adamello 16, 20139, Milan, Italy T: +39 02 5743 03259 F: +39 02 5743 03231 E: dana.branzei@ifom.eu W: http://www.ifom.eu/en/cancerresearch/programs/dna-repair/

Dana Branzei, Ph.D

Project Coordinator

Romanian molecular biologist Dana Branzei did her bachelor and doctoral studies at Tohoku University in Japan, continuing her scientific career in DNA repair and genome stability at the Riken Institute in Japan and then at IFOM in Milan, Italy. From 2008, she became head of the DNA repair laboratory at IFOM in Milan. Her laboratory studies mechanisms of DNA damage response and tolerance pathways in eukaryotes.

Electron microscopy (EM) analysis of repair intermediates.

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EU

NIH National Institutes of Health The National Institutes of Health in the US are the world’s single largest source of funding for medical research, supporting research into both well-known diseases and emerging threats to public health. Comprised of 27 individual institutes and research centers, the NIH is at the forefront of efforts to improve medical treatment

O

ne of the world’s foremost medical research agencies, the work of the National Institutes of Health (NIH) in the US covers a wide spectrum of activities, encompassing both basic and applied research. The NIH is comprised of 27 individual institutes and research centers, defining its overall mission as; ‘to seek ‘fundamental knowledge about the nature and behaviour of living systems and the application of that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability.’

The NIH can trace its roots all the way back to 1887 and the creation of a one-room laboratory within the Marine Hospital Service to examine new arrivals in the US for clinical signs of infectious diseases. Its priorities have of course evolved significantly since then, but the NIH has remained at the forefront of medical research, developing new therapies, vaccines, diagnostic tests, and other technologies that have improved the health of millions of people in the United States and around the world.

The NIH’s work today includes both analysis of the underlying mechanisms behind well-known diseases and efforts to anticipate new threats to public health. First described in 1906, Alzheimer’s disease has been the focus of a great deal of research, but there is still no known cure, and scientists working in NIH-funded projects continue to investigate the early stages of the disease and how it progresses. The ultimate goal has to be finding a cure, but researchers are also looking for ways to mitigate the disease and help patients in the short-term.

At the same time new threats to public health are emerging.

Scientists recently identified a new strain of bird flu (H7N9), and although it is not yet an airborne human infection, it could eventually mutate and be transmitted between humans.

Increasing levels of antibiotic resistance are another major concern; the Chief Medical Officer in England, Professor Dame Sally Davies, described the situation as “a ticking time bomb”, warning that if we lose the ability to fight infections then even routine operations will be highly dangerous.

Research balance The balance between addressing these longer-term issues with the goal of improving treatment for more immediate priorities is always a difficult one to strike. As the world’s largest single source of funding for medical research, the NIH supports both basic and applied research, which are the foundations of improved treatment. This has not only generated thousands of highlyskilled research jobs but has also stimulated commercial

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Background Images ©NIH Centre: Artistic rendering of the surface of a human dendritic cell illustrating the unexpected discovery of sheet-like processes that fold back onto the membrane surface. When exposed to HIV, these sheets entrap viruses in the vicinity and focus them to contact zones with T-cells targeted for infection. These studies were carried out using ion abrasion scanning electron microscopy, a new technology we have been developing and applying for 3D cellular imaging. Created by Sriram Subramaniam. ©NIH

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“The investigational vaccine regimen was shown to be well-tolerated and final analysis of the data found that the regimen was safe and 31 per cent effective in preventing HIV infection. This was the first time an investigational HIV vaccine had demonstrated an ability to prevent HIV infection among infected individuals”

Aerial view of the NIH Campus ©NIH development, with many new companies having been established off the back of research advances.

The structure of the National Institute of Allergy and Infectious Diseases (NIAID), one of the 27 institutes and research centres that form the NIH, reflects the many strands of its wider research agenda. The NIAID is comprised of two intramural divisions, four extramural divisions, the division of clinical research and the office of the Director, with the latter providing scientific leadership, policy guidelines, and overall operational and administrative coordination for the Institute.

Many of the scientists working at the NIAID, or those who are supported by it, focus on the institute’s core disciplines of microbiology, infectious diseases, and immunology. While much of this research is exploratory in nature, their findings over the years have led to a better understanding of the human immune system and the mechanisms behind a range of infectious and immune-mediated diseases. In today’s interconnected world, global disease threats are relevant domestically, so the NIH monitors disease threats across the globe.

The NIAID’s Office of Global Health Research, together with NIH’s Fogarty International Center, manages and supports international research programs that focus on diseases of importance in other countries. The NIH pays close attention to emerging infectious diseases, such as the new H7N9 bird flu, as they develop. This helps the organisation respond quickly to emerging health threats and, should the situation develop into a pandemic, to work to develop effective vaccines, treatments, and diagnostics.

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HIV and Gene Regulation Research Š NIAID

The study of human immune deficiency virus (HIV) is a global research priority. While much has been learned over the past 25 years about how HIV is transmitted, how the virus invades the cell, how it is reproduced and how it causes the progressive disease that leads to AIDS, there are still fundamental unanswered questions about the virus, particularly how it is regulated and expressed. Part of the NIAID, the Division of Acquired Immune Deficiency Syndrome (DAIDS) is devoted to the study of HIV/AIDS.

A sound understanding of how the virus works is of course fundamentally important to this and efforts to develop effective treatments. The HIV virus destroys CD4+ T cells, white blood cells crucial to maintaining the function of the human immune system, leaving the infected individual vulnerable to disease and infection, which ultimately leads to the development of AIDS. Gaining even more detailed information about how the virus attacks the body is crucial to generating new targets for therapeutic interventions and vaccines.

HIV/AIDS virus

This is hence a key part of DAIDS basic research agenda, which includes work on HIV pathogenesis, targeted interventions and research into possible cures. Looking at HIV pathogenesis specifically, one of the key goals is to determine the structure, function and mechanism of action of the viral genes and proteins.

Researchers are also looking at how they then interact with host cell genes and proteins, allowing the virus to enter the cell and then replicate, spreading the infection throughout the host.

Even though it was first recognised over 30 years ago, the HIV virus continues to spread, with 50,000 people in the U.S becoming infected each year. A range of anti-retroviral drugs are now available to treat the disease and prevent its progression, to the point where some patients have a near normal life expectancy, but there is still no known cure. Within DAIDS there are eight research programmes, from basic science through to vaccine development, with the ultimate aim of bringing an end to the HIV/AIDS epidemic.

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The viral lifecycle itself is fairly well-known. When infecting

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women it first traverses the mucus in the vaginal epithelium, gets into the vaginal tissues, and starts to enter certain target cells and then replicates inside those cells. Researchers have also been investigating the structure of the virus; NIAID-funded projects have generated significant information about the biology of HIV and the immune response to infection, including how HIV uses the host machinery to enter and exit the cell. The ongoing challenge facing the NIH is to translate this knowledge into improved treatment.

The Therapeutics Research Programme at DAIDS has helped define international guidelines for the treatment of primary HIV infection in adults and children, as well as for associated opportunistic infections and prophylactic regimens. The recommended initial regimens include two nucleoside reverse transcriptase inhibitors plus a nonnucleoside reverse transcriptase inhibitor.

binding to viral proteases and blocking the precursor steps to the production of infectious viral particles. The second class of antiretroviral drugs to be developed, protease inhibitors work on quite specific targets, so there is a risk that the virus could mutate and develop resistance; to reduce this risk clinicians often use several different drugs together acting against different targets.

Treatment regimens which combine these protease inhibitors with reverse transciptase inhibitors, commonly known as highly active antiretroviral therapy (HAART), have revolutionised the treatment of HIV in some parts of the world. This type of treatment has greatly reduced the incidence of AIDS-related opportunistic infections, raising life expectancy for people infected with HIV. However, such treatments can be difficult to follow due to their complexity and can also cause metabolic abnormalities.

Developing a vaccine

These nucleoside reverse transcriptase inhibitors (RTIs) are a class of antiretroviral drug. They inhibit the activity of reverse transcriptase, which is required for the replication of the virus, and so halt its progression and ongoing development. Two of the RTI’s recommended under international guidelines are emtricitabine and tenofovir, the latter being a so-called ‘pro drug’ which dissolves in the human body, allowing a relatively low dose to reach the site where it is required.

Research is therefore ongoing to develop improved therapies and even a vaccine, which has historically been our best weapon in preventing the spread of infectious diseases ever since the English physician Edward Jenner pioneered a smallpox vaccine in the late eighteenth century. Vaccines work by presenting a piece of the virus to the body’s immune system and causing an immune reaction. This primes the immune system so that when it is exposed to the real infection, it can aggressively attack it.

Another class of antiviral drugs used in treating HIV are protease inhibitors, which prevent the virus replicating by selectively

However, researchers have not yet been able to develop a vaccine against HIV, as the virus has unique ways of evading

Scanning electromicrograph of an HIV-infected H9 T-cell. © NIAID

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Secretary of State HIllary Rodham Clinton delivers a speech about HIV/AIDS at the National Insittutes of HealthIn November 2011. Also on the stage are NIH Director Dr Francis Collins (right) and NIAID Director Dr Anthony S. Fauci (left). © NIH Inset below: President Barack Obama is introduced by Dr Francis Collins, NIH Director, at the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative event in the East Room of the White House. © NIH

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the human immune system and the human body seems to be incapable of mounting an effective immune response against it. Scientists have been unable to identify what type of response is needed to prevent infection and control replication, yet there have been encouraging developments recently. In particular, an HIV vaccine regimen trialled in Thailand was found in 2009 to have a ‘modest preventative effect’ against the infection.

The investigational vaccine regimen was shown to be well-tolerated and final analysis of the data found that the regimen was safe and 31 per cent effective in preventing HIV infection. This was the first time an investigational HIV vaccine had demonstrated an ability to prevent HIV infection among infected individuals, representing an important step forward in research, while a team of NIH scientists have recently developed a new tool to identify broadly neutralising antibodies (bNAbs) capable of preventing infection by the majority of strains.

This new tool could greatly accelerate HIV vaccine research. The blood of some HIV-infected individuals shows a heightened ability to neutralise the activity of the virus, hence they are the focus of a great deal of research, as understanding how bNAbs against HIV develop could yield important insights for the design of a vaccine. However, previous methods of analysing blood samples did not generate specific information about the bNAbs acting against HIV, or the specific parts of the virus they targeted.

The new tool, a mathematical algorithm called neutralisation fingerprinting, promises to change this by enabling scientists to precisely determine the HIV bNAbs present in a blood sample. Blood samples contain mixtures of antibodies, so the new algorithm calculates the specific types of HIV bNAbs present and their proportion by comparing the blood’s neutralisation data with the fingerprints of known HIV bNAbs. This approach is significantly faster than previous methods used to analyse blood and could even be used on other viruses.

Biomedical and behavioural approaches The focus of researchers at DAIDS is very much on HIV though.

Alongside research into a possible vaccine, DAIDS also supports research into other aspects of prevention, including topical microbicides, as well as biomedical and behavioural approaches.

Research-based prevention strategies are helping keep infection rates low in some countries, but these are not always available in some parts of the world where the infection rates are relatively, in particular sub-saharan Africa.

The region has the world’s highest rate of HIV infection, accounting for 67 per cent of the estimated 33 million people living with HIV across the globe. The strategies used for HIV prevention in more developed nations may not be as effective here, so it’s important to take local circumstances and the cultural background into account.

DAIDS has established partnerships with community advisory groups, scientific investigators and other organisations, so prevention strategies reflect the local situation.

www.nih.gov

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A new approach to treating HPV Scientists at American drug research company NanoVir are using novel biological and chemical approaches to target human papilloma virus (HPV). The company’s co-founders, Dr Chris Fisher and Dr James Bashkin, explain how new DNA-binding compounds will improve treatment of HPV A small double stranded DNA virus with more than 100 individual genome types, human papilloma virus (HPV) is known to be the cause of over 99 per cent of cervical cancer cases, while it is also a major factor in a number of other conditions, some less serious and others also life-threatening.

HPV is a small virus that encodes few traditional antiviral targets, so has historically proved difficult to target, but today scientists at drug research company NanoVir are using novel biological and chemical approaches to develop new therapies against it. “We decided to use DNA-binding compounds that could be designed to bind to specific viral sequences of HPV. We set out to target an important regulatory region of HPV, called the origin of replication,” explains Dr. Chris Fisher, who co-founded NanoVir in Kalamazoo, Missouri together with Dr. James Bashkin.

Biologists and chemists work together at NanoVir to investigate the virus and develop new compounds. “The virus maintains its DNA as circular, extrachromosomal DNA molecules called episomes. There’s a long period of time after infection when episomes are maintained and replicated, and the viral DNA is quite different from the human DNA in structure and sequence,” says Dr. Bashkin. “It seemed to us that it would be a good potential target that would allow us to minimize any side-effects with the human system, and give us a good chance of attacking the virus directly.”

Most of those infected with HPV are able to clear the virus on their own, but the infection becomes persistent in a sub-set of people. Viral persistence is the largest risk factor for carcinogenic progression attributed to HPV; it can result in precancerous changes to the cell, or cellular dysplasia (or CIN1 and CIN2), causing alterations to the cell’s shape and its capacity to proliferate. HPV infected cells are not invasive cancers at or before this point, and Dr. Fisher says the changes are essentially reversible. “That’s where we’d like to interrupt the infection, to eliminate 30

the viral DNA, and return the cells to a more normal state. We have already accomplished this in vitro. It usually takes 15-20 or more years for that infected cell to result in an invasive cancer,” he outlines.

Currently there are few treatment options for women carrying HPV other than surgery, which can affect their reproductive health. By developing new drugs, NanoVir aims to provide an alternative to invasive surgery; their research currently centres on three strains of HPV. “The majority of the cancers caused by HPV, over 70 per

There’s a long period of time after infection when episomes are

maintained and replicated, and the viral DNA is quite different from the human host DNA in how it is maintained.

It seemed to us that this stage of infection would be a good target that would allow us to minimize any side-effects with the human system cent, are caused by just two strains – HPV 16 and HPV 18. So those are the two that we’ve focused on, while we also work with HPV 31, which is another high risk virus,” says Dr. Fisher. “These are called high-risk, mucosal strains of the virus – they infect urogenital mucosa, and are also implicated in a growing number of other infections and cancers, for example in the oral pharynx and the larynx. But they’re essential in cervical cancer.”

Eliminating viral DNA Researchers at NanoVir have been designing compounds to target the virus,

which are produced by Dr. Bashkin at the University of Missouri-St. Louis then sent to NanoVir for testing. The compounds combine to the viral DNA and affect it in several ways, including changing its shape considerably, which may be central to the antiviral activity. “We found a subset of compounds that had remarkable activity, in that they decreased the viral DNA levels to a much greater extent than if we had just blocked the virus’s ability to replicate. It was clear that the compounds were getting into cells, binding to the viral DNA and then causing a massive loss of the viral DNA from the cells. We synthesized more compounds to identify those that were most potent and effective in eliminating the viral DNA from the cells,” outlines Dr. Fisher. NanoVir researchers are now characterising how the compounds trigger a loss of viral DNA from cells, and what effect this has upon the cellular phenotype. “We are now sure that innate cellular defence mechanisms are activated by the compounds and identifying the HPV DNA as foreign or ‘non-self’.

We also know that the proliferative capacity of the cells returns to a more normal state following drug treatment. Will the cell eventually be unable to survive? Will it enter a state of quiescence? Or will it just enter into an apoptotic pathway, a cell death pathway, and die?” asks Dr. Fisher. Of course, skin cells normally have limited lifetimes. “It appears, at least in vitro, that HPVinfected cells slowly quiesce after they lose HPV DNA. We’re currently characterising what that state looks like for a population of cells, and making sure that it doesn’t result in integration of the viral DNA into the host DNA (integration is part of the carcinogenic progression of high risk HPV infections).”

The design of these compounds takes into account the detailed DNA sequence information available on the various types of HPV. The molecules themselves are designed to bind at important viral proteinviral DNA interaction sites; Dr. Bashkin is

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At a glance Full Project Title Mechanism of Action of Human Papillomavirus Antiviral Compounds (NanoVirPharm) Project Objectives NanoVir is a drug research company committed to the discovery of treatments for human papillomavirus (or HPV) using novel chemical and biological approaches to develop DNA-targeted therapies. By targeting HPV DNA rather than more traditional antiviral targets, the company has identified a series of compounds that dramatically reduce the viral DNA load of cells harbouring the virus.

Project Funding Project funded by three major grants from the NIH. Contact Details Project Coordinator, Chris Fisher, Ph.D. NanoVir 4717 Campus Dr. Kalamazoo, MI 49008 T: +269-372-3261 F: +269-372-8716 E: +269-372-8716 W: www.nanovirpharm.com http://www.ncbi.nlm.nih.gov/pubmed/21669229 [1] http://www.ncbi.nlm.nih.gov/pubmed/23365423 [2]

Chris Fisher, Ph.D. (left) Dr James Bashkin (right)

Dr. Bashkin is currently Professor of Chemistry and Biochemistry at the University of Missouri-St. Louis. He has won numerous awards including the Presidential Green Chemistry Challenge Award in 1998.

Dr. Fisher worked on cancer and infectious diseases drug discovery with Upjohn Company prior to forming NanoVir in 2003. He has served as permanent and ad hoc member of numerous NIH study sections.

Human HPV18 positive cells were engineered in vitro to differentiate into epithelia containing all the characteristic layers of skin that are normally found in vivo.

These layers include the basal layer (BL), the suprabasal layer (SL), and the stratum corneum (SC) or dead, cornified, outermost layer. Brown stained cell nuclei are found throughout the suprabasal layers in the untreated epithelium (left) indicating that HPV is compelling these cells to synthesize DNA abnormally. In the epithelium on the right, which was treated with Polyamide 25 to eliminate HPV, the dividing cells are limited primarily to the basal layer, indicating that the tissue has returned to a more normal state in addition to having extremely low levels of HPV DNA after treatment.

looking at various aspects of how the compounds bind to the virus at the University of Missouri-St. Louis. “We amplify certain regions of the viral genome, so that we have enough DNA to ensure we can study it with a wide range of techniques.

Then we literally add our compounds to these sections of viral DNA and find out whether or not they bind through a series of measurements. We determine the actual binding strength of our compounds to those different sections of viral DNA. We’re working our way through the entire genome of HPV16 at the moment with a couple of our compounds,” he outlines. While the ultimate focus is of course improving treatment of HPV, Dr. Bashkin believes that understanding precisely how the compounds work will help researchers improve them further. “We know that the compounds work in all of the systems that we’ve studied to date, which are human cell monolayers and more complex tissue cultures,” he continues. “The effectiveness of the final drug is what we care about. But when it comes to understanding how the drug candidates work, and being able to improve that activity and maximise its effectiveness, then the mechanism of action can be very useful.”

Clinical research The major focus now is on bringing these molecules into clinical research. The company is currently engaged in preclinical drug development, doing safety studies and looking at the residence time

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of a drug in an animal body, which Dr. Bashkin says is an essential step in development. “We’re looking at the possible side-effects that might occur – toxicity effects associated with compounds always have to be checked in a lot of detail before it’s possible to begin human trials.

So we’re in the middle of those pre-clinical development stages for two different lead compounds. We’ve also continued to work on improving antiviral properties for later-generation compounds, but we’re committed to taking our current generation of lead molecules through to the clinic,” he explains. Drug development is a long drawn-out, expensive process, so NanoVir is looking towards collaboration with larger partners.

“It can be difficult to find partnerships with companies unless you’re actually in the clinic and your compound has been successful in treating someone in the clinic. Our partnership with the University of Missouri and support from the National Institutes of Health in the U.S has been critical for us,” says Dr. Fisher. “We’re currently working toward an approved Investigational New Drug (IND) application with the FDA. We’re confident that, with an IND and the mechanistic data that we have, we will identify an appropriate partner to help us conduct clinical trials.

We will then be in the exciting position of treating women who have tested positive for HPV, hoping that our compounds work as well for patients as they do to eliminate viral infections in cells.”

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Protecting people against HIV infection is an urgent global health priority, particularly in the developing world. Dr Marc Baum of the Oak Crest Institute of Science in the US writes about his research into developing intravaginal ring technologies which can release drugs to protect women from HIV

Fabrication of intravaginal rings on a laboratory-scale injection molding system (left). View of a pod in the Oak Crest intravaginal ring releasing drug through a delivery channel into vaginal fluid (center). Close up of the 4 pod intravaginal ring (right).

Protecting women from HIV The battle against HIV is being fought on many fronts, with researchers looking at the structure of the virus, developing strategies to prevent it from spreading, and treating systemic infection with new methods. Based at the Oak Crest Institute of Science in California, Dr. Marc Baum is part of a research team investigating new methods of delivering drugs to prevent the virus from spreading after the initial infection event. “The fundamental goal of our research is to develop intravaginal ring (IVR) technologies that are proven to be safe and effective in protecting women from contracting HIV,” he outlines. There are different strategies to achieve this goal, one of which is to use multi-purpose technologies that combine more than one preventative technology in a single device.

“With vaginal rings, that could be a device showing promise for protection from HIV infection, but also having a contraceptive component. Or, you could have an IVR that’s protective against two sexually transmitted infections at the same time.

So you have an HIV ring that is also protective against genital herpes (HSV),” continues Dr Baum. “Those are parallel approaches to achieve a ring that is protective against HIV infection. That’s really fundamental, the most important of our goals.”

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Effective microbicides There is no clear pathway to follow in this work. Understanding how the virus works is fundamentally important to developing an effective microbicide, but earlier approaches were not successful in clinical trials, largely because of safety problems.

“The viral lifecycle is quite well-known. A logical approach is targeting different aspects of the viral lifecycle with a prophylaxis, so that you minimise the

and begins to replicate once it enters target immune cells. Once it reaches a certain threshold, these infections can then spread through the lymphatic system and become systemic. That’s when you have a problem – at that point it’s too late.

But if you can interrupt the proliferation of this starting population in the vaginal tissues at this very early stage, you can potentially prevent systemic infection,” he explains. This is not only about preventing

Once the virus reaches a certain threshold, these infections can spread through the lymphatic system and become systemic. That’s when you have a problem. But if you can interrupt the proliferation of this starting population in the vaginal tissues, at this very early stage, you can potentially prevent systemic infection chances of the virus going beyond the initial stages and infecting the host systemically,” says Dr. Baum. It may seem counter-intuitive to consider prophylaxis when the host is already infected, but Dr. Baum says the part of the virus that establishes itself in the early stages of infection is very localised. “It appears that, when somebody is infected by the virus, it traverses the mucus in the vaginal epithelium, passes into the vaginal tissues,

the spread of the virus, but eradicating it in the host, so researchers at Oak Crest are developing a novel IVR platform to simultaneously release multiple drugs that target the virus at different stages of infection. This work builds on an understanding of how the virus establishes itself in the host and its subsequent development. “The initial step is attachment and then incorporation into the cell. An entry inhibitor can potentially

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Cervix Ring

Vagina

Introitus R

L Coronal View

Ant

Post Longitudinal View

Drawing showing the pod intravaginal ring in the vagina. The ring sits at the top of the vaginal tract close to the cervix. prevent the virus from penetrating target cells where replication occurs. Once the virus is inside the cell, reverse transcriptase inhibitors (both nucleoside and non-nucleoside RTIs) interfere with reverse transcription, one of the very early stages of the viral lifecycle. Protease inhibitors and integrase inhibitors target subsequent steps of the viral lifecycle,” explains Dr. Baum. These drugs are already used to treat HIV; however, it is difficult to identify the best candidates and ideal dosage for prophylaxis. “You start with IC90 – the drug concentration where 90% of viral growth is inhibited – identified from cell culture studies. We know that this is probably not enough, so we ask; do we need to inhibit 99%, or 99.9% to prevent infection?” outlines Dr. Baum. Which drugs to use and how much of a drug, or combination of drugs, is required for preventing systemic infection are two of the major questions facing researchers.

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Once these questions are answered, the device needs to be formulated to release and maintain those drug levels over the IVR’s period of use, which could be 30

Pod intravaginal fabrication: ring blank ready for trimming and loading of drugcontaining pods.

days, or longer. The IVR is intended primarily for the developing world, so cost is an important issue in this regard. “In some ways a 90-day ring is better than a 30-day ring, because you can spread the cost of the ring over a longer period and make it less expensive,” points out Dr Baum. The total amount of drug in the ring needed for a 90-day device makes it challenging to design a ring that can deliver multiple drugs and last that long.”

Dr. Baum says there are also other factors to consider. “Do you have a ring with or without contraception? If you do it with contraception, does the woman remove it to have a period and then put it back in again? How does that affect the release of the anti-viral agents?” he asks. “You’d also have to do some extended safety testing – what if there’s more disruption of the vaginal microbiome (bacterial communities that are present in the vaginal tract)? How are these communities affected by the devices that are in place

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At a glance Full Project Title Pre-clinical development of novel antiretroviral intravaginal rings for HIV prevention (Pre-Clinical Studies)

continuously for 90 days, as opposed to them being replaced every 30 days?”

Adherence levels The device itself must be safe so that it does not counteract the protective effects of the drugs. Education and product acceptability also are essential for an effective IVR to be used. The CAPRISA 004 trial using a tenofovir gel was the first demonstration of prophylaxis against HIV, and unexpectedly HSV, using a topical microbicide, which Dr. Baum says was a big step forward. “That was a landmark study, because until then we really had no large-scale clinical evidence that any of this would work,” he says.

Researchers were also able to monitor adherence levels to these gels and its effect on protection. “They found that the high-adhering group in the trial had over 50% protection, compared to 39% across the board. So adherence definitely makes a difference, and I think that a vaginal ring has a much higher likelihood of solving the adherence issue than a vaginal gel. The gel has to be used pericoitally, in other words before and after sex, for it to be effective,” explains Dr Baum. “The ring provides sustained delivery of the compounds independently of sexual intercourse. If you have a good ring you have a very controlled, continuous release of the drugs that maintains steady-state concentrations in vaginal fluids and tissues. That helps prevent swings in drug levels and provides sustained protection.”

An effective, inexpensive way of protecting people against HIV is of course already available - the condom. However, many men in the developing world don’t want to use it, so Dr. Baum says there has been a shift towards developing femalecontrolled strategies. “In many cases there’s very little that women can do to protect themselves. A vaginal ring would overcome this hurdle,” he says. Although this research is primarily a humanitarian rather than financial endeavour, cost is still an important issue in terms of making IVR’s available in the developing world, and researchers are looking at

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various options. “The cost of the drugs themselves is the single biggest cost. Then you have the polymers and elastomers used in the ring fabrication and the manufacturing cost. You want the most efficient and inexpensive manufacturing process possible to keep those costs down.

You also want flexibility in the choice of elastomer, because that’s the second major cost after the drug,” explains Dr. Baum.

“These are all things to consider early in the development process, and their importance is greater now that these products begin to enter large-scale clinical studies.”

How the ring works. Drugs are released from the pod into vaginal fluid through delivery channels. The drugs then diffuse from the vaginal fluids through the thin surface mucosal layer (green) and into the underlying epithelium where we believe they form a decreasing concentration gradient as the drug penetrates through the epithelium, into the submucosal layer containing immune cells (white structures), and finally to the underlying lamina propria.

The depth of the blue color indicates the concentration of drug as it moves deeper into the vaginal tissue structure.

Project Objectives The primary objective of our intravaginal ring (IVR) program is to develop a safe and effective device for HIV chemoprophylaxis, with an emphasis on the needs of resourcelimited countries. To successfully meet this goal, we are developing novel IVR technologies, using new techniques to fully explore the devices’ PK and PD profiles, and conducting fundamental research into how the IVRs interact with the vaginal mucosa.

Project Partners The IVR Program at Oak Crest is carried out in close partnership with Auritec Pharmaceuticals, Inc., with the generous support of the National Institutes of Health, CONRAD, and the International Partnership for Microbicides.

Contact Details Project Coordinator, Dr Marc Baum Oak Crest Institute of Science USA T: +1 626 817 0883 E: m.baum@oak-crest.org W: http://www.oak-crest.org/Research/ Medical/rings.html Gunawardana, M.; Moss, J. A.; Smith, T. J.; Kennedy, S.; Kopin, E.; Nguyen, C.; Malone, A. M.; Rabe, L.; Schaudinn, C.; Webster, P.; Srinivasan, P.; Sweeney, E. D.; Smith, J. M.; Baum, M. M., Microbial Biofilms on the Surface of Intravaginal Rings Worn in Non-human Primates. J. Med. Microbiol. 2011, 60, 828-837.

Dr Marc Baum

Project Coordinator

Marc Baum received his doctoral degree in Organic Chemistry from Imperial College (London, UK). In 1998, he founded the Oak Crest Institute of Science (CA, USA, www. oak-crest.org), a Pasadena-based nonprofit science research organization where he serves as president and senior faculty. He has been actively leading a drug delivery program at Oak Crest since 2004 and was a core member of the team that developed the podintravaginal ring for HIV prophylaxis.

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Harnessing the properties of Tβ4 The thymosin beta-4 protein (Tβ4) is closely involved in tissue repair and regeneration, properties which researchers are aiming to harness in new drugs. Hynda K. Kleinman, Ph.D tells us about her work in developing new drug candidates using Tβ4, and how it could improve the treatment of cardiovascular conditions in particular The thymosin beta-4 protein (Tβ4) holds real therapeutic potential. The protein is known to be involved in tissue repair, as well as in regeneration of both the skin and eye after injury, attributes which could be used to improve treatment of several types of injuries and conditions. “Tβ4 is involved in repair after a heart attack, while it is also involved in repairing the central nervous system after traumatic brain injury, multiple sclerosis or stroke,” explains Dr Hynda K. Kleinman, Ph.D of RegeneRx Biopharmaceuticals Inc, a clinical stage

more about the molecule. “We knew that platelet levels of this molecule were high, and that platelets were among the first cells to arrive at the site of tissue injury. So we did a dermal healing study; we made punch biopsies in the backs of rats, then we put Tβ4 in the holes that we created in the skin.

They healed very rapidly,” she outlines. As a relatively small molecule with multiple distinct active sites, Tβ4 has only 43 amino acids so researchers are also able to synthesize smaller fragments which retain the molecule’s unique biological properties.

Tβ4 is involved in repair after a heart attack, while it is also involved in dermal and central nervous system repair after traumatic brain injury, multiple sclerosis or stroke and in eye injuries including dry eye drug development company based in Rockville, Maryland. The company is looking to develop drug candidates to target four main areas: dermal, neural, ophthalmic and cardiovascular repair, and research is ongoing into how the Tβ4 molecule affects each. “RegeneRx is mainly interested in getting Tβ4 to patients. Meanwhile a lot of people are also looking at the mechanisms of how this molecule works,” says Dr Kleinman. “They are looking at the receptors, the signalling pathways and its role in reducing inflammation and in the recruitment of stem cells.”

Thymosin beta-4 The Tβ4 protein itself is present in most cells in the body, as well as in fluids including saliva, tears, and blood. While working at America’s National Institutes of Health (NIH), Dr Kleinman found that the protein is up-regulated during blood vessel formation, then further research revealed

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“We knew there was an active anti-inflammatory site of 4 amino-acids at the N-terminal end of the molecule. It was also known that there was a central actinbinding domain that was comprised of 6 aminoacids. We actually made a 7-amino acid synthetic peptide containing the central actin-binding domain and that had activity for promoting dermal wound healing.”

These attributes hold great potential in terms of helping repair and regenerate tissue, while Tβ4 can also play a protective role. When an injury occurs, inflammatory molecules and cytokines are released that can cause more damage, but Tβ4 prevents the situation from getting worse. “When an individual suffers a physical trauma, mediators are released by the cells that can then cause collateral damage,” says Dr

Kleinman. The Tβ4 protein actually protects the cells from the agents that cause this damage. “We’ve used various cytotoxic agents, such as alcohol and NaOH, in the eye to generate injury and then added Tβ4. It protects the cells from cytotoxic damage,” continues Dr Kleinman.

Similar protection (i.e. decreased inflammation and accelerated healing) has been reported with neurotrophic keratitis and severe dry eye”. “In the brain of stroke patients there’s often something called excitotoxicity, where glutamate gets released and kills some of the neurons. What researchers have shown in vitro, is that Tβ4 protects the cells from glutamate toxicity. It promotes repair by recruiting stem cells, stimulating nerve regeneration,

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A mouse model of MI where the coronary artery is ligated and then 400 ng thymosin beta 4 is injected once along the boundary between the infarct and the border zones of the MI heart. This figure is from 4 weeks post treatment and shows a reduction in the scar formation (blue area) of the left ventricle (LV) with thymosin beta 4 treatment when compared to the control. Figure provided by Drs. Li Quan and Deepak Srivastava.

angiogenesis and other processes, but in addition it does also decrease fibrosis and scarring.”

These mechanisms are common to dermal, neural, ophthalmic and cardiovascular wound healing. After an individual suffers a heart attack they often lose circulation in an area of the heart muscle; the muscle dies and scar tissue is left behind, which can impair heart function and even cause death. “Sometimes people have multiple attacks and eventually the heart can’t function effectively, because there’s too much scar tissue. Tβ4 blocks the formation of scar tissue, and in some cases reverses it,” explains Dr Kleinman.

In experimental models, a vessel in the heart muscle is tied off to simulate

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blockage, then in other models researchers leave the vessel tied off for a period of time then untie it. “You get what’s called reperfusion injury – so even though you’re treating a heart attack by trying to unblock the vessel, there is going to be some secondary damage from the reperfusion” continues Dr Kleinman.

“Researchers have shown in re-perfusion injury models that Tβ4 also prevents significant damage to the heart.”

Phase-1 trial The company’s focus now is on bringing a drug to the market. A phase-1 clinical trial using injectable material, enhancing

the body’s initial response to injury, has been carried out in healthy human volunteers. “More Tβ4 is injected than the body produces itself. Typically, in response to injury in the heart, there is an up-regulation of Tβ4 – the heart endogenously tries to self-repair by making it. We’re augmenting that and sustaining it for a longer period of time,” says Dr Kleinman. This is particularly important for people with lower levels of naturally occurring Tβ4; research in other areas suggests they may be at higher

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At a glance Full Project Title NONCLINICAL STUDIES TO ADVANCE NOVEL DRUG FOR POST-STEMI CARDIAC REGENERATION Project Objectives To carry out preclinical repeated dose toxicity, safety pharmacology, and other studies required by the FDA for phase 2 and 3 clinical trials with intravenous administration of thymosin β4 in patients with myocardial infarction.

Project Funding 3.9 million euros Contact Details Project Coordinator, Hynda K. Kleinman, Ph.D RegeneRx Biopharmaceuticals Inc 15245 Shady Grove Rd. Suite 470 Rockville, MD 20850 USA T: +001-301-240-899-2749 E: hkleinman@dir.nidcr.nih.gov W: www.regenerx.com Goldstein, A.L., Hannappel, E., Sosne, G., Kleinman, H.K. Thymosin beta 4: A multifunctional regenerative peptide. Expert Opinion in Biology, 12:37-51, 2012.

Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D. Thymosin beta 4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 2004; 432: 466-472.

Tβ4 was first isolated from the thymus gland in 1981 by Dr. Allan Goldstein and his colleagues at The George Washington University School of Medicine and Health Sciences. It was initially thought to be important in the maturation of lymphoid stem cells and in inhibiting macrophage migration. Tβ4 is now known to present in almost every mammalian cell and functions to promote tissue repair and regeneration.

Hynda K. Kleinman, Ph.D

Project Coordinator

The inventions and scientific discoveries of Hynda K. Kleinman, Ph.D have resulted in 418 peer-reviewed publications and 11 patents. Her work on thymosin β4 and tissue regeneration has led to phase 2 clinical studies for dry eye and venous stasis and pressure ulcers. She is a consultant for RegeneRx Biopharmaceuticals Inc.

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risk of developing cardiovascular disease.

“An Italian group has shown that fibrosis occurs in patients with scleroderma, and they eventually get it in the lung,” continues Dr Kleinman. “They’ve found that patients with higher circulatory levels of endogenous Tβ4 have much less lung fibrosis. This is without adding any drugs, just by looking at the circulating levels. A similar finding of elevated levels of Tβ4 is reported as being protective in alcohol-induced cirrhosis of the liver.”

Once these types of fibrotic conditions have taken root they can quickly develop and worsen. Over time cardiovascular injuries lead to inflammation in the heart and the release of cyto-toxic factors, which cause further damage. “The idea is to try to block as many of those early steps as possible, or to reduce them,” explains Dr Kleinman. However, Dr Kleinman says there are still many hurdles to negotiate before a Tβ4 drug reaches the market. “Clinical studies are very expensive. It is really important to have a large study to obtain statistical significance,” she outlines.

“Another major hurdle is whether the drug has any side-effects that would make it unacceptable. In the U.S we are also required to do a lot of pre-clinical testing in animals at different stages during the process. For phase 2 and 3 trials, we have to have certain safety studies done, including toxicity and pharmacokinetics to complete the FDA requirements.”

Several studies have been completed under the current grant from the National Institutes of Health (NIH) in the USA (Table), including one on toxicity of the injectable material. The current grant has also supported pre-clinical studies in rats and rabbits, looking at the effects of various doses on fertility, as well as any malformations of the foetuses. “If the drug had any effect on pregnant animals then this would not be a suitable treatment for pregnant women. Those are the kinds of pre-clinical and safety studies that are required. So far the drug has proved itself to be very safe, even at very high doses, and even in pregnant animals” stresses Dr Kleinman. Drug development is a long process, so RegeneRx’s main focus is on Tβ4, including looking at other ways in which it could be applied. “RegeneRx is sharing Tβ4 and various fragments with multiple research groups around the world through Material Transfer Agreements to see if any of the molecules would also be active in treating certain injuries. The rationale for testing the smaller fragments is that they are less expensive and provide new drug opportunities,” says Dr Kleinman.

Table. Completed FDA required preclinical tests to support Phase 2 and 3 clinical intravenous use of thymosin β4 for heart attack patients. _____________________________________________________________________________ 1. hEGR Channel Test: in vitro test to assess effects of Tβ4 on the cardiovascular system and potential to delay ventricular repolarization 2. Repeated Dose Toxicity and Toxokinetic Study in Rats: daily 28 day intravenous injections of various amounts of thymosin β4 to determine potential toxicity 3. Embryo-Fetal Development in Rats and Rabbits (includes dosage-range finding for both species): injection of various amounts of thymosin β4 into pregnant rats (day 7-17 of gestation) and rabbits (day 7-19 of gestation) to detect adverse effects on development of embryo from implantation to closure of hard plate.

4. ADME (non clinical absorption, distribution, metabolism and excretion) Study in Rats: assess metabolic pathways of thymosin β4 that can be compared to man. _____________________________________________________________________________ Results: There were no adverse effects of thymosin β4 in any of these studies.

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A natural disaster is obviously a terrifying event for everybody in the affected area, but the dangers are particularly acute for those who don’t recognise the severity of the situation. Dr Jennifer Wells of the Tech-Aid Institute explains how her project will help people with intellectual disabilities prepare for the event of a natural or man-made disaster

Tech-Aid Institute provides information for all A natural disaster is obviously a terrifying event for everybody in the affected area, wreaking havoc on infrastructure and sometimes forcing people to leave their homes. However, the dangers are particularly severe for people with an intellectual disability, who may not recognise the severity of the situation. “People with an intellectual disability have more difficulty ascertaining what is going on in the

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world around them,” explains Dr Jennifer Wells of the Tech-Aid Institute, based in Eugene, Oregon. As the coordinator of the Live Smart Live Safe project, Dr Wells is developing educational programmes targeted at people with intellectual disabilities.

“The project’s overall goal is to provide information in concise yet understandable ways to help inform people with intellectual disabilities

about disasters and emergencies, and to help them understand how to deal with those situations if they occur in the areas where they live,” she outlines.

“There’s a lot of information on the internet about emergency and disaster preparedness, but it is all text-based.

Our programme is text-free: it’s made of animation, video, graphics and audio. So they don’t have to be able to read to glean information from our programme.”

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Effective preparation The programme is designed for people with mild or high-moderate intellectual disabilities, who often live on their own in apartments, in line with the wider move towards encouraging them to live as independently as possible. This allows people to build their confidence and key life skills, nevertheless Dr Wells says they do still need some level of support. “Some of them need help managing their finances, some need help with managing their apartments,” she says. Many also need help in preparing for the possibility of a natural disaster or a public health emergency, the area being addressed by the project. “The Live Smart Live Safe programme comes with a threering binder, which we call the 911 guide. 911 is the emergency phone number across the U.S. It has the content from the programme in illustrated form,” explains Dr Wells. “So it has drawings about a coming tornado, and it shows what to do. If somebody hears on the news that their area is on tornado watch, they can go to that book and look at the pictures about tornadoes, and it’ll tell them that they need to seek shelter. So it illustrates

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the content in the programme, which is extremely important, as not everybody with an intellectual disability has a computer.”

The programme provides relevant information covering 14 different types of disasters, ranging from chemical emergencies, tornadoes and floods, through to pandemics, wild fires and winter storms.

The U.S is of course a vast, hugely diverse country, and different regions face different

The goal is to use

this as an educational tool

so that when a disaster does occur, people have been

through it in the programme and have some

sense of what to do

risks, so the programme provides information specific to the area in which people live. “The programme is tailored by geographic region of the country so when somebody starts using the programme it asks; ‘Where do you live?’ A map of the U.S

comes up, which is then broken down into 10 regions. They click on the region where they live, then get content specific to the emergencies and disasters that tend to occur in that region,” explains Dr Wells. States on the East Coast may be prone to hurricanes at certain times, whereas on the West Coast there is a much greater earthquake risk; people are more likely to be forewarned in the former case, but in both situations people need to respond quickly. “ The goal is to use this as an educational tool so that when a disaster does occur, people have been through it in the programme and have some sense of what to do,” says Dr Wells.

It helps if people are aware of risks before they occur, which in many cases means listening to local weather reports and following the advice of the local authorities. Researchers from Tech-Aid have also conducted interviews with service providers across the U.S about how people with intellectual disabilities cope during public health emergencies, and it reveals that they can face problems when they reach a shelter. “During emergencies people with intellectual disabilities have

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Hurricane Sandy Credit: NOAA/NASA

At a glance Full Project Title LIVE SMART LIVE SAFE: EMERGENCY PREP. FOR PEOPLE WITH INTELLECTUAL DISABILITIES

actually been turned away from shelters because the people at the shelters one, didn’t know anything about intellectual disabilities. And two, perceived the person as unruly because of communication problems,” says Dr Wells. This might be due to stress levels, or the difficulty of dealing with a chaotic situation; Dr Wells believes clear communication is the key.

“In our programme we specifically teach people that if they need to go to a shelter, that they should tell the people at the shelter that they have a disability. It’s important to let people at the shelter know that they need help, so that they can help deal with the paperwork and any administrative issues,” she continues.

message is; when an emergency or disaster comes up, call one of those people on your emergency contact list and tell them you’re ok or ask them for help,” stresses Dr Wells. “So if there’s a product recall, they might have one of their emergency people come over and help them decide if their peanut butter needs to be thrown away or if it’s ok.”

The programme’s approach is also suitable for children and low literacy populations, as it breaks things down and explains them in a simple manner, so Dr Wells is keen to introduce it into schools in future. The current focus is on people with intellectual disabilities though; Dr Wells believes that helping them build

The more independent a person is the fewer resources it takes to help them. That’s where our work could have both

a social and an economic impact

Support network Friends and family often help with these kinds of tasks, but while the wider support network is of course important in helping people, the project’s focus is on educating the individual concerned on how to cope in an emergency. This can be both events which are predicted beforehand, such as an incoming storm, or an earthquake, which tends to happen quite abruptly, so the focus is subtly different in the latter case. “The programme focuses more on how to deal with the effects of an earthquake during the event, and what to do in the aftermath,” says Dr Wells. As part of the programme people develop a plan for the event of a public health emergency on which they list five emergency contacts, who can help deal with more mundane problems. “With issues like food safety we want people to listen to the news and really pay attention to what’s going on in their area. Another

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independent lives will bring wider social benefits. “The more independent a person is the fewer resources it takes to help them.

That’s where our work could have both a social and an economic impact,” she points out. Building on this work forms an important part of Dr Wells’ research agenda.

“We expect to do work that is similar to the Live Smart Live Safe programme, but directed more towards staff and families.

So, helping staff and families learn about the importance of emergency and disaster preparedness and helping people prepare effectively,” she continues. “In terms of people with intellectual disabilities, we’re researching other areas. We’re doing research in HIV/AIDS prevention and on preventing violence in the lives of people with intellectual disabilities.

Our programmes in the HIV/AIDS prevention realm are actually being used in Zimbabwe and Uganda, so those are some other areas where we’re pursuing further research.”

Project Objectives Research Content for a Comprehensive Emergency and Disaster Preparedness Program. Develop the Text-Free Program using Video, Animation,Graphics and Audio. Evaluate the Program with 42 Adults with Intellectual Disabilities.

Analyze the Outcome Data. Market the Completed Program Covering Fourteen Emergencies and Disasters.

Contact Details Principal Investigator, Dr Jennifer Wells, Ph.D. President Tech-Aid Institute 1000 Willagillespie Road, Suite 150 Eugene, OR 97401 T: +541-743-2692 F: +541-743-2696 E: jwells@techaidinstitute.com W: www.techaidinstitute.com This program was made possible by the NATIONAL INSTITUTE OF NURSING RESEARCH under Grant No. R44NR010051. Its contents are solely the responsibility of the Technological Assistance Institute for Intellectual Disability, LTD., Eugene, Oregon and do not necessarily represent the official views of the National Institute of Nursing Research or the National Institutes of Health.

Dr Jennifer J. Wells , Ph.D.

Principal Investigator

Dr Jennifer J. Wells is President of Tech-Aid Institute and has been developing interactive multi-media computer programs for people with an intellectual disability for the past 17 years. Currently Dr. Wells’ research focuses on emergency and disaster preparedness, reducing the spread of HIV/AIDS and violence prevention among people with intellectual disabilities.

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Putting alcohol policy on a firm footing Alcohol abuse costs Europe billions of pounds a year in healthcare costs, lost working days, and even crime, leading Governments to examine the impact of issues like advertising and pricing on consumption. Policy in this area should be built on sound evidence, says Dr James Nicholls, Research Manager at Alcohol Research UK

T

he cost of alcohol abuse to the National Health Service is the subject of intense debate in the UK. Stories of irresponsible binge-drinking are a media staple, and alcohol abuse is a significant burden on the NHS. The Health & Social Care Information Centre found that 198,900 hospital admissions in the UK in 2010/11 were primarily attributable to alcohol consumption, while an NHS study in May 2011 found that the NHS spends £2.7 billion a year fighting alcohol abuse.

This has led to calls for a minimum price on alcohol to curb consumption. The measure would undoubtedly prove controversial though, as the Government is unlikely to win too many votes if it’s perceived as penalising occasional drinkers.

The issue is still under consideration, with libertarians arguing against minimum pricing while much of the medical establishment supports intervention, in some cases citing research into links between alcohol abuse and crime, rates of absenteeism and healthcare costs.

The decision must have sound foundations if it is to be effective in terms of relieving the burden on the NHS. As an independent charity committed to reducing alcohol-related harm, Alcohol Research UK has a major role to play in these terms.

We spoke to Dr James Nicholls, Research Manager at Alcohol Research UK, about alcohol consumption patterns, the economic impact of alcohol abuse and the possible impact of minimum pricing.

Alcohol consumption

EU Researcher: Is alcohol consumption in the UK on the rise?

Dr James Nicholls: Alcohol consumption has actually been going down overall since about 2004-05. However, prior to that it had gone up steadily from the mid-to-late ’60s onwards. The key point is that consumption in the UK reached a historically high peak in the mid-2000s, and any recent decline needs to be seen in that context. Within that, beer consumption has been in longterm decline since about the ’70s, whereas wine consumption has increased exponentially over the last 3-4 decades.

In terms of consumption patterns, drinking is declining most

quickly amongst younger drinkers, the 18-24 age group. It’s still high among 45-65 year-olds, the heaviest-drinking group. At the other end of the scale the number of abstainers is increasing as well but that’s very variable by region, as are drinking trends generally.

EUR: Where are people drinking alcohol? Is it mainly in pubs?

JN: It’s estimated now that three out of every four alcohol units are bought in off-licences or supermarkets, so people are drinking mostly at home. The amount we drink in pubs is small by comparison to the amount that we drink at home, and that’s been another major change. Around 80-90 per cent of alcohol was bought in pubs in the early ’70s, it’s now about 50 per cent.

EUR: You mentioned that consumption is actually going down; has that had an impact on alcohol-related hospital admissions?

JN: Not directly, because of two main reasons. One is that there’s a lag between consumption trends changing and hospital admissions changing, particularly where you’re dealing with conditions like chronic liver disease. Over the period where we had a long increase in consumption there was a clear rise in liver disease.

If you look at the incidence of non-communicable diseases from the early ’70s in Britain, most of them have declined. But the one that’s increased is liver disease. Hospital admissions have started to flatline slightly, but they haven’t declined to the same degree as consumption.

The other issue is that the way alcohol-related admissions are calculated has changed. For a number of years official figures on hospital admissions were based on what are called alcohol-attributable fractions, an estimate based on the aggregate number of diseases that people have presented for which may be wholly or partially caused by alcohol.

A couple of years ago the Government decided that only illnesses that are entirely

There’s lots of evidence from Europe that pricing affects consumption, particularly from the Nordic countries...

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caused by alcohol would be counted in the figures. The partially attributable figures are much higher and have increased much more significantly – the wholly attributable figures are lower, but still increasing.

EUR: Is this the way the cost of alcohol-related diseases to the NHS per year is calculated? Does this mean it’s particularly difficult to calculate the impact of binge-drinking?

JN: Generally yes. We use alcohol attributable fractions, alongside A&E data, to estimate the cost of alcohol to the NHS. The stories about alcohol harm that get into the media tend to focus on young people and binge-drinking, which slightly overrepresents the importance of that particular issue as part of the overall problem. In terms of costs to society as a whole, long-term health impacts are at least as important as antisocial behaviour.

If people are concerned about anti-social behaviour then yes, many cases involve public drinking, and that will often tend to involve younger people. Health problems are to do with how much people are drinking. When you look at how much people drink, it’s older people who tend to drink more, but it’s not as newsworthy.

EUR: That must have an impact on things like drink-driving?

JN: It’s difficult to determine the precise impact of alcohol on people’s response speed or perceptions. It’s also very hard for most people to gauge how much they’ve drunk in relation to the drink-drive limit. This is why many people are calling for a reduction in the existing drink-driving limits in the UK, which are among some of the most relaxed in Europe.

This is also why alcohol labelling is much more focused now on units than it used to be. So you tend to get units on labels rather than just alcoholic strength. People’s awareness of units has increased in the last ten years or so. However, it is still difficult for drinkers to keep track of how many units they are drinking, and we know that most people tend to underestimate how many units they have consumed when asked.

EUR: Education must be a key part of this?

JN: It’s generally accepted education is less effective in reducing

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harm than supply-side interventions. I think one concern around education interventions is that they are often piecemeal and not implemented consistently.

The problem is that if you have an education programme that’s designed to achieve a particular outcome, but it’s not implemented consistently across the board, then you’re unlikely to achieve that outcome. So the challenge with education is not just the design of the programme, but designing programmes that teachers can realistically deliver.

Alcohol advertising

EUR: Are there quite clear rules around alcohol advertising to young people?

JN: The regulations around alcohol advertising are very strict in terms of explicitly marketing to young people. There are grey areas though, particularly around social media marketing, which is not very well researched – a lot of activity goes on there. Also, advertising is self-regulated and there are serious questions to be asked about how effective self-regulation can ever be in this area.

There are questions about how effective age barriers are on websites, how you can prevent young people from following drinks manufacturers on twitter. There are some safeguards on Facebook, because people tend to be honest about their age there, but there’s very little that you can do on Twitter.

EUR: Is this an argument in favour of a complete ban on alcohol advertising?

JN: There are all sorts of problems around social media marketing to young people. Mainstream marketing is a constant process of people sailing close to the wind and seeing what they can get away with.

The thing about social media marketing is that it’s extremely hard to track exactly what the marketers are doing. A lot of the marketing takes the form of conversations established by brands, where the consumers basically do the work for them. By the time a complaint about online advertising has gone through all the various processes and been adjudicated on, the actual marketing communication itself will have been and gone – marketing online works very quickly. So yes, it’s a real problem, and is often one of the grounds on which people call for a complete ban.

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reduction in alcohol consumption?

JN: Yes. This is a bit ironic given that most of these Mediterranean countries drink rather more than we do, and until very recently most of them had much higher rates of alcohol-related disease as well.

We do tend to idealise Mediterranean drinking. To an extent it’s true; the evidence seems to be that if you drink regularly rather than in short bursts then it’s less harmful. But the thing about Mediterranean drinking is the levels at which alcohol is being consumed are often very high, so that the overall harm is often quite high as well.

The problem now in Britain is that we aspire to that Mediterranean approach, so we drink every day, but we also drink to excess.

That’s not really a recipe for great public health.

JN: Advertising doesn’t work in isolation, and I think bans or

EUR: And this leads in to the debate on minimum pricing; would

restrictions can only really work as part of a broader set of policies.

Take smoking – people involved say that banning tobacco advertising contributed to what they call the ‘de-normalisation’ of tobacco. So it made smoking less of an everyday activity. I don’t think an advertising ban would stop problem drinking overnight, but it might be part of a cultural move which denormalises routine alcohol consumption, and so reduces some of the harm caused by drinking.

you expect that to have an impact on consumption?

EUR: What does the international evidence say on this?

JN: There’s a ban on alcohol advertising in France, but consumption has been on a long downward trend there anyway, so it’s hard to identify precisely what role the ban played.

However, we know that advertising to young people increases the likelihood that they will start drinking, and can increase the amount they consume if they are already drinking alcohol.

EUR: Do you expect that a ban on advertising would lead to a

EUR: We still have a culture of quite long working hours, and people often have a drink to relieve stress I suppose…

JN: The funny thing is that that was not the case to anything like the same extent twenty or thirty years ago. And when that was the case people would have gone to the pub.

Nowadays it’s perfectly fine for us to come home and think; ‘long day at work, I think I’ll open a bottle of wine’ and then start drinking it. That’s considered perfectly normal.

That’s a significant cultural change. By and large it was unheard of in most of the population even twenty years ago, never mind forty years ago. So those kinds of things can change quite dramatically.

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JN: There’s lots of evidence from Europe that pricing affects consumption, particularly from the Nordic countries. They have a history of quite strict price controls on alcohol that were overruled by the European Union on accession, and in a couple of cases there were noticeable increases in consumption. Recent research from Canada, where some provinces have a form of minimum unit pricing, shows it is associated with significant reductions in alcohol-related harms.

However, the detailed effects of minimum unit pricing are complex, and we do still rely primarily on economic models to predict the impact. On the one hand minimum unit pricing is very intuitive – you just go; ‘cheap alcohol is the problem, so we’ll just set a floor price.’

But on the other hand, when you look at the models, the way it’s predicted to work across the population is actually quite complicated.

I think one of the problems around the debate on minimum unit pricing in the UK is that the expected impacts of policy are often poorly understood – even among Ministers.

EUR: Is this an issue you plan to explore? What are your research priorities?

EUR: France and the Mediterranean countries are often held up

JN: Our current flagship project is with Liverpool John Moores

as an example of a more responsible attitude to drinking…

University looking at a phenomenon which they’ve called the

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alcohol-harm paradox. Levels of alcohol consumption are similar across different socio-economic groups. In fact, they’re slightly higher in more affluent households. But if you look at alcohol-related harms, particularly alcohol-related health harms, they’re between five and six times higher in the most deprived households. It’s something of a mystery why that’s the case.

The project with John Moores is looking to understand why the harms that alcohol causes are skewed towards areas of deprivation; whether it’s the way people drink, diet, access to healthcare and treatment.

We’ve funded a lot of work on brief interventions to identify and tackle problem drinking, and are currently exploring how these can be effectively delivered in a range of settings. We are also looking in some detail at issues around social media: how alcohol marketing operates in that environment, how attitudes to alcohol are shaped by social media and so forth. We are currently working with many of the leading alcohol research centres in the UK, so are very excited about the findings that will emerge over the next couple of years.

We want to understand how harm works in a more detailed way, how interventions work, and how culture can be affected by policy.

conflict with commercial interests, and Governments throughout history have struggled to manage this tension.

EUR: Is it about balancing values and evidence in a way?

JN: We aim to provide the best quality evidence to inform the debate. We want to explore the areas that need exploring so that people will have the best possible information on which to make those political decisions. There’s an interesting debate about the role of evidence in policy though. Policy needs to be evidencebased, but it is also about values. We are not in the business of trying to influence the values on which people make decisions, but we are interested in saying; ‘whatever your values are, this is the evidence you need to work from.’

www.alcoholresearchuk.org

EUR: Is it fair to say that the UK Government is being pulled in several different directions?

JN: On the one hand the Conservatives have got a free market gene, which would tell them not to intervene in the market. But on the other hand they’ve got a kind of moral conservative gene, which says they need to control bad behaviour. Those two things go head-to-head when it comes to alcohol.

They are also subject to constant pressure from industry to maintain and hands-off approach to regulation. The current challenge to minimum unit pricing, being led by the Scotch Whisky Association along with groups like the Wine and Spirits Trade Association, is a clear example of industry pressure on Government. The reality is that public health priorities often

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Dr James Nicholls, Research Manager at Alcohol Research UK

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Molten carbonate fuel cells could have a significant role to play in reducing society’s overall carbon footprint, but contaminants can limit their lifetime and effectiveness. Dr Stephen McPhail of the MCFCContex project tells us about their research into how to prevent the contamination of the fuel cell stack

The future of fuel cells Reducing our carbon footprint is widely acknowledged as one of modern society’s top priorities. Molten carbonate fuel cells offer rich potential in these terms as a way to both capture CO2 emissions and provide a source of renewable energy, but the presence of contaminants can cause them to degrade and lose effectiveness over their lifetime, an issue researchers from the MCFC Contex project are working to address. “We’re looking at the degradation phenomena in molten carbonate fuel cells (MCFCs), which are fed with biogas from waste water treatment. We’re looking especially at how to prevent the contamination of the fuel cell stack from all the contaminants that are likely to come from the biogas,” outlines Dr Stephen McPhail, the project’s scientific coordinator. In MCFCs any hydrocarbon fuel can be converted into electricity, but fuel processing and

conditioning (i.e. purification) need to be specifically and carefully designed; Dr McPhail says monitoring gas quality is an important issue in this regard. “We aim to ensure that the right quality of fuel is sent to the MCFC stack,” he explains. “That is important because it allows you to control the stack and possibly intervene if critical conditions arise. It also allows you to really optimise the design of the clean-up system, so that you don’t over-dimension it – or under-dimension it for that matter.”

Carbon capture During operation of the MCFC, fuel is fed to the anode side where electricity is generated, and an oxidant – usually air – is fed to the cathode side, which releases the energy from the fuel without burning it: this is the secret of the MCFC’s ultra-clean power generation. In the process, CO2 is extracted from the cathode stream, which opens up a potentially enormous range of

new applications. The project is also looking at using MCFCs in the outlet streams of conventional, combustion-based power plants to separate the CO2 in exhaust fumes, which could help countries reduce emissions in line with the targets set out in the Kyoto and Lisbon protocols. While developing renewable energy would seem the most sustainable, long-term route to this goal, Dr McPhail believes it’s also important to think about more immediate measures.

“Carbon capture and sequestration is a technology that bridges to a future energy system in which there’ll be much more input from renewables,” he says. In the case of both carbon separation and when used with biogas from waste water treatment, the presence of contaminants can affect the performance of MCFCs. “The most important contaminants are of either sulphurous or silicon origin. They are the main contaminants we’re looking at,” continues Dr McPhail. “With the CO2 separator we’re looking at a different kind of gas, the tailpipe gas from a power plant. There the sulphurous oxides are the main contaminants - they react electrochemically with the anode, which is on the fuel side of the MCFC.”

Aerial view of Waste-Water treatment facility at Matar ó, Spain

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These contaminants can have a significant impact on the effectiveness of a fuel cell. When sulphur enters an MCFC it reacts in a negative way, in the sense that it almost de-activates the nickel, which is the active material in the anode.

“The nickel is usually used to make the hydrogen react, but if sulphur is mixed in with the hydrogen then the sulphur reacts with the nickel preferentially over the hydrogen. So it creates a nickel sulphide species which is no longer active towards the hydrogen reaction. So basically what you have is a gradual loss in performance of the fuel cell that can even lead to a catastrophic failure if the sulphur is significant, or if exposure is longer than a certain time. Siloxanes have a different effect. They are basically glassy compounds – the risk there is that they deposit on the fuel cell and create a completely inactive silicon layer,” says Dr McPhail. With carbon separation, the project is looking at the contaminants on the air side. “The fuel cell will be fed on the fuel side with a regular fuel, like natural gas, which is clean. On the cathode side – the air side – it would be fed with the outlet gases from a conventional power plant (a coal-fired plant for example) and it would extract the CO2 from there, avoiding its emission to the atmosphere where it would increase the greenhouse effect,” explains Dr McPhail.

A lot of combustion products are filtered out before the flue gas is emitted into the atmosphere to meet existing regulations on emissions of nitrous oxides, sulphurous oxides and organic compounds. These contaminants have different effects on the performance of

the fuel cell. “The fuel cell is extremely sensitive to sulphur, because it reacts catalytically. Also, sulphur tends to travel through the cell and react at the fuel side, despite the fact that it’s fed at the cathode side. On the other hand, other contaminants like nitrous oxides seem to have no effect on the fuel cell,” says Dr McPhail. On the biogas side of the project’s work, researchers are looking at the way the fuel cell behaves with different biogas compositions, especially from waste-water treatment. “We’re looking at a kind of validation and

advised that even a low level is unacceptable. “It’s much more costeffective to focus on the clean-up system, and make it totally reliable than to try and develop a fuel cell stack that is more resistant to these very insidious contaminants,” explains Dr McPhail. “Our work on the design of an optimal clean-up system will lead to a prototype that will be run directly at a municipal waste-water treatment site in Spain.” The composition of the gas is an important issue in this regard, so the project is also working to develop a system to detect gas composition

We’re looking at the degradation phenomena in molten carbonate fuel cells, which are fed with biogas from waste water treatment. We’re looking especially at how to avoid the contamination of the fuel cell stack from all the contaminants that are likely to come from the biogas benchmarking of the cell components with different biogas compositions,” continues Dr McPhail. “We started an investigation into the maximum toxicity levels acceptable for the fuel cell stack.

Now we’re shifting more towards the secondary application of the fuel cell and seeing what the effect is of cathode-side pollutants like sulphurous oxides. The contaminant effects there are rather unknown because of this mechanism that transports the sulphurous oxides from the air side to the fuel side.”

This research is in line with feedback from industry. While MCFCs can still function with some level of contamination, the project’s industrial partners have

and contaminants. “We’re looking at an innovative system for measuring the complete composition of the biogas in real time, so we have a continuous, sensitive system that controls the quality of the gas going through the clean-up system and coming out,” outlines Dr McPhail. “That system is being worked on by the Technical University of Munich, and it couples laserinduced plasma spectroscopy with Raman spectroscopy to analyse the main components and the trace contaminants.

These trace contaminants are the most important, because they can potentially destroy the stack – it’s a real challenge to detect really low concentrations of contaminants on line, in real-time.”

Waste-Water treatment facility at Matar ó, Spain

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At a glance

Transportable system

Full Project Title Molten Carbonate Fuel Cell catalyst and stack component degradation and lifetime: Fuel Gas CONTaminant effects and EXtraction strategies (MCFC-CONTEX)

The project aims to develop a transportable system which can provide instant analysis of the gas composition in that particular location. This means combining plasma spectroscopy and Raman spectroscopy in a single machine, which Dr McPhail says is a technically demanding task. “We aim to calibrate all the spectra from these analysis techniques to identify all the various compounds and components in biogas,” he outlines. These compounds will have an impact on the lifetime of the fuel cell, so researchers are also working

Project Objectives • To increase understanding of poisoning mechanisms in the MCFC • Define safe operating condition limits for the MCFC • Set up a numerical model for prediction of contaminant-induced degradation effects • Develop a prototypal clean-up system optimized for upgrading waste-water biogas to MCFC requirements • Develop a reliable trace species detection system for monitoring of fuel quality and process control Consortium Partners • ENEA – Italian National Agency for New Technologies, Energy and Sustainable Economic Development (I) • Technische Universität München (D) • TUBITAK Marmara Research Centre (TK) • Università di Genova – DICAT (I) • Kungliga Tekniska Högskolan (S) • OVMICCPET (RO) • Joint Research Centre (B) • University of Perugia (I) • CETaqua Water Technology Centre (E) Contact Details Project Coordinator, Dr.Ing. Stephen McPhail Unit Renewable Sources, Hydrogen and Fuel Cells Via Anguillarese 301 00123 Rome - ITALY T: +39 06 3048 4926/4869 F: +39 06 3048 3190 E: stephen.mcphail@enea.it W: http://mcfc-contex.enea.it/ S.J. McPhail, V. Cigolotti, A. Moreno (2012), “Fuel Cells in the Waste-to-Energy Chain - Distributed Generation through Non-Conventional Fuels and Fuel Cells”, Springer, London. ISBN 978-1-4471-2368-2

As recently as ten years ago molten carbonate fuel cells lasted a maximum of about 20,000 hours, even in perfectly clean and controlled conditions. Following several important research advances they’re now guaranteed for about 40,000 hours, equating to around five years of operation; this is a significant improvement, but Dr McPhail says there is still room for further development. “MCFCs work through a very clean process, but because of that their operating conditions need to be carefully controlled. These active components – the anodes, cathodes and electrolytes – do tend

Carbon capture and sequestration is a technology that bridges to a future energy system in which there’ll be much more input from renewables on models to predict how certain conditions will affect the performance of the stack over time. “We’re really interested in having a model that can predict how certain conditions will influence the performance of the stack over 10,000, 20,000, 30,000 hours. It would be very beneficial to have a model that can accurately respond to all the variations in composition that we see, so that its kinetic behaviour and its reaction to changes in the inputs is representative of what happens in a real fuel cell,” says Dr McPhail. “So what happens if I change the fuel composition from a 60–40 balance between methane and CO2 to 40-60, or if I change the humidity level from 10 per cent to 50 per cent? And how will that affect the ultimate lifetime – and therefore payback time – of the MCFC stack?”

to age in operation,” he says. The MCFC is already well positioned in the commercial market, with sizes ranging from 300 kilowatts to multi-megawatts; Dr McPhail says the MCFC should now target the double figure scale of megawatts. “This is a sought after size in power generation in terms of de-centralisation, moving away from big, centralised power plants controlled and managed by extremely big multi-nationals and the fuel industry, to a more distributed system which could work better for large organisations,” he outlines. “Large farms, food industries, municipal facilities etc. often have a lot of organic waste to get rid of. That is a cost item. If you can convert it into fuel, and that fuel to highly efficient and ultra-clean electricity, which can be done with these waste flows, you can turn cost into profit.”

Dr.Ing. Stephen McPhail

Project Coordinator

Mechanical Engineer specialising in fuel cell systems, PhD in microfluidics, professionally active in research on high-temperature fuel cells since 2007, especially in combination with renewable energy sources. Member of the “Advanced Fuel Cells” Implementing Agreement of the IEA (Annexes 23 and 24) and of Working Group 11 (SOFC) of the IEC’s Technical Committee 105.

900 kW MCFC power plant running on biogas from Waste water treatment (Tulare, USA)

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The world’s climate system changed dramatically during the mid-Pleistocene transition around a million years ago, but debate continues over the main causes. By in-situ analysis of ice from deep within ice sheets the European Research Council Advanced Grant ICE & LASERS project aims to shed new light on the topic, as principal investigator Dr Jérôme Chappellaz explains

Unlocking the secrets of the Antarctic ice-sheet The climate system changed dramatically during the mid-Pleistocene transition, from inter-glacial climatic sequences, where an inter-glacial period occurred every 40,000 years, to a climate cycle with a typical periodicity of 100,000 years. The question of what drove this change, which occurred around a million years ago, is still the subject of intense debate; by looking at ice from deep in the Antarctic ice-sheet, researchers from the ICE & LASERS project hope to shed new light on the topic. “One hypothesis is that this change was related to the concentration of greenhouse gases in the atmosphere. So we need to precisely evaluate this concentration at that time, and the only way to do that is to use ice cores,” says Dr Jérôme Chappellaz, the project’s scientific coordinator. “Our first workpackage deals with developing a new laser instrument which would be able to qualify a site in Antarctica where we could get ice as much as a million years old.”

The second part of the project uses techniques from both ice core science and laser physics to analyse the greenhouse gases in ice cores. Researchers in the project are developing new instruments for laboratory applications to accurately measure the isotopic ratios of greenhouse gases such as methane and CO2, as well as other trace gases such as carbon monoxide.

“That is, we actually look at the changes in greenhouse gas concentration in the past; how the composition of the isotopes within these greenhouse gases has changed. The reason for that is to establish constraints on why greenhouse gas concentrations change,” explains Dr

Chappellaz. It has historically been very difficult for scientists to measure the isotopic composition of greenhouse gases, as ice core samples were very small and the signals correspondingly weak, an issue Dr Chappellaz is working to address.

“With these laser instruments we plan to make progress both on the accuracy and the speed of acquiring measurements, so that we can gain more reliable statistics,” he outlines.

These measurements can help researchers understand the mechanisms by which greenhouse gases are either released into the atmosphere or removed from it. A molecule of CO2 is comprised of one atom of carbon and two atoms of oxygen; the vast majority of these carbon atoms are C12, which has six neutrons and six protons, but Dr Chappellaz is looking in particular at the C13 isotope, which has an additional neutron. “It turns out that the amount of C13 in a given organic element can change depending on the way the carbon was

Ice core drilling in the Taylor Glacier blue ice field, Antarctica © Xavier Faïn, CNRS/LGGE/IPEV

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exchanged with a different reservoir. We look at the evolution through time of this tiny amount of C13 in the molecules of CO2 in the atmosphere,” he outlines. This work is crucial to understanding the feedbacks between climate and the carbon cycle. “The mid-Pleistocene transition may have led to real changes in greenhouse gas concentration. By looking at that we can evaluate what we call the climate sensitivity – by how much climate changes naturally, when you change the concentration of greenhouse gases by a given amount,” says Dr Chappellaz.

Ice cores Actually getting the ice cores in the first place is enormously complex and expensive though. The oldest ice brought to the surface so far is 800,000 years of age from a depth of around 3,260 metres; it is difficult to locate where to drill the ice cores the project is looking for at these kinds of extreme depths. “We usually use radar profiles to estimate where to go in Antarctica, which give us internal echoes in the ice, and we can track these echoes to former drilling sites. But when we get close to the bedrock – the bottom of the ice-sheet – these echoes become very weak. Then if

we use an ice-sheet model, model the flow of the ice through time and try to date the ice layers inside the ice sheet, the uncertainties are very large,” explains Dr Chappellaz. The project is developing a probe which Dr Chappellaz believes will enable researchers to identify suitable sites much faster than is currently possible. “We want to evaluate if a site, which has been fully estimated from ice modelling and radar, is really the right site. We also want to do it fast – within a single season in Antarctica,” he stresses.

The probe will be able to not only qualify potential sites but also quantify the climate variation, helping researchers get the most important information on climate and greenhouse gases. A laser instrument is embedded in the probe, so researchers can make measurements in situ, without needing to bring ice cores back to the surface. “We’re sending the probe from the surface down to the bedrock so we will acquire a full profile – we’ll get information about climate and greenhouse gases at a range of depths.

This allows us to check the continuity – we can check if there is any inversion of layering, any folding due to ice flow which would compromise the record. We can also

validate the behaviour of the probe itself as we already have data on greenhouse gases and climate in Antarctica for the last 800,000 years thanks to the EPICA ice core drilling,” outlines Dr Chappellaz.

“However, the only information we have at the moment on the mid-Pleistocene transition comes from ocean sediments.”

These marine sediments have provided researchers with a wealth of information about climate during the mid-Pleistocene transition, but they haven’t yielded any precise information about atmospheric composition. Research into ice cores is therefore complementary to the data from the marine sediments. “Ice sheets are a unique archive. With the snow layers transforming into ice, they hold a record of environmental conditions and climate in polar regions for hundreds of thousands of years,” points out Dr Chappellaz. Antarctica is also the world’s main reservoir of fresh water and is very sensitive to changes in atmospheric composition. “The amplitude of temperature change in Antarctica is larger than in other regions, because of what we call polar amplification, which means there are much bigger changes in polar regions,” explains Dr Chappellaz. “So typically in Antarctica, when there’s a transition from a glacial to an inter-

General layout of the embedded OFCEAS spectrometer.

The overall length will be ~1200 mm, the diameter will be kept below 70 mm

Background Image: ; Remote field camp on the blue ice field of Taylor Glacier, Antarctica © Xavier Faïn, LGGE/CNRS/IPEV Inset Top: Freshly drilled ice core at Talos Dome, Antarctica © J. Chappellaz, CNRS/LGGE/IPEV Inset Bottom: Detail of internal parts of the laser instrument © Olivier Pascual, LGGE/CNRS

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EU Research

glacial climate, the temperature change is of the order of 9ºC, whereas at the global scale it is on average 5ºC.”

Climate simulations This is just one of the many reasons why Antarctica is so important to understanding the global climate, how it is formed and how it is likely to evolve.

The behaviour of the ice-sheets is central to future changes in sea levels, while the interaction between ice dynamics and the Austral ocean will affect CO2 exchanges, all issues which will affect the future evolution of the climate. “Climate simulations rely on climate models, which need to be tested against past conditions.

We bring information about past climate changes and sensitivity to CO2 changes, and the climate models running for 21st century simulations will have to be evaluated against the data we’re going to produce. That’s how to improve their credibility,” says Dr Chappellaz. This data can also be correlated with specific historical events. “We have a very good record of climate changes in Antarctica for the last millennium, where we can see the impact of natural volcanic eruptions.

Additionally we can look at the possible

human contribution to biomass burning changes,” continues Dr Chappellaz.

This research is highly relevant to our understanding of the global climate, yet with the project gaining funding from the ERC, they also have the opportunity to branch out into other areas of interest, such as probing the world’s oceans for studying dissolved gases. This high level of academic freedom is greatly valued by Dr Chappellaz.

“Scientific progress often happens at the edge of the original topic of interest. So it’s great that the ERC provides us with the opportunity to look in any kind of scientific direction,” he says. The administrative burden is also reasonably light, so researchers can really focus on the science, and they have the flexibility to adapt to emerging evidence. “If you change your mind as the PI of an ERC-funded project you are allowed to do it, because the ERC understand how science works,” explains Dr Chappellaz. “I would really encourage funding bodies to move as much as possible towards the spirit of the ERC. That is, to place more confidence in the researcher, to make wide open calls for proposals on very wide topics, and to limit the narrowing down that we see today on the central questions that projects address.”

Climate simulations rely on climate models, which need to be tested against past conditions. We bring information about past climate changes and sensitivity to CO2 changes, and the climate models running for 21st century simulations will have to be evaluated against the data we’re going to produce

At a glance Full Project Title Innovative Concepts for Extracting climate and atmospheric composition records from polar ice cores using new LASER Sensors (ICE&LASERS) Project Objectives The ERC Advanced Grant ICE&LASERS project aims at developing new tools at the frontier between ice core science and laser physics, in order to address two major challenges in paleoclimate science : the causes of a large climate shift ~1 million years ago, and of natural greenhouse gas concentration changes.

Project Partners • Laboratoire de Glaciologie et Géophysique de l’Environnement (LGGE, CNRS Université Joseph Fourier - Grenoble) • Laboratoire Interdisciplinaire de Physique (LIPhy, CNRS - Université Joseph Fourier - Grenoble) • Laboratoire des Sciences du Climat et de l’Environnement (LSCE, CEA - CNRS Université Versailles St Quentin) • Division Technique de l’Institut National des Sciences de l’Univers (DT-INSU) Project Funding • European Research Council (ERC) Advanced Grant ICE&LASERS • Agence Nationale de la Recherche (ANR) SUBGLACIOR • BNP Paribas Foundation • EquipEX CLIMCOR Contact Details Jérôme Chappellaz Senior Scientist (Directeur de Recherche) at CNRS Laboratoire de Glaciologie et Géophysique de l’Environnement (UMR 5183 CNRS-UJF) 54 rue Molière - Domaine Universitaire BP 96 - 38402 St Martin d’Hères Cedex FRANCE T: +33 (0) 4 76 82 42 64 E: jerome@lgge.obs.ujf-grenoble.fr W: www.iceandlasers.org

Dr Jérôme Chappellaz Senior Scientist

Dr Jérôme Chappellaz is Directeur de Recherche (senior scientist) at CNRS. He conducts research on past climate and greenhouse gas changes based on ice cores drilled in polar regions, developing new tools (notably based on isotope geochemistry) to decipher these changes. This year he receives the Shackleton medal of the European Association of Geochemistry.

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PlugBoat 2013 World Electric & Hybrid Boat Summit

Be part of the event and: • learn from each other’s experience; • present their work and achievements; • find partners to develop synergies & build new projects; • join forces to lobby relevant authorities to get support.

Nice- France, 10th - 11th October 2013

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1st World Electric & Hybrid Boat Summit, aims at providing a global platform to foster exchange of views between R&D actors, industry, authorities, endusers and NGO’s dealing with electric Boats.

www.plugboat.com

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Wireless microsystems for healthcare applications Wireless body area networks hold real potential across a wide range of healthcare and lifestyle applications, including cardiac implants, hearing aids, activity monitors and even pedometers. We spoke to Dr Vincent Peiris of the WiserBAN project about their work in miniaturising the communication layer of wireless body area networks The development of wireless microsystems has been at the core of many recent technical innovations, and researchers continue to explore new ways in which they could be applied. One area in which they could potentially be used is in healthcare and lifestyle-related applications, such as in cardiac implants or hearing aids, as part of an overall wireless body area network bringing together a range of technologies. “You would first need sensors to monitor the various physiological parameters. Then you would need data processing to identify whether everything is working as it should, and then you need radio transmission – in principle to communicate either with other devices worn on the body, or with an external hand-held device,” says Dr Vincent Peiris, coordinator of the WiserBAN project. While the overall system is extremely complex, the main focus of the project is on the wireless communication layer of the system, including some of the local signal

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processing. “The project is not about pushing new sensor technologies or new applicative software, it’s really about miniaturising the communication layer.

It’s a wireless microsystem for healthcare project,” explains Dr Peiris.

The requirements for the technology are driven by the project’s four industrial partners, each focused on a specific application. Their requirements are very stringent, which has allowed researchers

The WiserBAN System on Chip (SoC) is co-assembled with tiny MEMS devices on a 4mm x 4mm 2D System in Package (SiP).

to extract a common set of specifications for the radio layer; one of the key requirements is the size of the microsystem. “We are targeting a complete radio module in the order of 4x4x1mm 3 for this radio layer,” says Dr Peiris. Radio chips are already getting smaller and smaller, now the WiserBAN consortium aims to miniaturise the radio, the microprocessor and the traditional external components altogether by more than one order of magnitude. “One of our strategies is to use or develop technologies which lend themselves to miniaturisation at these levels,” he outlines. “There will be a 2.4 GHz radio in this microsystem, there will also be a microprocessor with DSP (Digital Signal Processing) functionality to do sensor data processing locally.

There is a radio architecture to replace the bulky crystal oscillator with silicon resonator technology, and there is a miniaturisation SiP (System in Package) platform to be able to create tiny modules, kind of 2-D modules that will

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Miniature 2.4GHz antennas

Silicon Resonator MEMS Propagation Study

WiserBAN SiP WiserBAN SoC (2.4GHz RF & DSP chip)

BAW & SAW RF MEMS

WBAN Communication Software

The WiserBAN SiP (System in Package) integrates a heterogenous set of miniature microsystem and microelectronics components into a tiny 3D stack. be stacked one on top of the other in less than 4x4x1 mm 3. The 2.4 GHz radio architecture exploits MEMS and CMOS technologies so as to achieve very efficient wake-up and turn-off times, which is crucial in order not to waste energy and reach long autonomy.”

An end-user driven consortium The wide range of potential applications for such a technology is reflected in the project’s overall structure, which brings together the academic and commercial sectors to share knowledge and expertise.

The French company SORIN is developing cardiac implants, which Dr Peiris says have some specific requirements. “Cardiac implants need to work in a very low-power fashion to ensure several years of autonomy, and that applies also to the wireless communication layer. The radio however is a very power-greedy

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component,” he explains. “The cardiac implant basically stores loads of measured data. Usually a few times per day – although it depends on the medical use case – they will send a burst of information towards the remote monitoring device. Basically during that short moment you have to transmit a lot of data. But once that’s done it goes back to standby mode and a lowpower, low-energy situation. If the implant monitored every single heartbeat and sent information about it continuously, it would really ruin the battery life of the implant.”

Other use cases in the project are quite different, in particular hearing aids, an area in which Siemens Audiology Solutions in Germany is driving the requirements.

“The idea is that this application could give people with a hearing impairment a more comfortable life. For example, when they use their mobile phone or are listening to the radio,” says Dr Peiris. The hearing

instrument would work during most of the day and be re-charged overnight. “In this use case scenario you need fairly high data rates to ensure audio quality that is sufficiently good for voice and music,” continues Dr Peiris.

“A third use case is cochlear implants, which are basically devices that are used for medical rehabilitation of people with serious to profound sensorineural hearing loss. There the idea is to bypass the nonfunctioning part of the cochlea and deliver sound signals directly to the hearing nerve. Cochlear implant systems can be used effectively by both pre-lingually and post-lingually deafened children and adults. For the Austrian company MED-EL who is driving this case, the use of a miniature wireless microsystem that can be embedded directly within the implant will allow it to receive audio signals and convert them into electric pulses needed

EU Research

At a glance to drive the auditory nerve and send the information to the brain which recognizes the signals as sound.”

The fourth use case is insulin pumps, which are used to dispense insulin and at the moment are usually worn around the belt and concealed under the clothes. The idea here, which is driven by the Swiss company Debiotech, is that the patient can connect the device themselves without having to go to a doctor. “It comes in the form of a tiny box that contains an insulin reservoir for around seven days, they plug it into a canula auto-insertion skin patch, it clamps, and then the insulin can be dosed by the device,” explains Dr Peiris. The

with hearing aids, and the other scenario is where the technology is implanted.

“For each of these two scenarios we will have what we call a generic demonstrator platform that lends itself either to be worn or else to be implanted,” says Dr Peiris. The industrialization of the products is outside the scope of WiserBAN, but Dr Peiris is working closely with the project’s industrial partners, who will have a major part to play in the ongoing development of the technology. “We have started the system integration phase of the project which is one of the crucial technology challenges of the WiserBAN project, where we take

One of our strategies is to use or develop technologies which lend themselves to miniaturisation. There will be an ultra-lowpower 2.4 GHz radio in this microsystem, there will also be a microprocessor with what’s called DSP functionality to do data processing locally, and it will enable wireless connectivity for novel solutions for healthcare and lifestyle devices been worn or implanted

Full Project Title Smart miniature low-power wireless microsystem for Body Area (WiserBAN) Project Objectives The WiserBAN project will create an ultra-miniature and ultra low-power RF micro-system for wireless Body Area Networks (BAN) targeting primarily wearable and implanted devices for healthcare, biomedical and lifestyle applications.

Project Funding €7 Million Project Partners There are 13 project partners.

Full details at http://cordis.europa.eu/ search/index.cfm?fuseaction=proj. printdocument&PJ_RCN=11442484 Contact Details Project Coordinator, Vincent Peiris, Head of the RF and Analog IC group, CSEM CH-2002 Neuchâtel Switzerland T: + 41 32 720 5115 E: vincent.peiris@csem.ch W: www.wiserban.eu

Vincent Peiris PhD application here is simply to control and monitor the effectiveness of the insulin pump. “A miniature and low-power wireless link allows people to even monitor their insulin levels with their mobile phone. This is a much more comfortable way to control insulin levels, or wireless capability could even be used to allow an external medical service to monitor the parameters of the device and check that everything is as it should be,” outlines Dr Peiris. “The insulin pump does not necessarily need a high data rate. The notion of the long-term autonomy of the device is applicable here, because with a low-power approach the battery is smaller, meaning that the device the patient wears is smaller. So it’s less obtrusive and more comfortable for the patient, not to mention the improvement in terms of monitoring what’s going on and interacting with the device.”

the individual components and put them together and they have to interact efficiently to enable proper microsystem functionality. Once that is done we will enter the demonstrator, proof-of-concept phase,” he says.

Vincent Peiris holds a PhD from the Swiss Federal Institute of Technology in Lausanne, and has been the Head of the RF and Analog IC Program at CSEM since 1999. His research interests and expertise are in the area of RF CMOS microelectronics and low-power transceiver design for wireless sensor networks and wireless body area networks. He has been project leader for several large size RF transceiver developments involving Swiss and European industrial partners and is currently the Coordinator of the EU FP7WiserBAN project.

Wireless commonality The different use cases will require different settings of the wireless network, but there is some commonality between the different use cases in terms of the architecture of the wireless network, so the project is currently focusing on developing two demonstrator cases. One is where the technology is worn, such as

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Project Coordinator

Tiny WiserBAN 3D-SiP will yield less than 4mm x 4mm x 1mm volume.

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Portable power for electronic devices

When you’re tapping away at your laptop it’s easy to forget that portable electronic devices depend on a reliable source of energy. We spoke to Professor Aarne Halme and Anders Lundblad of the ISH2SUP project, supported by Fuel Cell and Hydrogen Joint Undertaking (FCH-JU), about their research into novel solutions for hydrogen storage on both the mobile and portable scale Many people today rely on portable electronic devices like phones and laptops in their everyday lives, using them in the office, at home or to work remotely. We increasingly expect to be able to use these devices even in remote areas, but this still depends on a reliable and logistically easy source of portable energy, an area which forms the primary research focus of the

Prototype power pack

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ISH2 project. “The project’s main goal essentially is to develop technology to power-up portable electronic devices in situations where the grid is not immediately available,” says Aarne Halme, Professor of Automation Technology at Aalto University, the project’s technical coordinator. Researchers are developing two concepts in the project, and also comparing their capabilities with respect to different types of applications. “One is a cassette which is based on sodium borohydride (SBH). If you react SBH with water then hydrogen is released – the hydrogen is then used in micro fuel cells, which can power up electronic devices,” continues Professor Halme. “The second concept is different. It uses alcohol – ethanol could also be used, but in this case we’re using methanol. The methanol is electrolysed; it’s fed into an electrolyser, which splits it into carbon dioxide and

hydrogen. The hydrogen is removed and fed to the fuel cell, which powers up the electronic device.”

Low-temperature technologies These two concepts are both so-called low temperature technologies, and while they have not yet reached practical application the commercial sector is involved in their development. The ISH2

Prototype power pack internal view

EU Research

system can be thought of as a hybrid, comprised of a hydrogen production unit and a PEM fuel cell, which is being developed by Swedish company myFC. “We are supplying the fuel cell and electronics for a demonstrator device,” says Anders Lundblad, the company’s founder and Chief Technology Officer.

Where electrolysing water generates hydrogen, the fuel cell in effect performs the reverse function. “You take hydrogen and oxygen, and generate electricity from that. So you can actually generate hydrogen from water, and then use it in a fuel cell. However, the problem is that you need more energy to generate that electricity than you get from the fuel cell.

If you start with water to generate hydrogen, then go back to water, you lose something in the process because of catalytic losses,” explains Lundblad. “But you need so little energy to electrolyse methanol that if you burn the hydrogen you get out of it in a fuel cell then you will get excess energy, as long as you have a well-designed system.”

The power system includes also a rechargeable battery for both start-up purposes and to support the fuel cell in case it doesn’t produce enough energy to

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The NaBH4 cartridge development (CEA) charge the electronic device. This can be thought of in a similar way to a hybrid car, where a back-up battery can be used

so far; a five watt charger which is likely to be used mainly for mobile phones and a 10 watt charger for mini-laptops/ tablets, while researchers are also investigating which of the two concepts are best suited to particular applications.

“Both the SBH and methanol concepts have some of their own features, which we are exploring to see what kinds of applications they could be used in,” outlines Professor Halme. “Both of these technologies will be further developed in certain products. It might be that this SBH technology could be provided in quite small cartridges which people could purchase from local shops.”

Both the sodium borohydride and methanol concepts have some of their own features, which we are exploring to see what kinds of applications they could be used in to support the engine when required. “If you have more power than is needed to drive the car then you charge the battery, while if the engine has less than is needed then you take energy from the battery,” says Lundblad.

Two demonstrator products have been made

For the moment however the project is focused on developing novel, portable solutions for hydrogen storage.

Researchers are developing technology designed to release hydrogen from methanol and SBH; Professor Halme says both concepts are able to generate

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At a glance Full Project Title In situ H2 supply technology for micro fuel cells powering mobile electronics appliances (ISH2UP) Project Objectives The main objective was to research and develop fuelling systems for micro-fuel cells based on in-situ production of hydrogen using two new concepts. One concept is based on NaBH4 as the fuel and the other on utilising electrolysis of methanol. The primary application area is fuel cell based power sources of mobile and portable electronic appliances.

Project Funding Budget: €1,7 Million EU funding: €1 Million Project Partners •A alto University, Finland, Coordinator • CEA, France • myFC, Sweden • Hydrocell, Finland Contact Details Project Coordinator, Dr Aarne Halme, Professor emeritus, Aalto University, Director, Centre of Excellence in Generic Intelligent Machines T: +358 50 555 3390 E: aarne.halme@aalto.fi W: http://autsys.tkk.fi/en/ISH2

Dr Aarne Halme

Project Coordinator

Professor Dr Aarne Halme is emeritus professor of automation technology and the Head of Centre of Excellence in Generic Intelligent Machines at Aalto University. The Centre works among other things in the field of new energy technology, such as fuel cells and hybrid power systems. Fuel cell research is focused to small scale applications as well as applying PEM technology as part of hybrid energy systems in intelligent vehicles.

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hydrogen on demand, which can then be used to power-up an electronic device. “In both cases the hydrogen is still in a chemical compound before we release it in situ. The SBH for example is contained in a normal plastic cartridge; when you want to release the hydrogen, you remove a seal (sprint?) from the cartridge and you put the SBH in contact with water. The reaction starts there and it releases hydrogen – the pressure can be controlled easily with a small valve. With the electrolyser, the current controls the release of the hydrogen from the methanol, so it’s even easier to control the release of the hydrogen,” he outlines. The power requirements of phones and laptops vary, so the project is also developing a control mechanism. “This mechanism controls the current of the electrolyser or the output pressure of the SBH cassette. This means the hydrogen required to generate the power needed at the time is obtained from the storage, and not more,” explains Professor Halme.

Conventional chargers This approach offers more flexibility than conventional chargers, enabling people to charge their electronic devices even in remote areas. Safety is of course paramount if the concept is to be commercialised, and while it is logistically very difficult to transport hydrogen, Professor Halme says there are no such difficulties with methanol. “It’s not a problem to transport our fuels. Both methanol and SBH cartridges are allowed on airplanes as long as they are certified,” he outlines. Professor Halme and his colleagues are looking towards the potential commercial applications of their research, while they are also investigating

alternatives to methanol and SBH. “We are very interested in replacing methanol with ethanol,” he continues. “There are some problems in terms of chemical engineering at the moment, but it looks like it is possible. So this widens the opportunity to commercialise this technology, because ethanol is available everywhere, so we are trying to make the concept work also with ethanol. The current problem with ethanol is that in the electrolysis process some bi-products are produced, which might be harmful for the platinum catalyst.”

Researchers are investigating ways to protect the catalyst in the ethanol case, which as outlined above is well suited to the commercial market. The project is working with the commercial sector to get their concept onto the market, which Professor Halme believes has some significant advantages over current technology used in small-scale charging devices. “We are competing in a way with so-called direct methanol fuel cell (DMFC) technology, which is the dominant technology for building smallscale charging devices for non-grid use,” he outlines. Methanol can be loaded in much higher concentrations in the ISH 2 concept than in the DMFC technology, in which methanol has to be diluted with water to quite a high degree before it can be fed it into the fuel cell; the project is now looking to bring these kinds of benefits to the commercial marketplace.

“The Intellectual Property Rights are owned by the university at the moment.

We are looking at whether we could establish a start-up company out of that, or license the technology further to some established companies,” says Professor Halme.

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THE ROAD TO FUEL CELL POWER FOR TRANSPORT

According to some estimates, by the year 2030, there could be 1.6 million electric vehicles powered by fuel cells using Britain’s roads. These vehicles would be able to refuel at one of the 1,150 hydrogen refuelling stations required to provide full national coverage

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onsidering that many people do not expect the full commercial launch of fuel cell powered cars, or fuel cell electric vehicles (FCEVs), to really begin until 2015, and that the UK is not in the forefront of countries preparing for such a launch - Germany, Scandinavia, Japan and the USA, in the form of California, are in the vanguard - the UK’s position could still be quite impressive.

That is the view of the UK H2 Mobility Project, which comprises government and industry bodies.

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The H2 Mobility Project is one of many global initiatives focussed on the introduction of fuel cell technology. In Europe, the Fuel Cell and Hydrogen Joint Undertaking (FCH JU) is a public-private partnership between the European Commission, industry and research communities that was established in 2008, and recognises that hydrogen is one the very few near-zero-emissions energy carriers that could play an important role in the future EU low-carbon energy and transport sectors.

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Fuel cells combine hydrogen with oxygen to produce water and, in the process, electricity is formed by an electro-chemical reaction. With a fuel cell, hydrogen and air flow constantly into the cell so it never goes dead, unlike an electric battery which can become exhausted. As long as there is a flow of chemicals hydrogen and oxygen - into the cell, electricity will be delivered.

Hydrogen, produced by renewable power and used locally, can de-carbonise transport and reduce air pollutants at the local, especially urban, level.

The European Union is committed to reducing its greenhouse gas (GHG) emissions by 80 per cent by 2050, which will require a 95 per cent reduction in road transport emissions. This will focus on two complementary objectives - increasing the share of public transport and promoting the use of lowemission vehicles.

In 2009, the FCH JU, launched originally as a joint technology initiative (JTI), launched a €140 million call for research topics under the 7th Framework Programme, whose future could be as part of the Horizon 2020 programme, which was launched by the European Commission in the summer of 2012. Around half of the €140 million funding was provided by the commission, matched by in-kind contributions of industrial partners.

Transport was one of the four application areas - the others being stationary power, hydrogen production and early markets, plus another crossing these for support activities. Within the application areas, the aim of many project topics was to accelerate the introduction of fuel cell and hydrogen energy topics on to the market two to five years sooner than estimated, by investigating bottlenecks in the whole range of applications.

The JTI wanted not just breakthrough research but to realise real demonstration projects, including “the use of hydrogen-fuelled buses and fuel cell vehicles”.

It also wanted to help develop hydrogen storage and improve fuel cells’ durability, performance and cost-efficiency to make green applications such as power stations and laptops ready for the market.

On the buses

Refueling station, 2007, Air Liquide (and above with car)

Fuel cell powered laptop

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Because bus networks are, by the nature of their business, environmentally sound - the more people use buses, the fewer will use cars - it is not surprising that one of the current FCH JU projects is the Clean Hydrogen in European Cities Project (CHIC). This project involves integrating 26 FCH buses in daily public transport operations and bus routes and the respective infrastructure in five cities across Europe - Aargau (Switzerland), Bolzano/Bozen (Italy), London (GB), Milan (Italy) and Oslo (Norway). An important part of the project will be to assess the environmental, economic and social impacts of hydrogen-powered buses.

CHIC is supported by the FCH JU with €26 million of funding, and has 25 partners across Europe, along with industrial partners for vehicle supply and refuelling infrastructure. CHIC’s objective is to move these demonstration buses towards full commercialisation starting in 2015, although Fuel Cell Today believes that widespread deployment could happen as early as 2014. This view is based on the number of commercial bus manufacturers now involved in developing and trialling fuel cell models, coupled with the innovation and cost reductions being seen from the suppliers of fuel cell systems for this application.

European bus manufacturers that have supplied buses for demonstrations include Van Hool, Rampini, VDL, APTS and Wrightbus –

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Hydrogen and oxygen evolution in transparent alkaline electrolyser.

Fuel cell cars can achieve much higher conversion efficiencies than conventional engines, that use only 20-25 per cent of the fuel’s energy with fuel cells from Ballard, UTC Power and Hydrogenics in most cases.

Daimler uses two of its own fuel cells in its bus - these are the same module as those in its FCEV - but the next-generation Citaro fuel cell hybrid buses boast a 25 per cent greater range, 35 per cent increase in fuel cell efficiency and a 50 per cent greater durability than its previous generation bus used in the CUTE project while at the same time reducing fuel consumption by 45 per cent.

The CUTE project, which ran from 2006-2009 under the Sixth Framework, comprised 47 fuel cell-powered buses in regular public transport service in ten cities on three continents.

Among its conclusions was that the purchase price of future buses had to be reduced and that the hydrogen infrastructure had to be developed to enable buses to operate with minimal special support as part of a standard public bus fleet.

Cars for the future Before looking at the infrastructure implications for the widespread introduction of fuel cell-powered buses, it may be helpful to examine the status of the FCEV car, as these are the vehicles that generate most coverage in the media.

The new generation FCEVs dispense with the internal combustion engine, replacing it with fuel cell and electric motors, with the fuel cell providing electricity to power the motors. FCEVs are similar to battery-electric cars, which have been around since the 1950s, and hybrid electric vehicles that combine an electric motor and internal combustion engine have also found some market success.

Fuel cell cars can achieve much higher conversion efficiencies than conventional engines, that use only 20-25 per cent of the fuel’s energy. Fuel cells can achieve up to 60 per cent and the fuel cell with the greatest potential for automotive applications is the proton exchange membrane fuel cell (PEMFC), which takes hydrogen and turns it into electricity to drive a vehicle. But the issue with hydrogen is on-board storage.

Hydrogen is the favourite fuel for fuel cells because it is quite easy to create through electrolysis or by extracting it from natural gas, but its low density presents a challenge for on-board storage. Compressed containers rated at from 350 bar up to 700 bar have been developed. Hydrogen gas refuelling has been developed and proven safe and easy to use over a number of years. Refuelling is very similar to petrol refuelling, with a flexible hose connection between the dispenser and the car.

On-board hydrogen storage is more efficient and effective than on-board reforming a hydrogen-rich fuel, as the equipment to do this is complicated, bulky and heavy, added to which would be the weight of the methanol.

Most major car manufacturers are aiming towards large-scale production from 2015, but the UK’s Institute for Public Policy Research (IPPR) has warned that, despite earlier initiatives, the UK risks being left behind.

Despite this, 3,300 new electric vehicles have been registered in the UK over the past two years and the Department of Transport recently made a further £37 million available to install more roadside and home garage battery-charging equipment.

In the USA, General Motors (GM), which undertook pioneering fuel cell technology work in 1968, says production ought to be ready by 2015 “in specific geographic regions where refuelling infrastructures exist.”

GM’s Project Driveway, begun in 2007, is said to be the largest-ever fuel cell demonstration fleet, with more than 100 Chevy Equinox vehicles, which have now accumulated more than 2.5 million miles. GM is also involved in a programme with the Gas Company of Hawaii to co-operate on a fuelling infrastructure that would take hydrogen from key points along the Gas Company’s 1,100 mile-synthetic natural gas pipeline for use as transportation for fuel for fuel cell vehicles.

Larger-scale production of a hydrogen-powered vehicle has begun in Korea, with the

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first Hyundai iX35 Fuel Cell rolling off the assembly line in Ulsan in February 2013. Hyundai plans to make 1,000 cars by 2015, the same year that Toyota and Honda plan to begin serial production, with limited mass production of 10,000 units from 2015 onwards.

The first Hyundai vehicles are targeted largely at the public sector and private fleets. Vehicle lease contracts have already been signed for municipal fleets in Copenhagen, Denmark, and Skåne, Sweden.

Since October 2011, the FCH JU has been providing earlier versions of these vehicles to EU policy makers and the public as fuel cell demonstrators.

Also in Europe, an existing co-operative agreement between BMW and Toyota was extended earlier in 2013 to include fuel cells with the aim of entering the mass market around 2020.

Another fuel cell vehicle partnership, that between Daimler and Ford, gained a third partner with Nissan-Renault. Daimler and its partners anticipate mass production beginning in 2017, following small series production of the Mercedes-Benz B Class F-CELL, which began in 2009. It holds a 700-bar hydrogren tank and has an operating range of about 400 kilometres.

Indeed, one of the major issues for FCEVs is hydrogen refuelling networks and the UK H2 Mobility Project also highlighted the importance of the hydrogen refuelling stations (HRS) infrastructure to the acceptance of fuel cell vehicles. It anticipates that 65 stations across the UK would provide sufficient initial coverage to start the market, covering major population centres, largely through targeting particular areas and national trunk routes.

The UK HRS network, which requires £62 million investment between now and 2020, is anticipated to be able to cover its operating costs by the early 2020s and break-even by the late 2020s, by which time the investment is expected to be £418 million.

Close-to-home refuelling for the whole of the UK could be provided by 2030, with 1,150 HRS stations.

Worldwide, there are currently 208 HRS installations, but with the introduction of fuel cell vehicle demonstration programmes, more stations are being built in cities throughout Europe, adding to the 80 European stations currently in operation. The European total equates to rather more than one third of worldwide capacity.

During 2012, 27 new hydrogen refuelling stations opened throughout the world. The major oil companies , or supermarket chains in the UK, have yet to decide whether to invest in providing hydrogen at the pump.

There is, clearly, still some way to go before the required infrastructure is in place to attract the major manufacturers to be able to commit to full-scale and economically attractive production rates.

The price of FCEVs also has to be attractive to the consumer. The UK H2 Mobility Project found that 10 per cent of the UK car-buying population would consider buying FCEVs even with an adverse total cost of ownership of diesel vehicles. For the other 90 per cent, the cost comparison would need to be very similar. Nevertheless, there is a clear opportunity for FCEV deployment in the UK.

www.fch-ju.eu

Project: Clean Hydrogen In European Cities

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Feedback from end-users is crucial to guiding the development of any product, and the machine tool industry is no exception. Marcus Michen of the Transparency project explains how knowledge-based collaboration between component suppliers, machine tool suppliers and end-users will change the way machine tools are designed and operated

Collaboration to boost the machine-tool industry The European machine-tool industry is an important cog in the continental economy, yet component suppliers, machine tool suppliers and end-users often fail to share information effectively.

By fundamentally changing the way production systems are developed and used, the Transparency project could have a significant impact in this area. “One objective of our project is about sharing information. We also aim to improve the different lifecycle constraints or performance predictions, and to improve the way information is provided during the lifecycle of the machine tool,” says Marcus Michen, the project’s scientific coordinator. This could also improve the efficiency of the design process.

“During the design process you have to make predictions, on for example lifecycle costing, or overall equipment effectiveness. For this you have to estimate the usage scenario of this machine tool you are designing, to define the right costs and to choose the right components to build the machine,” explains Michen. “We want to enhance this process by using better quality data. This will mean we can have better predictions based on the usage scenarios for the machine, and therefore for the machine itself, or the kinds of components that should be used.”

not only on the specific or defined cycles at the beginning,” he stresses. This kind of information will be shared via a knowledge base which can be updated with relevant information. “We have a semantic-based wiki system. Inside this wiki system we have developed a model of the machine tool architecture, then there are the relations between the attributes of the

Distributed Collaboration Co-Design Environment.

Active components A second kind of prediction is being implemented in active components.

Researchers have added sensors inside components to track usage, so Michen says it will be easier to predict when they need to go into maintenance. “This is based on the real usage of this component,

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different components and the different groups inside the machine tools, which is our base model. We are using this for what

we call the co-design environment, a developed extension inside the wikisystem, which then guides the designer through the design process, based on the knowledge inside this wiki-system,” continues Michen. “One of the benefits of this wiki system is that it’s easily extendable with new information. You have this semantic layer, but you also have this semantic reasoning inside so that you can have the dependencies between different components, architectures, tools and also new items like reports.”

A component supplier can add information about their component inside the wiki, while machine designers have their own profile. The list of components is centralised in the system, allowing designers access to relevant information. “The designer knows how to define the requirements for the components, and based on the information the supplier puts in the wiki system, they can then get suitable components, choose between them and do first calculations there,” explains Michen. The machine structure itself is based on models that have been developed in this wiki system and co-design environment process, so that the designer can define different levels of detail even at a very early stage of development. “So you have the standard design phase where you design your machine tool in detail. For the Transparency project we defined a predesign phase which allows you to make a detailed estimate of what kind of designs could be useful,” outlines Michen. “It is very helpful to restrict the different architectures relevant for the detailed design phase.”

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The actual end-users of these tools also have a part to play in improving the system. Some information can be sent to the semantic system based on the usage profile of the active components, while end-users can also provide it directly. “Maintenance staff on the shop-floor can also provide information.

You can even have feedback directly from the end-user, the operator themselves, in the form of a report or just comments,” explains Michen. All these different kinds of information can be stored inside the wiki system and will be linked automatically to existing data items inside. During the pre-design phase, the designer can see relevant information for the new design they plan to develop. “The idea is that you collect data over time – then if you have to start a new design, you can look at different kinds of information,” continues Michen. “We started our knowledge system with data from earlier machines. If you are building your first machine tool then you can collect

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information and put it in the wiki system. Suppliers would also put in their data, maybe operators or other people would put in theirs, and then if you start a new design phase you have an improved database. The longer the system operates the better the data in it and the more beneficial it is for both the designer and the end-user.”

and see the usage profile, including several key performance indicators. We can also involve automatic dataexchange processes based on mobile devices if necessary, so we can attach mobile devices to the wiki system,” he outlines. These kinds of interfaces can be provided to not only end-users, but also to operators and maintenance staff. “If

We have a semantic-based wiki system. Inside this wiki system we have developed a kind of model of the machine tool architecture, then there are the relations between the attributes of the different components and the different groups inside the machine tools, which is our base model Data collection The data itself is collected in various different ways. With the active components it is collected through an automated process and then stored inside the component itself, which Michen says opens up further possibilities. “If the end-user allows it then the machine tool supplier can connect to this component

you have an internet connection you can also use Human-Machine Interfaces with the machine, which can directly send data to the wiki system itself, based on the actions on the machine level,” continues Michen. “But the end-user has to allow this process. If they don’t then we only have the experience of the designer and the in-house maintenance

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At a glance people. But we have the possibility, if the end-user allows it, to get more data at different levels.”

then this allows systems more interaction, but we would have to implement those calculations in a more dynamic way,” he says. To implement calculations inside a This approach can currently be used just co-design environment you currently for individual components; the next step have to fill out some values, from which could be to have complete machines with you get results and then proceed with the those kinds of design; Michen components says there could inside.

This be an would give a alternative kind of usage approach. “The “Companies estimate, that more profile for a next step could component and be to make than 50% of their added value is by also a usage these kinds of knowledge; but 50% of the profile for the calcu lations companies state itself, that they use whole machine during the their knowledge only by 20-40%.” based on the lifetime of the status of each equipment, just component, to compare how while Michen it was planned, believes there are also other avenues how it is now, and maybe also to improve which could be explored. “We could the predictions of the tool itself. If you calculate the lifecycle costings and run these calculations also during overall equipment effectiveness and in lifetime you could improve your estimates future also make the consumption of from the beginning of the design phase, resources more efficient. If it’s based on or from the beginning of the machine real shop-floor data rather than estimates tool. This could be the next approach.”

Fraunhofer IAO:

Full Project Title TRANSPARENCY - Adaptive Business Collaboration by progressive knowledge sharing and engineering Project Objectives The vision of TRANSPARENCY is to enable European machine tool builders to establish knowledge-based business collaborations with machine designers, machine tool end users and component suppliers for the design and operation of specialised machine tools.

Contact Details Project Coordinator, Marcus Michen (Dipl.-Inform. (FH) MBE) Fraunhofer Institute for Manufacturing Engineering and Automation IPA Nobelstrasse 12 70569 Stuttgart Germany T: +49 (0) 711 / 970 - 1033 E: Marcus.Michen@ipa.fraunhofer.de W: www.transparency-project.eu Periodic Report Summary http://cordis.europa.eu/fetch?CALLER=NEW_ RESU_TM&ACTION=D&RCN=53119 Web horizon 2020 http://www.2020-horizon.com/ TRANSPARENCY-Adaptive-BusinessCollaboration-by-progressive-knowledgesharing-and-engineering%28TRANSPARENCY %29-s7764.html Web Summary http://www.semafora-systems.com/en/ research-development/

Marcus Michen

Project Coordinator

Marcus Michen is project leader for factory optimisation and data analysis.

He joined Fraunhofer IPA in 2008 and graduated in computer engineering and gained a masters of business engineering. His focus is validation and verification of production and machine data as well as modelling and simulation of logistics and automation processes.

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The countries around the Baltic Sea face many of the same social and economic challenges, so it makes sense to work together. We spoke to Karin Nygård Skalman, Lotten Svensson and Johanna KilpiKoski of the StarDust project about their work to coordinate innovation around the Baltic Sea region

Boosting innovation around the Baltic Sea The countries around the Baltic Sea have a long history of economic and social cooperation, a tradition that is being maintained today. Countries including Germany, Poland, the three Baltic Sea nations, as well as the Nordic countries, face many of the same societal challenges, so it makes sense to work together, says Karin Nygård Skalman of the StarDust project. “The reason behind establishing the project was to integrate our efforts, especially in areas that we see as being particularly important, such as health, transport and clean tech. Those are key pillars of

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the project,” she outlines. The project brings together academia, business and the public sector to develop new solutions to the common challenges facing the countries around the Baltic Sea, which will also help the region compete effectively in the global market. “Sweden has a population of around 9 million, and only 5 million people live in Finland. We are very export-dependent, but we can also cooperate to develop a larger domestic market – that’s one of the major ideas behind the project,” says Ms Nygård Skalman.

Innovation capacity The key to this is capitalising on the skills of companies, researchers and public officials across the region. The project is bringing different partners together to tackle major challenges like protecting clean water, ensuring elderly people are able to stay at home for longer with the help of products and concepts for smart kitchen solutions, and managing marine transport supply chains. “We’re trying to boost our innovation capacity by linking strong research milieus together with companies and public organisations. We aim to do this in a smart and

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complementary way,” explains Ms Nygård Skalman. Effective collaboration between these different partners could then open up new commercial opportunities. “Our objective is to provide a platform for sustainable cooperation and business opportunities in the clean water sector,” says Johanna Kilpi-Koski, coordinator of StarDust’s sub-project Clean Water. “We are helping actors who might have technologies or research results which could later be commercialised and globalised. Our approach is triple-headed – local authorities, companies and the research sector are all working together.”

This approach is designed to accelerate the process of innovation, with a view to product development.

This means combining innovation with an understanding of the commercial market.

“We are combining competences in the entire region to speed up innovation, using smart specialisation on a macroregional level. It is a new approach and we have to learn how to actually work together,” says Ms Nygård Skalman. The

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fruits of this work are already in evidence, with the sub-project developing new solutions that will help elderly people live in comfort and maintain their independence for longer. One example of product development in kitchens comes from Lotten Svensson, coordinator of the

and not from the front. The microwave oven is also easier to handle with big buttons and signs – different solutions are built into the kitchen area.”

These solutions are still at an early stage and are not yet in mass production, but with the demographics of the

We’re trying to boost our innovation capacity by

linking strong research milieus together with companies and public organisations. We aim to do this in a smart way, to boost our innovation capacity

Comfort In Living project: “If you are in a wheelchair it can be difficult to reach some shelves in your kitchen. With our new solutions you can just push a button and the shelf starts to move down to a level where you can reach it. You can also move benches closer to you, so you can come in with the wheelchair and sit by a table. Also, when you put things in the dishwasher, you can stove it from the top

European population changing rapidly, they could well have wider potential. The effectiveness of the solutions does not come at the cost of their aesthetics either, which remains an important consideration, as Ms Svensson is keen to stress. “Design is important to our target group, which is elderly people; they still want to have nice things and to be active,” she says. However, they usually

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Satellite Images ©ESA

At a glance Full Project Title The Strategic Project on Trans-national Commercial Activities in Research & Innovation, Clusters and in SME-Networks (STARDUST) Project Objectives StarDust is a part of the BSR Stars Programme, which is a flagship within the EU Strategy for the Baltic Sea Region. It is a first-of-its-kind innovation programme assembling representatives from ministries and innovation agencies in ten countries with the aim of strengthening competitiveness and economic growth in the Baltic Sea Region.

Project Funding Co-financed by the European Union’s Baltic Sea Region Programme 2007-2013.

Total budget €6.5 million.

Project Partners Co lead partner: Vilma Puriene, Ministry of Economy of the Republic of Lithuania Contact Details Project Coordinator, Karin Nygård Skalman SE-101 58 Stockholm, Sweden Office: Mäster Samuelsgatan 56 T: +46 (0)8-473 3068 E: karin.nygardskalman@vinnova.se W: www.vinnova.se State of the Region Report 2012 “The Top of Europe Bracing Itself for Difficult Times: Baltic Sea Region Collaboration to Sustain Growth”

by Baltic Development Forum, page 89

Karin Nygård Skalman

Project Coordinator

have to make some concessions to their advancing years, so the project is working on product design. “Pressure is on the legs and the back when you sit down, so you need springs that can ‘release’ this pressure. Researchers have developed patented springs for mattresses that really release the pressure on the body so that it’s not on one single point,” explains Ms Svensson. “They are trying to see if they can also use it for chairs, so you don’t get aches and pains when you sit so much. The spring is crucial here – it could also be used for very thin materials on chairs. This is an old technique, but we’re adapting and improving it.”

Target market There is a big market for these kinds of solutions. At the moment they are still fairly expensive, but as they are produced in greater volumes Ms Svensson hopes the price will come down, offering big economic opportunities for the countries around the Baltic Sea. “In my opinion we must look at the global market, because there is a big market for these solutions across the world,” she says. Similarly with protecting water quality, Ms Kilpi-Koski is working closely with other countries in the Baltic Sea region, which could open up new commercial opportunities. “We are working closely with a water management company, SUE Vodokanal, in St Petersburg.

We have a platform with them which gives companies, researchers and other stakeholders the opportunity to share best practice, solutions and technologies with Russian water management companies.

That gives European water companies and universities more business possibilities, as well as more research and development opportunities,” she outlines. “We are now trying to spread our approach throughout the Baltic Sea region, and we have started discussions in Poland and Lithuania to establish a water competence centre similar to the one which already exists in St. Petersburg. This is so that they can educate their water management companies, and also students and pupils, to respect the water supply and waste water treatment facilities.”

The wider goal of this work is to design strong regional hubs that have a global competitive edge. One area with great potential is mobile technology and IT; the project aims to bring together large enterprises with smaller enterprises to encourage technical development. “Many SMEs want to be part of the development of new services and get the chance to cooperate with big companies like Ericsson and Nokia. They can participate and find mechanisms through which they can work together with universities and big companies. The big companies can use the creativity of the SMEs,” says Ms Nygård Skalman. In today’s highly competitive global marketplace, Ms Nygård Skalman believes this kind of collaboration is crucial to strengthening the regional economy.

“One of the strategic ideas here is that it’s usually easier to cooperate with someone who is closer geographically or culturally” she stresses. “This will make us even more fit for cooperating with the rest of Europe and globally.”

Karin Nygård Skalman is Program Director at VINNOVA, the Swedish Agency for innovation, where she leads the BSR Stars Programme.

The project will increase linkage between actors in research and innovation milieus, clusters and SMEs in the macro region and thereby increase prosperity in the region.

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EU Research

Political parties originated as societal organisations, but over time have transformed themselves into professionalised organisations much closer to the state than civil society, raising important questions about how democracy functions. Professor Ingrid van Biezen of Leiden University tells us about her research into the regulation of political parties, and its effects on democracy

Investigating the impact of party regulations on democracy Political parties have historically been structured as societal organisations, typically with large memberships and strong roots in civil society. However, they have now transformed themselves into much more top-down, professionalised organisations, says Ingrid van Biezen, Professor of Comparative Politics at Leiden University. “They have basically seen their societal ‘anchorage’ wither away,” she says.

This does not mean that parties have become less important as political actors, but it does point to changes in how they function in modern representative democracy, an issue at the heart of the Re-conceptualizing party democracy project. “There are several objectives to the project. One is to carry out an empirical investigation of the ways in which the law regulates political parties.

That involves an empirical, comparative analysis of party law in post-war European democracies. We have built an online database to make these data available.

Another is to investigate what the increasingly strong relationship between parties and the state implies for the democratic system and democratic legitimacy,” continues Professor van Biezen.

The role of political parties is now explicitly stated in many countries’ written constitutions, and Professor van Biezen is investigating what these references say about their democratic system. “Do they say something about party finance, party registration or internal party democracy? Or do they stipulate, as many constitutions do, something about the democratic importance of political parties for democracy, political participation or pluralism?” she says. There are important regional differences between the older democracies in Western Europe and those that emerged in postwww.euresearcher.com

communist Europe following the fall of the Berlin Wall, reflecting the different democratic histories of European nations. The project explores these regional variations. “We examine these laws and constitutions for what they tell us about the underlying ideas about political parties and democracy, as well as their effects on the functioning of some aspects of the political system,” says Professor van Biezen.

Relationship with the state Studies have shown that while political parties’ links with society have become weaker, their relationships with the state have grown stronger, fundamentally changing the way democracy works. The project is analysing these links with the state, which may take several forms. “One is the way in which the state regulates or manages political parties. This project aims to investigate how this is done. How do countries regulate the behaviour and activities of political parties? That’s the

empirical dimension,” outlines Professor van Biezen. One important consideration is political finance. “We’re looking at the way in which parties are financed, for instance by state subsidies, and how that is regulated; the sources of income they can accept, or the kinds of expenditure that are permissible and so on. Other important dimensions of party regulation are the party organisation itself, or access to electoral competition,” says Professor van Biezen.

This could mean things like internal party democracy and grass-roots organisation, or registration requirements and eligibility to participate in elections, which directly affect the way the system functions as well as people’s perceptions of it. Professor van Biezen and her team are analysing all European democracies during the entire post-war period to explore the effect of these regulations on the political system. “What is the effect of registration requirements on the openness of the system for instance?

What is the effect of party finance rules

Share of state subsidies to total party income

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on the chances of new parties entering the political arena? What is the impact of rules about internal democracy on the way in which parties function and operate?” she asks. The team are seeking to put this information in a broader context. “We relate these questions to socalled performance indicators. These include satisfaction with democracy, trust in political parties and public confidence in the system,” continues Professor van Biezen.

These indicators are going in a generally downward direction across all European democracies. Party membership has fallen to around 5 per cent of national electorates and voter turnout is falling, while other indicators of conventional political participation are also on the decline.

“Levels of party identification are down and levels of political cynicism are up in many European democracies. Party systems have become much more unstable because people are less and less inclined to vote for the same party from one election to the next,” explains Professor van Biezen. This is not necessarily a bad thing for democracy, but it is undoubtedly transforming our view of political parties.

Having once been viewed as a threat to democracy, they are now generally seen as a public good essential to the democratic process. “I’ve argued, drawing from existing scholarship, that political parties are akin to public utilities, in the sense that they are a public good and it is difficult to see how representative democracy could function without them,” says Professor van Biezen.

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Democratic functions This would suggest that the state has a role to play in ensuring that political parties fulfil their democratic functions effectively, which arose at least in part from the development of mass democracy. At the time the franchise was extended, Professor van Biezen says, the need grew for intermediary organising mechanisms to channel the relationship between citizens and representatives. “The emergence of modern political parties is very much

is under quite heavy attack. “They enjoy little trust and people have less and less confidence in them,” continues Professor van Biezen. “They’re increasingly seen as opportunistic, or even incompetent and corrupt, taking advantage of their access to the resources of the state.”

Party funding is a major issue in these terms, particularly around the concern that private donors may exert an undue influence over political parties. The majority of European countries therefore

This project aims to investigate how the state or manages political parties. How do

regulates countries regulate the behaviour and activities of political parties? That’s the empirical dimension

associated with the rise of modern mass democracy. But that doesn’t mean that they were always viewed positively,” she says.

It’s only in the period since the Second World War that political parties have come to be viewed as necessary and desirable; but at the same time their legitimacy today

Website screenshot

currently subsidise political parties through public funds, but this was not always the case. “The state has always kept political parties at arms length, because they were seen as private societal organisations,” says Professor van Biezen. This meant they could run their business in whatever way they wanted; nowadays party funding is often strictly regulated, but it is not clear if that means political parties are performing their democratic functions more effectively.

“The calls for more transparency on party donations and expenditure, and measures to reduce corruption and so on come at the same time as evidence emerges that political parties, despite their alleged importance for democracy and their unique role as representative agencies, do not seem to be performing so

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At a glance Full Project Title Re-conceptualising party democracy (Party Democracy) Project Objectives 1) to fill a noticeable gap in the literature on the relationship between political parties and the state by providing necessary comparative empirical evidence of the process by which political parties have become regulated by public law in European liberal democracies, the different modalities of party regulation and its development over time.

2) to create a comprehensive and searchable online database of party regulation, which will bring together all references to political parties in the body of law of democratic European states in the post-war period.

3) to contribute to a better theoretical and empirical understanding of the role of political parties within the institutional framework of contemporary representative democracies by creating a bridge between the empirical analysis of political parties and normative democratic theory.

Project Funding €1,619,522

Waves of party regulation well in that role. So there’s a big paradox there,” stresses Professor van Biezen.

The widespread disillusionment with the political process is not solely down to the parties themselves though, and some political scientists argue that true democracy requires active participation and more regular involvement in politics than just voting. However, others take a different view. “Liberal theorists may argue that democracy is essentially a procedure to reconcile conflicting interests and opinions.

They take a less substantive but more procedural view of democracy; as long as people have the opportunity to express their views – during elections for instance but also through other means – and there is sufficient competition between competing views, then the system works,” explains Professor van Biezen. “However, I think that without a critical level of active involvement, legitimation problems are going to become very visible and pronounced. That’s what we’re seeing at the moment.”

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There’s a great deal of scope for further research in this area, and Professor van Biezen is keen to explore the effects of party regulation in more detail, both in terms of its effects on political participation and the legitimacy of the political system. Professor van Biezen also plans to investigate other types of regulations. “We’re working on a project on gender, for example. The most obvious regulatory example here is quotas – the extent to which that promotes or hinders the participation of women,” she outlines. “We also plan to expand this notion of parties as public utilities and look at their relationship with the state, through collaborative research with scholars who investigate party patronage. To what extent do parties have the prerogative and power to make party political appointments within the state apparatus and what does that tell us about their entrenchment within the institutions of the state?”

Contact Details Project Coordinator, Prof. dr. I.C. van Biezen Professor of Comparative Politics Department of Political Science Leiden University PO Box 9555 2300 RB Leiden The Netherlands T: +31 71 527 3779 E: i.c.van.biezen@fsw.leidenuniv.nl W: www.partylaw.leidenuniv.nl

Professor Ingrid van Biezen

Project Coordinator

Ingrid van Biezen is Professor in Comparative Politics at Leiden University.

She has previously taught at the University of Birmingham (UK) and the Johns Hopkins University, and has held Visiting Fellowships at Yale University, the University of California, Irvine, and the European University Institute.

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Developed nations are characterised by not only high levels of material prosperity, but also political and institutional stability that encourages development. We spoke to Professor Torsten Persson of the Statecap project about his research into the role of state building in the development process

Investigating the capacity of the state The prosperity of a nation is closely linked to the strength of state institutions and their ability to peacefully resolve conflicts of interest. The role of the state in the development process is an area of great interest to Professor Torsten Persson, the overall coordinator of the Statecap project. “Statecap is a two-pronged project, dealing with questions that have not really been thought to be connected, at least up to now. One is about the general features of development, in particular the role of the state in the development process,” he says. The project is looking at development as a multi-dimensional

violence, in the form of repression or even civil war. So what we mean by development is this clustering of different outcomes, not solely GDP per capita.”

Weak states and political violence State capacity plays a key role in this.

Strong state institutions allow governments to fulfil their classical functions. “We’re interested in looking at both stronger and weaker states. Stronger states can collect considerable amounts of revenue, support market activities through a sound legal system, and supply services such as health and education to the

In developed nations, we see that people are relatively rich, but we also see that state institutions and policies are in good order. Conflicts of interest, which arise in all societies,

tend to be resolved peacefully

process, not purely in economic terms. “In developed nations, we see that people are relatively rich, but we also see that state institutions and policies are in good order.

Conflicts of interest, which arise in all societies, tend to be resolved peacefully,” says Professor Persson. “On the other hand, in very poor countries, institutions sometimes malfunction in a multidimensional way. Their conflicts are often resolved by

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population,” continues Professor Persson.

Developed nations are generally characterised not only by relatively high levels of material wealth, but also by institutional and political stability, the absence of which Professor Persson says can be a hindrance to building the state.

“In societies where the state is mainly used as a tool for the ruling elite to enrich itself – which sadly is too often the case – we predict that political instability makes

incumbents reluctant to engage in state building; if instability is high it is likely that the current elite will not be ruling in the future, such that a stronger state will be used against its own interests. So the motivation to build a stronger state will then be much weaker than would otherwise be the case,” he explains. While free and fair elections are clearly central to the idea and practice of democracy, Professor Persson also emphasizes another aspect of democracy.

“We argue that executive constraints are just as important, checks and balances to regulate the power of a leader once that leader has been appointed,” he says.

If leaders aren’t constrained in how they use power, then they are more likely to use it for their own benefit rather than acting in the common interest, which acts as a disincentive

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to long-term investment in the state. “It’s more palatable to invest in the state if you know that a prospective successor will pretty much do similar things to you because they are compelled to consider the rest of the population in their use of power,” continues Professor Persson. “To summarize, when political institutions entail few constraints on the executive, high political turnover can deter state building – the incumbent group doesn’t have the motives to invest in the state, because opposition groups may turn the

tools of the state against the current incumbent group, once they take over.”

Weak states, with unstable institutions, have a harder time to fulfil the functions of government and build a strong society.

In such circumstances conflicts of interest are more likely to erupt into violence; Professor Persson and his colleagues analyse political violence as being one of two types. “One type would be repression – where a government represses part of the population through violent means to increase its chances of staying in power.

The other would be two-sided political violence, namely the emergence of outright violent conflict between an insurgent group and the government. Of course, political violence can have different roots,” he says. These may be a conflict over natural resources, longstanding ethnic tensions, or the underrepresentation of a particular part of the population. “We aim to diagnose under what circumstances you get a peaceful outcome, you get a repressive outcome, or when that repression can turn into civil war,” says Professor Persson. “We find that many of the same factors that contribute to weak states also contribute to political violence. Such common roots – together with feedback effects between poverty, weak state institutions, and the prevalence of violence – help us understand multidimensional development failures, such as the ones we observe in Somalia and other failed states.”

Climate change

Degree of state weakness in terms of income, state capacity, and absence of violence. More red means increasing weakness, while more yellow means increasing weakness.

Source: Besley, T. and T. Persson, Pillars of Prosperity: The Political Economics of Development Clusters, Princeton University Press, 2011.

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The other area of the project’s research is climate change and its impact on human welfare.

Most impact studies of climate change take the form of case studies on particular places at particular times. “Therefore, we want information about large-scale impacts over long time periods, data on which many people claim is very hard to get,” says Professor Persson. The project is using historical records and other data sources to model the impact of temperature variability on the entire African continent, a region that Professor Persson says is likely to be strongly affected by climate change. “The climate in Africa is already harsh and societies are vulnerable. So it’s particularly important to learn about what might happen there,” he continues. “We’re looking at very fine-grained data, both across time and space, on Africa’s weather history over the last fifty years. This is combined with various data sources. One concerns individual birth histories – we

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At a glance Full Project Title State Capacity, Conflict, Development, and Climate Change (STATECAP) (ERC Advanced Grant 249580) Project Objectives One part of the project seeks to explain development clusters: the close correlation between economic well-being, functioning state institutions, and peaceful resolution of political conflicts. Another part seeks to improve our knowledge about the social and economic effects of weather fluctuations, and thus inform the debate about climate change.

Project Partners • Timothy Besley, LSE • Masauyki Kudamatsu and David Strömberg, Stockholm University Project Funding Funded by the European Research Council.

Contact Details Project Coordinator, Professor Torsten Persson Room: A800, Institute for International Economic Studies, Stockholm University S-106 91 Stockholm, Sweden T: +46 (0)8 16 30 66 F: +46 (0)8 674 78 01 E: torsten.persson@iies.su.se W: www.iies.su.se/~perssont W: www.pillarsofprosperity.info Besley, T. and T. Persson, Pillars of Prosperity: The Political Economics of Development Clusters, Princeton University Press, 2011.

Professor Torsten Persson

can study about a million births over the whole African continent and look at whether a particular child born at a particular place in a particular month, survived or if they perished in the first year of life. That’s the outcome variable we’re interested in – infant mortality is the biggest health problem in Africa next to AIDS, and it’s quite plausible that weather fluctuations and climate are major factors behind it.”

Thus, the project is studying records of extreme weather in the past and assessing their impact on infant mortality. Two mechanisms seem to be particularly important in the link between weather and infant mortality, namely maternal malnutrition and malaria. “Lack of rain in an economy that’s dependent on agriculture has a big impact; the more severe a drought that affects a particular pregnancy, the more of an impact it has on infant mortality. We can localise droughts in time and space, and confirm that this is the case,” says Professor Persson. The other channel is weather conducive to malaria, particularly when it develops into an epidemic. “The malaria mosquito and the parasite that transmits the disease from human to human are heavily dependent on both temperature and rainfall; rainfall because you need a certain viscosity of the ground for the mosquitoes to survive, temperature for the same reason and also for parasite growth,” explains Professor Persson. “A year with

enough rainfall and temperatures capable of producing a malaria epidemic of six months in a place that usually doesn’t have much malaria – so people haven’t developed much immunity – results in very high levels level of mortality for infants whose mothers were pregnant during the epidemic.” Such information can pinpoint particular areas at risk in Africa, when it is combined with forecasts of warming and weather variability under future climate change.

Stepping outside of the Statecap project, predicting the future evolution of the climate is of course an enormously complex task. Yet, many scientists argue that the level of carbon dioxide (CO2 ) trapped in the atmosphere makes some level of climate change inevitable, even if nations implement stricter limits on carbon emissions. However, it is difficult for politicians to take this kind of decision, for two reasons. “First, the benefits of taking action now may only be felt 25-30 years down the line and the political system is not always good at dealing with such long-term issues,” Professor Persson points out. “The second reason is that the benefits of taking action are global – CO2 spreads over the whole atmosphere, so there’s a big free-rider problem – and this makes it particularly hard to take the necessary action. We don’t have enforcement at the global level because of the nature of our nation-state societies. So any agreement has to be self-enforcing.”

In March 2013, NASA’s Operation IceBridge scientists began another season of research activity over Arctic ice sheets and sea ice. IceBridge, a six-year NASA mission, is the largest airborne survey of Earth’s polar ice ever flown. It will yield an unprecedented three-dimensional view of Arctic and Antarctic ice sheets, ice shelves and sea ice. These flights will provide a yearly, multi-instrument look at the behaviour of the rapidly changing features of the Greenland and Antarctic ice. ©NASA / Michael Studinger

Project Coordinator

Torsten Persson holds the Torsten and Ragnar Söderberg Chair in Economic Sciences at the IIES of Stockholm University. He is also a Centennial Professor at the London School of Economics, and has held visiting positions at leading universities as Harvard, Princeton and Berkeley.

His current research focuses on development, political violence, and climate change.

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