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EU Research Winter 2016

ELEVATING ELEVATING TRANSPORT TRANSPORT TECHNOLOGY ELEVATING TRANSPORT TECHNOLOGY

TECHNOLOGY

Horizon 2020 - The Road Ahead

Breakthrough in HIV

The Next Step in Cancer Treatment

Disseminating the latest research under FP7 and Horizon 2020 Follow EU Research on www.twitter.com/EU_RESEARCH

Editor’s No B rexit still dominates all the science news and that doesn’t look likely to relent until some clear decisions are made by the powers that be.

There is concern both from the EU and the UK about how research funding will be impacted. Whilst universities in the UK stand to lose millions, the UK contribution to EU funding has also been significant.

There are many potential levers that could break up good science collaboration but the biggest problem, the problem that creates all kinds of difficulties, is obviously the research funding.

A story that surfaced in the Guardian indicates that some EU partners are gearing up for Brexit by avoiding working with British scientists as they will have less chance of securing project grants. The story hinges on a confidential survey of the UK’s Russell Group Universities, where it was revealed that British academics were being asked to give up leadership roles as they are seen as a financial liability.

As a seasoned editor and journalist, Richard Forsyth has been reporting on numerous aspects of European scientific research for over 10 years.

He has written for many titles including ERCIM’s publication, CSP Today, Sustainable Development magazine, eStrategies magazine and remains a prevalent contributor to the UK business press. He also works in Public Relations for businesses to help them communicate their services effectively to industry and consumers.

Another great concern is funding schemes for EU students in UK Universities. What will happen? Jo Johnson, Minister of Universities and Science said at the Universities UK conference in September, that there was a ‘burning need for clarity’ around EU student funding. Whilst everybody in power chants ‘we are looking for the best deal possible’ there is a lack of commitment to any direction prior to beginning negotiations with the trigger of Article 50. No one therefore, feels reassured.

The EU and UK still sit poised in what feels like a kind of nervous anticipation of the implications and processes that will define Brexit. These are tense times, specifically for researchers, who have seen hassle-free collaboration within Europe as a given rather than a privilege. It would be a great shame for scientists to retreat away from each because of politics. We really need, as a science community, to hold it together as much as we can – we owe it to the science. Collaboration drives success Hope you enjoy the issue.

Richard Forsyth Editor

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Contents 27 OSAI

17 CAR T-cell therapy

4 Research News EU Research takes a look at the latest scientific and research news from around the globe

10 AIROPico Relatively little is known about human picornaviruses, a large family of viruses that can cause severe disease, and no therapy is currently available for infections. The AIROPico project aims to gain new insights into these virus infections and the diseases they cause, as Dr Katja Wolthers and Dr James Geraets explain

12 NuclearActin While the organisation of the cell nucleus is known to be a critical factor in many essential biological processes, the mechanisms that mediate and maintain this organisation are still not fully understood.

Dr Maria Vartiainen tells us about her laboratory’s research into the role of actin in nuclear organisation

14 SUREPIRL The SUREPIRL project is working to develop a new laser system to drive water directly into the gas phase without runaway nucleation growth or shock waves and is free of any ionizing radiation effects. This work has lead to near scar-free laser surgery and has opened up new avenues of scientific investigation, as Dr Wesley Robertson explains

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Immunotherapy is attracting an increasing amount of research attention for cancer treatment, encouraged by recent technical breakthroughs. We take a closer look at two of the major areas of research, checkpoint inhibitors and CAR T-cell therapy, that could help boost the body’s defences against cancer

20 DelCancer Researchers in the DelCancer project are using gene editing techniques and experimental models of cell transformation to shine new light on the development and progression of breast cancer, as Dr Anna Sablina explains

22 BONEMETTNC Evidence suggests that the progression of breast cancer depends on interactions between cancer cells and the surrounding microenvironment. Researchers in the BONEMETTNC project aim to dissect the role of the microenvironment in breast cancer metastasis, work which could open up new therapeutic avenues, as Dr Thordur Oskarsson explains

24 SOX-BMI1 Glioma stem cells play a significant role in the initiation, maintenance and development of certain forms of tumour, including glioblastoma multiforme, a highly malignant form of brain cancer.

New strategies to directly target these cells could lead to great improvements in treatment, as Dr Ander Matheu of the SOX-BMI1 project explains

Membranous nephropathy is the second-most common cause of nephrotic syndrome. The OSAI project is using novel technological approaches to shed new light on the disease, research which could lead to the development of rapidly acting new therapies, as Principal Investigator Professor Pierre Ronco explains

30 FACESSVEP The human brain has a remarkable ability to recognise and remember faces, even in different situations and across large time gaps. How do we do it? Professor Bruno Rossion tells us about his work in investigating how the human brain builds a visual representation of a face, research which could lead to new insights into how the brain functions

34 DISCON Recent global history is marked by several instances of civil conflict, where people of the same nationality have taken up arms against each other. The role of the disease environment in outbreaks of civil war has so far been largely overlooked, says Professor Uwe Sunde of the DISCON project, an EU-backed initiative taking a fresh look at the topic

37 Light4Function The creative power of chemistry lies in the ability of scientists to shape matter in unprecedented ways and generate new substances and materials with unique and advantageous properties. Now, researchers in the Light4Function project are looking to the next step, aiming to use light to control the timing and location of chemical and physical processes, as Professor Stefan Hecht explains

EU Research

40 X-Plane Aviation The aviation industry is a major contributor of the pollutants responsible for climate change. There is now a high demand to focus on innovative aircraft designs that would not only cut emissions dramatically but would create more efficient and quieter airplanes for us to fly in.

44 I²MPECT Reducing carbon emissions is an increasingly urgent priority for the airline industry, while operators are also investigating ways to improve operational efficiency and reduce maintenance costs. The I²MPECT project aims to develop an innovative power converter which could have a significant impact on the airline industry, as Karl Weidner and Oliver Raab explain

46 ALPES ALPES and AeroGust are developing new methods to speed up and improve the accuracy of key processes involved in the design of more environmentally friendly aircraft. Professor Jonathan Cooper explains the methods and the objectives of the projects that will lead to more efficient and cost effective aircraft designs

48 AeroGust

Under the leadership of Dr Ann Gaitonde and Dr Dorian Jones, AeroGust focuses on the interaction of gusts with aircraft. As with ALPES, this project is aiming to scale down the bulk of work in the design process

49 ECOROADS Strict application of two specific EC directives leads to a fragmented approach to road safety inspections, which has important safety implications. Adewole Adesiyun spoke about the Ecoroads project’s work in establishing a common approach to road safety infrastructure inspections and tunnel safety management

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50 ROADART Truck communication between could enable new vehicle applications in order to both greatly improve fuel efficiency and reduce congestion on European roads. The ROADART project aims to improve robustness of wireless communication on hardware, software and also at the application side, as Dr Christos Oikonomopoulos explains

52 PROMINENT Energy-efficient technologies could help reduce the environmental impact of inland waterway transport, providing an efficient alternative to road transport, as Prominent project coordinator Jaap Gebraad explains

54 INSPEC2T

Dr George Leventakis, coordinator of the INSPEC2T project, tells us about their work in developing a new solution for community policing, including a mobile application for two-way communication

58 FLEXYNETS

Dr Roberto Fedrizzi tells us about the FLEXYNETS project’s work in developing a new generation of District Heating and Cooling networks that will reduce energy losses during transportation, while also facilitating waste heat recovery

60 STORM

Johan Desmedt tells us about the H2020 STORM project’s work in developing, deploying and demonstrating a generic DHC network controller, which can be applied across both existing and new networks

62 TILOS

We spoke to Dr Dimitrios Zafirakis about the TILOS project’s work in establishing a smart energy microgrid on the island of Tilos which, together with communityscale battery storage, will help more closely match renewable energy supply to demand

EU Research Winter 2016

ELEVATING ELEVATING TRANSPORT TRANSPORT TECHNOLOGY ELEVATING TRANSPORT

TECHNOLOGY

Horizon 2020 - The Road Ahead

Breakthrough in HIV

The Next Step in Cancer Treatment

Disseminating the latest research under FP7 and Horizon 2020 Follow EU Research on www.twitter.com/EU_RESEARCH

EDITORIAL Managing Editor Richard Forsyth 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 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 Cover image copyright:<a href=’http://www.123rf.com/ profile_eyeidea’>eyeidea / 123RF Stock Photo</a>

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RESEARCH

NEWS

The EU Research team take a look at current events in the scientific news

Worlds Most Dangerous Greenhouse Gas to be Frozen Out A landmark deal has been reached between more than 150 countries to phase out the use of a type of gas which exacerbates global warming. Hydroflurocarbons (HFCs), a common type of organofluorine compound, are widely used in refrigerators, air conditioning units and aerosol sprays, but they will be gradually phased out over the coming years.

This could have a real impact, as HFCs account for a significant proportion of emissions. “Already, the HFCs used in a refrigerators, air conditioners, inhalers.... are emitting a gigaton of CO2 equivalent pollution into the atmosphere annually,” said US Secretary of State, John Kerry, in an address at the United Nations.

This is roughly equivalent to emissions from 300 coal-fired power plants, underlining the wider impact of HFC use, and the importance of reducing it. This will also affect national economies, so three different pathways for reductions have been put forward in the agreement, seeking to reduce emissions while also protecting economic interests.

The richer, more economically developed nations will limit their use of HFCs within a few years, while a group of developing nations will

freeze their use of HFCs from 2024. Another group of developing nations, including Iran, Pakistan and India, will not start freezing their use until 2028 at the earliest.

This represents a significant departure from previous thinking, in which HFCs were viewed as a way of replacing the hole in the ozone layer over the Antarctic that was first observed in the ‘80s. 197 countries signed the Montreal protocol on substances that deplete the ozone layer in 1987, which agreed to phase out the use of chlorofluorocarbons (CFCs).

At the time, HFCs were hailed as an effective replacement for CFCs, as they don’t contain chlorine and so don’t affect the ozone layer.

The two poles’ ozone holes have indeed reduced in size since the protocol was signed, but concern has been growing about the uninted consequences of HFCs, particularly with respect to emission levels.

The new agreement, signed in the Rwandan capital Kigali, has been hailed as an important step in this regard. “It’s a monumental step forward, that addresses the needs of individual nations but it will give us the opportunity to reduce the warming of the planet by an entire half a degree centigrade,” secretary Kerry told BBC News.

©NASA

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EU Research

Ice broken on construction of polar research vessel Construction has officially begun on the UKs new polar research ship, the RRS David Attenborough, named in honour of the veteran broadcaster. Projected to cost £200 million, the ship will be around 125 metres long and capable of breaking through 1 metre thick ice, an essential requirement for operation in polar regions.

The ship itself will be equipped with advanced instrumentation, providing a multi-disciplinary research platform to support a wide range of science. Researchers will be able to study the ocean, seafloor and the atmosphere, building a deeper understanding of the Antarctic and how it is changing.

The new vessel will be built at Merseyside shipbuilder Cammell Laird, which won the contract after a 12-month competitive tender process.

The ship is designed to help maintain the UKs place at the forefront of ocean and climate research, and will be ready for operation by 2019.

“I know that the work they will be doing onboard the new polar ship will be important, not only for science but for the whole world, because what happens down in the Antarctic is crucial for what happens to the climate of the earth,” said Sir David.

Leave behind your earthly concerns

If ever you find yourself bemoaning the state of your city, your nation, or even the planet as a whole, then be aware that an alternative living space is being developed. It’s called Asgardia, a new orbiting, pacifist nation state in space.

The name itself derives from Norse mythology, in which Asgard was a city in the sky. The city is envisaged as a fully independent nation, with a government, national anthem and embassies, while there are even plans to become a member of the United Nations.

So who can become a citizen of Asgardia? In principle, anybody, and indeed 300,000 people have already expressed an interest, triple the original target, and the number is growing rapidly as word spreads and more interest is generated.

The first citizens are likely to be those who already work in the space industry, but citizenship is not limited solely to any group. The project website emphasises that Asgardia concept combines philosophical, legal and scientific/technical aspects, each of which is central to the project.

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The next step will be to launch a satellite in 2017, with the longterm plan being to establish a space station. For now however, prospective citizens of Asgardia remain earth-bound, enjoying a relatively new form of dual citizenship, as Dr Igor Ashurbeyli, the founder of the Vienna-based Aerospace International Research Center, which is directing the project, explains: “Physically the citizens of that nation state will be on earth; they will be living in different countries on earth, so they will be a citizen of their own country and at the same time they will be a citizen of Asgardia,” he says.

The new space nation will play both idealistic and practical roles.

Ashurbeyli hopes to help prevent earth conflicts being transferred into space, while Asgardia will also offer some protection against space threats such as asteroids and open up new commercial opportunities.

“The ultimate aim is to create a legal platform to ensure protection of planet Earth and to provide access to space technologies for those who do not have that access at the moment,” says Ashurbeyli.

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Building on the legacy of Expo 2015 A great deal of attention was focused on the Italian city of Milan during Expo 2015, as it hosted debates and discussions on many of the most pressing issues we face, including food sustainability.

One of the key legacies from the event was the Milan Urban Food Policy Pact, an agreement signed by the mayors of 130 cities across the world.

The pact is based on the principles of sustainability and social justice, with the wider aim of developing more sustainable food systems.

With more than half of the global population currently living in cities, and the proportion set to rise further as the process of urbanisation gathers pace, food sustainability is a major global challenge.

Brexit ripples hit UK universities It’s only three months since the UK narrowly voted to leave the European Union, but the effects are already being felt, particularly in the research sector. Many UK universities have reported that European academics are turning down research posts, while the continuing uncertainty is likely to affect the number of undergraduate applications.

This comes at a time when UK research has been riding high. Britain has four universities in the top 40 of the CWUR world university rankings, more than any other European country, while the 2016 Nobel Prize for physics was jointly awarded to three British-born physicists for their work in theoretical discoveries of topological phase transitions and topological phases of matter.

There is a caveat here however, and it may point towards future problems in retaining research talent in the UK. While the three Nobel laureates – David Thouless, Duncan Haldane and Michael Kosterlitz – were all born and educated in the UK, they all now work in the US; the government’s approach to science funding in the early ‘80s was a major factor in Haldane’s decision to migrate.

“There was a depressing atmosphere in British science at the time because of stupid government ideas that one should do something ‘useful’” he recalled. Many other British scientists followed the path abroad in the early ‘80s, and there are concerns that Brexit could have a similar impact over thirty years on, leading to a ‘brain drain’ of research talent.

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The pact makes a number of recommendations with respect to this agenda, while at the same time acknowledging the different cultural and economic circumstances affecting individual cities.

Milan for example has a very different socio-economic profile to Johannesburg, Dubai and Rio de Janerio, all cities which have signed up to the pact.

There has to be scope for local authorities to respond to specific concerns, and Milan itself has wasted little time in acting. The city has set out a food policy, bringing together the environment, trade, transport, agriculture and waste management departments, which is complemented by grass-roots initiatives such as Recup, a local scheme which collects and shares unsold market produce.

Nike shoes go back to the future It’s over 27 years since Michael J Fox pulled on a pair of self-lacing shoes in Back to the Future, and now the trainer industry has caught up with science fiction. Nike is offering 89 pairs of limited-edition Nike Mags, which are equipped with lights and can be auto-tightened using power laces.

The ‘adaptive fit’ system means the shoe can be modified to the contours of the wearers foot, giving a comfortable fit. The self-lacing mechanism is initiated by pressure on the sole, so no more fiddling around with your laces.

The shoes will be sold in an auction in a collaboration between Nike and the Michael J Fox foundation, which was established by the actor after he was diagnosed with Parkinson’s disease.

Nike CEO Mark Parker said this was a powerful source of motivation in developing the shoes.

“Though it initially shared only a few seconds of screen time with Michael, the idea behind the Nike mag unlocked something much biiger at Nike. It sent us down an uncharted path of innovation, but it also opened our eyes to our ability to fight some of the world’s biggest challenges.”

One of the 89 pairs will be sold via a raffle, costing $10 to enter, with the others sold at auction, with all the proceeds going to the Michael J Fox foundation.

EU Research

Laying the foundations for tomorrow’s communications This year marks the 150th anniversary of the laying of a cable across the Atlantic, ushering in a new era in communication across the globe. While there had been earlier attempts at laying a cable, and indeed telegrams had been passed along it between Europe and America, it was not until 1866 that a durable cable was laid down on the seabed, providing the foundations for faster communication.

Now, 150 years on, companies are once again putting down cables on the seafloor, hoping to speed up communication and strengthen connections. These cables are essential to the communications that we take for granted today; if you’ve sent an e-mail to someone abroad, or had a look over a foreign-based website, then you’ll have made use of undersea cables at some point.

The Global Sentinel will soon be travelling across the oceans, laying the cables that will form the backbone of communication between the US and South America. Robots dive down to the seabed with tightly-spooled cable, where a trench is created, after which the cable is laid into the ocean floor and buried.

This will play a central role in communication and data exchange, far dwarfing the proportion transmitted via satellite.

“95 percent of all telephone and data is transferred over submarine cables, not satellite,” says Jeff Sanders, a captain at TE Connectivity SubCom, one of the world’s largest providers of underocean fiber-optic cable.

The drones that deliver A type of unmanned aerial vehicle, drones have become widely known for their use in military applications, now a US company has started using the technology to deliver medical packages in Rwanda. California tech business Zipline is the company behind the deliveries, in what is believed to be the world’s first commercial drone delivery service.

The drones themselves are being used to deliver medical supplies, including blood, plasma and coagulants to hospitals in relatively remote and inaccessible rural areas, which are hard to access by road. The Rwandan government was keen to bring supplies to hospitals more quickly, and brought Zipline on-board.

The overall system itself is designed to be extremely simple to use. Health workers can simply request a blood drop via a text message and the drone will deliver it within 30 minutes, allowing doctors and staff to respond much more quickly; this represents an effective and efficient method of delivering medical supplies, believes Zipline co-founder Keller Rinaudo.

“What this represents is an opportunity to... leapfrog over the absence of roads and provide first-world medical care to every single person in the country, regardless of where they live,” he says.

London pays tribute to Polish mathematicians The story of how the Enigma codes were cracked during the Second World War is widely known in the UK, but what is perhaps less widely known is the central role that Polish mathematicians played. The Polish Cipher Bureau had been working to de-code German military messages from 1932, and they passed their knowledge on to the British at the outbreak of war, giving codebreakers at Bletchley Park a crucial leg-up in their efforts.

While British mathematician Alan Turing was a central figure in cracking Enigma, the role of the Polish mathematicians should not be overlooked. “Alan Turing and his colleagues at Bletchley Park were given a huge boost by the work of the Poles, who handed over their secrets in July 1939, and they told them all sorts of secrets that the British didn’t actually know,” explained Sir Dermot Turing, the nephew of the famed mathematician.

This work was recognised in a recent ceremony at the Polish embassy in London, part of a series of events highlighting the contribution of the nation’s mathematicians and celebrating their achievements. The scale of the Polish contribution to cracking Enigma was not widely acknowledged in post-war Europe, in part due to ideological differences; this is a perception that the Polish authorities are now working to correct.

“Our contribution to Enigma is something that we learned a lot about as children in Poland but we have a feeling that the knowledge is not so widespread,” said Maciej Pisarski, deputy chief of mission at the Polish Embassy in Washington. “It was a crucial association which gave the allies the edge over the Germans.”

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Breakthrough in HIV treatment?

There have been significant advances in HIV treatment since the virus first emerged, with antiretroviral therapy (ART) allowing patients to manage the condition and maintain a relatively normal lifestyle While ART is thought to have saved over 7.8 million lives over the last 15 years, it does not ‘cure’ the virus as such, rather it suppresses it and prevents further progression.

The ART approach can suppress the multiplication of active T-cells infected with the HIV virus, but it is unable to target T-cells when they are not active, leaving a reservoir of the virus within an infected individual. Achieving sustained remission by removing all infected cells from an individual remains an important goal in research.

A pioneering recent study between five leading UK research establishments backed by the NHS holds real promise in these terms. The partnership brought together Oxford University, the University of Cambridge, Imperial College London, Kings College London and University College London, with the shared goal of researching how to eradicate the disease.

The partnership itself owes much to the initiative of the National Institute for Health Research (NIHR), who helped first bring the researchers together six years ago. Mark Samuels, managing director of the National Office for Clinical Research Infrastructure (NOCRI) believes broadbased collaboration is essential to tackling major research challenges like eradicating HIV.

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“This was a meeting of some of the UK’s top medical research leaders, and it was a privilege to encourage joining forces,” he said. “We understand the power in brokering crucial relationships to pioneer health breakthroughs, and this meeting was a prime example of that.”

Kick and kill

From these beginnings, researchers worked to develop a new therapy to treat HIV and eradicate all infected cells, not just those which are active. In the ‘Kick and Kill’ initiative, researchers studied how to activate dormant HIV-infected cells – which are not affected by existing ART methods – and then eradicate them.

The new therapy is designed to enhance the visibility of these inactive yet still infected cells, so that the virus can then be tracked down and destroyed in every part of the body. A key step is to first boost the patient’s immune system, at which point the dormant cells can then be identified and attacked by the immune system.

This approach has proved successful in laboratory tests, now scientists are moving on to test the therapy on a 44-year old British man. The full results will not be known for several months, but researchers are hopeful that the therapy will prove effective in clearing the disease.

EU Research

ITU report reveals patterns of global internet use The International Telecommunications Union (ITU) has released its annual Measuring The Information Society report, analysing the state of ICT development across 175 countries, and it reveals some sharp regional disparities. While overall internet use is growing, driven in large part by increased use of mobile phones, distribution of these devices is highly uneven.

At the top of the list comes the Republic of Korea, while seven European countries featured in the top ten, with Europe overall having the highest average IDI level among all global regions.

Nearly all of the countries surveyed had improved their IDI values in comparison to the previous year, but ITU Secretary-General Houlin Zhao says there is still scope for further development.

The level of mobile penetration in some countries exceeds 100 percent, yet this does not mean that everybody has access to a mobile phone, as some people have multiple subscriptions. The ICT Development Index (IDI) gives a more detailed picture of the information society in each country, combining eleven indicators on ICT access, use and skills.

“To bring more people online, it is important to focus on reducing socio-economic inequalities,” said. “Education and income levels are strong determinants of whether or not people use the internet.

ICTs will be essential in meeting each and every one of the 17 Sustainable Development Goals, and this report plays an important role in the SDG process.”

Scientists probe the fate of Schiaparelli spacecraft The last set of data received from the Schiaparelli spacecraft could hold the key to understanding what went wrong with the mission.

The 576 kg spacecraft, developed by the European Space Agency (ESA), was designed to validate certain scientific instruments, but contact was lost before the final stages of its descent to the surface.

All seemed to be going well initially, after Schiaparelli successfully separated from its mothership. the ExoMars Trace Gas Orbiter, ready for the final stages of its approach to the red planet.

However, early indications suggest that an unexpected event disrupted the later stage of the spacecraft’s approach under a parachute, leading to some discrepancies in the data.

“There’s a point where the parachute was released, and this is where the data we preliminarily analyzed from the Entry Descent and Landing Demonstrator Module (EDM) do not match, exactly, our expectations, and this is what we have to understand,” said

Andrea Accomazzo, head of the solar and planetary missions division at the European Space Operations Center.

It’s not all doom and gloom though. While scientists are of course looking into the reasons behind the problems with Schiaparelli, it’s important to consider the wider perspective, and important foundations have been laid for future missions, in particular ExoMars 2020, which aims to deliver a European rover and a Russian surface platform to the surface of Mars.

“We can confirm that the cornerstone of the ExoMars 2020 mission is now in place,” said David Parker, head of the ESAs Human Spaceflight and Robotic Exploration division. “The Trace Gas Orbiter is now ready for both parts of its long-term mission. We have 100 kilograms of science instruments in orbit around Mars now, so we’re ready to undertake the really exciting science to understand the origins and distribution of trace gase.”

Chasma Boreale, Mars ©NASA/JPL-Caltech/ASU

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Relatively little is known about the prevalence and transmission of human picornaviruses, a large family of viruses that can cause severe disease, and no therapy is currently available for infections. The AIROPico project aims to gain new insights into these virus infections and the diseases they cause, as Dr Katja Wolthers and Dr James Geraets explain

Picornaviruses go back under the research microscope Human

picornaviruses such as enteroviruses, rhinoviruses and parechoviruses from the Picornaviridae family mainly infect children and can cause a wide range of conditions, including respiratory disease, meningitis and encephalitis. While these viruses are the most common of all infectious agents, relatively little is known about their underlying structure and pathogenesis, an issue researchers in the AIROpico project are working to address. “We are working on human picornaviruses, in particular the enterovirus group and the parechovirus group,” says Dr Katja Wolthers, the project’s coordinator. These viruses have not always been thought to be a research priority, but Dr Wolthers believes that they require attention. “Polio for example is caused by a picornavirus. Polio viruses are nearly extinct now, because of the WHO initiative, but there are also a lot of non-polio enteroviruses out there that cause sometimes very severe diseases,” she says. “We believe that picornaviruses are an important group of viruses that need attention.”

Picornavirus structure The AIROpico project is making an important contribution in these terms, bringing together researchers from the academic and commercial sectors to investigate several different aspects of human picornaviruses.

The first workpackage centres around structural determination and pathogenesis of picornaviruses, with the project developing 3D cell culture models which allow researchers to study the viruses in human material. “These cell culture models are almost like very small, tiny little organs, which we can study in the laboratory,” explains Dr Wolthers. With these models, researchers can investigate

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key questions around picornaviruses, including how they enter cells and what mechanisms they use to replicate. “We have cultured human airway epithelium. We recently also managed to get human gut material to grow in the laboratory, which gives us a wonderful way to study the entry of the human picornaviruses,” continues Dr Wolthers.

Researchers at the University of Helsinki are playing a central role in this work, using sophisticated techniques like X-ray crystallography and cryo-electron microscopy to image the viruses. With these techniques, researchers can analyse the structure of these picornaviruses. “We can draw a lot of important insights from seeing how a virus is made,” stresses Dr James Geraets, a post-doctoral fellow at the University of Helsinki who is also working on the project. It is possible to look at where a particular drug binds to a virus for example. “Quite a few drugs target the capsids – the outer edge of the picornavirus,” continues Dr Geraets. “By imaging that, we can potentially find out how that drug prevents the virus from operating. Does it block it binding to a receptor that it needs to access to get into a cell? Or does it simply prevent the capsid from opening up and releasing the genome?”

This work is closely related to other key elements of the project’s agenda, helping build a body of knowledge which can then inform research into improved diagnosis and treatment. Current typing methods for identifying the specific virus type are quite laborious, so researchers from both the academic and industry partners are working together to develop faster methods; Dr Wolthers says there has already been significant progress in this regard. “One of our partners (TIB MolBiol)

has developed a very neat chip for human rhinoviruses, so we can see which specific type of rhinovirus is infecting the patient,” she outlines. Research is also continuing into improved diagnostic tests for other picornaviruses, some of which represent a major threat to public health. “There have been several outbreaks of infections of enterovirus D68 in recent years. It causes sudden, quite severe respiratory disease, especially in children with a pre-disposing condition like asthma. The project has developed a fast method of detecting this virus,” says Dr Wolthers.

A number of diagnostic tests for other picornaviruses have also been developed within the project, notably for enterovirus A71, a virus which causes polio-like symptoms and is increasingly common in Asia. The project’s work in investigating defence mechanisms against picornaviruses takes on even greater importance in this context. “We are studying humoral immunity, and we are also interested in developing therapeutic antibodies,” explains Dr Wolthers.

While the project’s research will help lay the foundations for

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At a glance Full Project Title Academia-Industry Research & development Opportunities for Picornaviruses (AIROPico) Project Objectives The general aim of the AIROPico project is to build up a sustainable, interdisciplinary, integrated academia-industry consortium to explore and unravel mechanisms of human picornavirus pathogenesis and to develop fast diagnostics, novel treatment options and additional therapy strategies.

Project Funding AIROPico received funding from the European Union’s Seventh Framework People Programme under REA grant agreement no 612308.

therapeutic development, Dr Wolthers says there’s still a lot of work to do before this can be achieved, and the current focus is on more immediate objectives. “We hope to build a more detailed knowledge base, and potentially identify small molecule compounds that might be interesting to big pharmaceutical companies,” she outlines.

also know that we can work on certain compounds, on antibodies, and demonstrate their therapeutic potential.”

Close collaboration This work has been built on close collaboration between the academic and commercial sectors. While the commercial sector overall has a different ethos to academia, Dr Wolthers believes each can

We have cultured human airway epithelium. We recently also managed to get human gut material to grow in the laboratory, which gives us a wonderful way to study the entry of the human picornaviruses The project is also working to generate monoclonal antibodies as potential therapeutic antibodies, research which could be of great interest to the pharmaceutical industry. No antiviral treatments against picornaviruses have been available since the drug pleconaril was taken off the market in 2002, after which many companies were reluctant to investigate picornaviruses; Dr Wolthers says the project’s work could encourage the industry to look at this area again.

“We’re aiming to gain more knowledge on the picornaviruses, so that they are considered more viable targets for the pharmaceutical industry,” she outlines.

“We know it’s not feasible to fully develop a compound within the timeframe of the project, but we

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benefit from the other’s expertise, pointing to the example of ArcDia, a partner in the AIROpico consortium. “They work in rapid diagnostics and they use antigen testing for that, but they lack rhinoviruses, which is why they are happy to have access to academic knowledge. We have more time to work on this area than a company normally would,” she explains. Many staff have spent time on exchanges within the consortium, sharing knowledge and strengthening ties, which will help encourage further collaboration and continued research. “There is interest in our fast-typing and detection methods, and we have also contributed to the new 3D cell culture models that will elicit more knowledge on how these picornaviruses work,” says Dr Wolthers.

Project Partners As an Industry-Academic partnership there are currently four companies and four academic sites participating. For more information on the company leaders and researchers involved, please visit the website. (www.airopico.eu) Academic partners: Dr. Katja Wolthers, Academic Medical Center, Amsterdam, NL; Prof. Sarah Butcher, University of Helsinki, FI; Dr Petri Susi, University of Turku, FI; Prof.

J.Neyts, University of Leuven, BE; Industry partners: Dr. Olfert Landt, TIB Molbiol, DE; Dr. Monica Jara, AbBcn S.L., ES; Dr. K. Palm, Protobios, EE; Dr. Janne Koskinen, ArcDia International Oy Ltd, FI; Contact Details Project Manager, R. Venkatachalam, PhD E: r.venkatachalam@amc.uva.nl Project Coordinator, Katja Wolthers PhD M.D. Laboratory of Clinical Virology L1-109 Dept of Medical Microbiology Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam The Netherlands T: + 31 2056 65619 E: k.c.wolthers@amc.uva.nl W: www.airopico.eu

Katja Wolthers PhD M.D. Katja Wolthers PhD M.D. is a medical microbiologist/virologist working in the picornavirus field since 2005. She is an AMC Principal Investigator on Molecular Epidemiology and Pathogenesis of Human Parechoviruses and Enteroviruses. She is now coordinator of AIROPico.

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Fibroblast with actin in green and nucleus in red and blue.

Actin cytoskeleton in a fibroblasts shown by phalloidin staining in red.

Investigating the biological significance of nuclear actin While the organisation of the cell nucleus is known to be a critical factor in many essential biological processes, the mechanisms that mediate and maintain this organisation are still not fully understood.

Dr Maria Vartiainen tells us about her laboratory’s research into the role of actin in nuclear organisation The cell nucleus

is known to be a highly compartmentalised organelle, and this organisation plays a critical role in many essential biological processes, from gene expression to the maintenance of genomic integrity. The mechanisms that actually mediate and maintain this organisation are not fully understood however, an area that Dr Maria Vartiainen and her research group aim to investigate in the NuclearActin project. “The wider goal in our research is to look at how the cell nucleus is organised,” she outlines.

The working hypothesis is that actin, a type of protein that is involved in many cellular processes, plays a critical role in this organisation, now Dr Vartiainen and her colleagues aim to investigate this further. “We’re using specific ways of manipulating actin in the nucleus, then we aim to identify what the actin is actually binding to in the nucleus, and thereby learn about how it contributes to nuclear organisation,” she says.

This represents a new area of research, as previously it had not been possible to manipulate nuclear actin levels specifically without affecting cytoplasmic actin, which is an important part of the cyto-skeleton and is central to many of the biological functions of cells. However, researchers have since been able to identify the mechanism by which actin is brought into the nucleus, opening up new avenues of investigation. “We have been able to identify the nuclear import mechanism for actin. This has enabled us to do this research,” says Dr Vartiainen. It is now possible to manipulate levels of actin in the nucleus while leaving cytoplasmic actin intact; this will enable

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researchers to look at a number of key questions around the biological significance of actin. “What happens if you reduce levels of nuclear actin? What happens to cellular functions? These are the underlying questions in our research,” says Dr Vartiainen.

Nuclear actin Researchers are using the fruit fly drosophila melanogaster as a model system in this work, along with several mammalian cell lines, aiming to gain new insights into the molecular mechanisms by which actin operates in the nucleus. Nuclear actin itself has been linked to many processes in the nucleus, especially those involved in gene expression. “It has been linked to the regulation of transcription factor activity, to DNA damage response and to the

function of the RNA polymerase for example,” says Dr Vartiainen. However, little is known about the role of actin in relation to the function of the RNA polymerase and many other important biological processes. “That’s why we want to understand the binding partners for nuclear actin for example. We can then build a deeper understanding of how it actually affects these important nuclear complexes. This essentially applies to all nuclear actin functions,” explains Dr Vartiainen.

A key step is of course to first identify the proteins that bind to nuclear actin. Dr Vartiainen and her colleagues are breaking new ground in this respect with the development of sophisticated new methods. “We have developed novel microscopic methods to identify the binding partners, that’s a new technical development. We are also creating new models to study nuclear actin,” she outlines. A novel multi read-out fluorescence microscopy screen will be implemented within the project, from which researchers can identify the binding partners of nuclear actin and investigate them in greater depth than previously possible. “The fluorescence microscopy screen itself has multiple readouts, so in addition to identifying the novel binding partners, we can also study the effect of these partners on transcription factor activity,” continues Dr Vartiainen.

The project is using several different techniques to analyse these proteins, including chromatin immunoprecipitation, sequencing and transcriptomics. Researchers aim to gain

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At a glance Full Project Title Actin as the Master Organizer of Nuclear Structure and Function (NuclearActin) Project Objectives The cell nucleus is a highly compartmentalized organelle, and its organization has critical for many essential processes, from gene expression to maintenance of genomic integrity.

NuclearActin project studies the role of actin in nuclear organization, by using a combination of genomic and imaging techniques.

Project Funding Main funding ERC Starting grant, other funding of the lab: Academy of Finland, Sigrid Juselius foundation, Finnish Cancer Foundation and Biocentrum Helsinki.

GFP-actin expressing cells in control (left) and Exportin-6 (right) depleted conditions, which block nuclear export of actin, and thus accumulates actin in the nucleus.

a deeper understanding of the biological significance of nuclear actin through this work. “We’re looking at fundamental processes around gene expression,” says Dr Vartiainen. While research in the NuclearActin project is largely fundamental in nature, dysregulation of actin has been linked to failures in cell function, something which Dr Vartiainen and her colleagues are investigating in

research in this area in future, outside the current scope of the NuclearActin project. Within the project itself, researchers will continue to investigate the biological significance of nuclear actin. “We want to identify which genes depend on actin for their expression – we’ve already gained a lot of data on that, and we’re currently checking through it.

We hope to identify novel nuclear

We’re using specific ways of manipulating nuclear actin in the nucleus, then we aim to identify what the actin is actually binding to in the nucleus, and thereby learn about how it contributes to nuclear organisation the laboratory. “We recently collaborated on a paper with researchers in the US, where we showed that in certain laminopathies there is a defect in nuclear actin polymerisation. Laminopathies are a group of diseases caused by mutations in the nuclear envelope proteins, and they often lead to myocardial and cardiac dysfunction,” she outlines.

A number of questions remain around the role of actin in laminopathies, and Dr Vartiainen plans to pursue further

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functions that depend on actin, through these novel binding partners,” says Dr Vartiainen. Researchers now plan to publish some of the initial results from the project. “We need to publish the results from the fruit fly models, and we also have the preliminary analysis of the nuclear actin interactions,” continues Dr Vartiainen. “This project has also resulted in many novel lines of research that we are going to continue to pursue in the laboratory.”

Contact Details Project Coordinator, Institute of Biotechnology University of Helsinki PO BOX 56 00014 Helsinki Finland T: + 35 8919 159419 E: maria.vartiainen@helsinki.fi W: http://www.biocenter.helsinki.fi/bi/ vartiainen/ Dopie J, Skarp KP, Rajakylä EK, Tanhuanpää K, Vartiainen MK. Active maintenance of nuclear actin by Importin 9 supports Transcription.

PNAS 2012 109(9):E544-52

Dr Maria Vartiainen

a obtained her PhD Dr Maria Vartiainen in 2002 from University of Helsinki, and then worked as a post-doc with Richard Treisman at LRI-CRUK in London. Since 2007, Maria has been a group leader at the Institute of Biotechnology in Helsinki, acting also as the scientific leader of the Light Microscopy Unit.

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New laser concept that leaves no scars The SUREPIRL project is working to develop a new laser system to drive water directly into the gas phase without runaway nucleation growth or shock waves and is free of any ionizing radiation effects. This work has lead to near scar-free laser surgery and has opened up new avenues of scientific investigation, as Dr Wesley Robertson explains The discovery of

a new laser method to drive water directly into the gas phase without unarrested nucleation and shock waves holds important implications for surgical procedures and the detection of single molecules. Proteins and biomolecules need to be brought into the gas phase before they can be analysed using mass spectrometry, yet current methods of performing this transformation have some significant limitations.

“The main inefficiency is in taking molecules from the solution, bringing them into the gas phase, and charging them for analysis,” explains Dr Wesley Robertson. Based at the Max Planck Institute for the Structure and Dynamics of Matter, Dr Robertson is closely involved in the SUREPIRL initiative, a multi-disciplinary project developing a new laser concept which builds on the work of Professor R.J Dwayne Miller’s research group. “Experimental advances in Professor Miller’s group a few years ago allowed melting to be induced and observed on the atomic time level with ultrafast time resolution, this has led to the development of a new method of transforming a liquid or a solid directly into the gas phase,” he continues.

A key step in this work was the development of experimental methods to create the first ‘atomic movies’ which allowed researchers to study the phase transitions between solids, liquids and gases and study molecular behaviour in greater depth. Out of this research, a new laserbased method of transforming a liquid or solid directly into the gas phase without causing shock wave damage has been developed; an analogy can be drawn here with the process of melting a block of ice.

“Imagine that you want to melt a block of ice by heating it. Typically you would expect the outside of the block to melt while the parts closer to the centre stay frozen,” says Dr Robertson. However, by depositing enough energy throughout the ice, on a time scale faster than energy redistribution, it instead melts uniformly in a process called homogenous nucleation. “That’s one way to think about the work of the project,”

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continues Dr Robertson. “We can perform an equivalent process on water rich tissue to drive molecules into the gas phase.”

DIVE effect The DIVE (Desorption by impulsive vibrational excitation) effect, a novel mechanism for laser ablation – essentially the cold vaporization of tissue – is an important element of the project’s research.

Previously, researchers investigated phase transitions in metals, using electron diffraction techniques to study matter on the femtosecond (10 -15 of a second) timescale, work which led to some important insights.

“It was found that under certain energy deposition conditions, the nucleation sights are limited to a few atoms during the phase transition, and without shock wave damage,” explains Dr Robertson. Building on this finding, researchers then set out to develop a laser that could couple to water, the PIRL (Picosecond Infrared Laser). “DIVE achieves ablation by coupling energy through the vibrational modes of water. The PIRL is an IR (infrared) laser and the pulse width is really short - it’s a pico-second (10 -12 of a second) laser,” continues Dr Robertson.

This represents a mechanism to drive a phase transition on an extremely rapid

timescale. With the PIRL laser, energy is focused down to the dimension of a single cell, enabling more precise surgery. “The energy is dumped into the water vibrational modes in a specific volume – it goes through the OH stretching mode of water into translational motions which drive tissue ablation, on a timescale shorter than the time it takes for the heat, or other energy, to be transmitted,” says Dr Robertson. “The material transitions from the solid to the liquid to gas without shock wave damage, and without the development of these large nucleation sites.”

This is an important issue in surgery, as explosive growth of nucleation sites can lead to significant collateral damage. This has historically limited the use of lasers in surgery, as Professor Miller explains.

“Think of the violence of boiling water, in which small bubbles form at nucleation sites, or defects grow and grow and then violently collapse. This is exactly what occurs with conventional lasers used for surgery,” he says. “To remove material you have to convert solid to liquid to gas and out. Nucleation growth and collapse leads to shock wave damage. Ultimately the energy escapes the initially excited zone by either shock waves or thermal diffusion

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to adjacent tissue or material leading to massive damage. Alternatively very short femtosecond pulses are used, but cut by plasma formation, which is effectively ionizing radiation. The inability to avoid collateral damage to surrounding tissue has greatly limited laser applications and prevented lasers from reaching the long held promise of reaching the fundamental – single cell – limit to minimally invasive surgery. The PIRL scalpel concept has reached this limit and by simultaneously avoiding ionizing effects, gives perfect molecular fingerprints of the tissue for in situ pathology and image guidance.”

The PIRL system is designed to completely eliminate the growth of nucleation sites and heat transfer, helping minimise the impact of surgical procedures on surrounding soft tissue and cartilage.

This approach leaves no scar tissue, as the cells at the cut zone are all perfectly viable, and there is no damage beyond the first cell line of contact. “With this IR laser that couples to water, you can focus enough energy on a small volume to cause water molecules to go into the gas phase on an extremely fast timescale,” explains Dr Robertson. The PIRL laser focuses energy down to the dimension of a single cell, operating at a pulse width of a few picoseconds; this is shorter than the pulse widths related to thermal transfer and acoustic relaxation time, but not so short as to lead to more damaging effects when used in surgery. “It’s not so short that you get effects like plasma formation or multiphoton excitation, which can be very damaging,” says Dr Robertson.

Mass spectrometry Researchers are now aiming to explore the wider potential of this technology, including in both surgical and biodiagnostics applications. While the project brings together researchers from several different scientific disciplines, Dr Robertson himself is focused primarily on the development of mass spectrometry tools. “We’re developing new systems to use this technology and apply it for mass spectrometry,” he outlines.

Bringing proteins into the gas phase efficiently is a key step. “Methods like MALDI (Matrix-assisted laser desorption/ ionization) and electrospray ionization are used to bring proteins and other molecules into the gas phase, so that they can be analysed by mass spectrometry. We’re trying to come up with a new way to bring proteins into the gas phase for analysis,” says Dr Robertson.

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Currently, inefficiencies in creating and detecting molecules mean it’s not possible to detect every single protein, biomarker or lipid in a blood sample. Now Dr Robertson and his colleagues aim to develop systems to extract proteins more efficiently. “We’re working to develop a system to extract proteins from water and tissues really efficiently. We’re basically using the laser pulse to extract intact proteins and complexes directly from

effectively extract proteins, protein oligomers, even whole viruses directly from tissue and actually laser transinfect functional viruses,” he says. “This is a major innovation for surgical biopsies, where now a laser can be used to sample biomolecular signatures from tissue with minimal collateral tissue damage or sample damage.”

The wider goal in this research in terms of mass spectroscopy is to move tools

We’re developing a system in which we’re extracting proteins from tissue and water solutions really efficiently, and with high sensitivity water and tissue” he outlines. “With this approach, proteins could potentially be extracted from tissue much more efficiently than currently possible.”

The energy is deposited into a very small, thin layer of water. The energy in those vibrational modes is transferred to the translational motions of water on the timescale of pico-seconds, stripping away water molecules, leaving intact, undamaged proteins. “You’re left with cold analytes, desolvated with the water softly stripped away,” explains Dr Robertson.

This represents a far more efficient method of extracting proteins; Dr Robertson and his colleagues plan to continue their research in this area. “In a recent publication, we showed that we could then

towards the fundamental limit of single protein detection. With current mass spectrometry techniques, identification is limited to molecules that are reasonably high in abundances; once this limitation has been overcome, Dr Robertson says new avenues of investigation will open up. “We’ll be able to extract proteins more efficiently and ionise them more efficiently. We’ll also be able to move to new regimes in all areas of science. We won’t be limited any longer to only looking at molecules in high abundance, or molecules we know of beforehand, so this will open up new areas of investigation,” he outlines. All molecules are injected into the gas phase to give a snapshot of the composition and all

Minimally Invasive Nanobiopsy Collector

Picosecond InfraRed Laser (PIRL)

Abiation Plume Tumour Tissue

Healthy Tissue

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At a glance

Project Objectives SUREPIRL is a collaborative project in physics, analytics, and medicine for picosecond laser technology application in bioanalytics and surgery.

molecular details are conserved to uniquely identify the tissue or material; some of these molecules play essential roles in cells, such as signalling or modulating neural activity, reinforcing the wider importance of the project’s research. “These molecules are present in really small numbers, and we’re not really able to detect them with current technology, unless we really know what we’re looking for,” continues Dr Robertson.

Project Funding The SUREPIRL project is funded by the European Research Council as an Advanced Grant Seventh Framework Programme and by the Max Planck Institute.

With this IR laser that couples to water, you can focus enough energy on a small volume to cause water molecules to go into the gas phase on an

Full Project Title Picosecond Infrared Laser for Scarfree Surgery with Preservation of the Tissue Structure and Recognition of Tissue Type and Boundaries (SUREPIRL)

Project Partner • UKE Hamburg Contact Details Professor R. J. Dwayne Miller Max Planck Institute for the Structure and Dynamics of Matter Building 99, Room O2.099 Luruper Chaussee 149 22761 Hamburg, Germany T: +49 (0)40 8998-6200 E: ard.groupadmin@mpsd.mpg.de W: www.surepirl.eu B.J. Siwick et al., “An Atomic-Level View of Melting Using Femtosecond Electron Diffraction,” Science, 2003, 302(5649), 1382-1385.

M.L. Cowan, B.D. Bruner, N. Huse, J.R. Dwyer, B. Chugh, E.T.J. Nibbering, T. Elsaesser, and R.J.D. Miller, “Ultrafast Memory Loss and Energy Redistribution in the Hydrogen Bond Network of Liquid H2O,” Nature 2005, 434(7030), 199-202.

signals to let the body know that there’s been some damage, leading to scar tissue,” explains Dr Robertson. Historically the use of lasers in surgery has been limited, as the shock waves and heat led to burning and tissue damage, yet these problems have now been resolved in PIRL, offering an effective surgical tool to precisely target damaged cells without leaving a scar. “You’re basically taking this cell and either cutting it in half, or transforming

extremely fast timescale Scar-free surgery Researchers in the project are also exploring the potential use of the PIRL laser in certain surgical procedures, which could bring significant benefits over existing techniques. While scalpels and other surgical tools are commonly used in everyday procedures, they can also cause collateral damage to surrounding cells. “When you cut with a scalpel, you’re basically shearing the flesh, you’re ripping cells apart over a long distance from the incision site. So the cells that are damaged send out

the entire cell into the gas phase,” says Dr Robertson. “There’s minimal to no damage to surrounding cells.”

The project is working in close collaboration with surgeons at a hospital in Hamburg to refine the PIRL laser further.

With the PIRL laser, the surgical intrusion is of a size around just the cross-section of a hair, and Dr Robertson says the evidence suggests that it is a highly effective tool.

“We’ve shown in a recent publication that the scar formation following surgery with PIRL is minimal, even less than with the gold standard scalpel,” he says.

Professor R. J. Dwayne Miller

Professor R. J. Dwayne Miller is the Director of the Group for Atomically Resolved Dynamics at the Max Planck Institute for the Structure and Dynamics of Matter. He was the recipient of the E. Bright Wilson Award in Spectroscopy from the American Chemical Society in 2015, the most recent of many academic and professional honours he has gained during his career.

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The next step in cancer treatment Surgery, chemotherapy and radiation are among the most common methods of treating cancer, but immunotherapy is attracting an increasing amount of research attention, encouraged by recent technical breakthroughs. We take a closer look at two of the major areas of research, checkpoint inhibitors and CAR T-cell therapy, that could help boost the bodyâ&#x20AC;&#x2122;s defences against cancer

T

he idea of immunotherapy dates back to the late 18th century, when Edward Jenner produced the first vaccine to prevent smallpox, and researchers continue to develop new methods of stimulating the immune system as a way of treating disease. By harnessing the power of the immune system and exploiting the specific properties of cancer cells, researchers hope to develop effective, long-lasting immunotherapies that combat tumours and protect against disease.

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The idea of immunotherapy may have a long history, but it is only relatively recently that technical breakthroughs have brought new cancer therapies closer to practical realisation. For example, the PD-1 protein (Programmed Cell Death 1), a molecule that plays a major role in regulating the immune system and in cancer immune evasion, was discovered in the early â&#x20AC;&#x2DC;90s, laying the foundations for the development of a new class of drugs, the PD-1 inhibitors.

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Checkpoint inhibitors These drugs fit broadly within the wider category of ‘checkpoint inhibitors’, which remove so-called ‘brakes’ within the immune system that can hamper the response to cancer cells, and so enable the immune system to pursue cancer more aggressively.

Checkpoint molecules play an important role within the immune system, helping prevent an overly aggressive immune response; in the case of PD-1 almost acting as an off-switch to prevent T-cells from attacking other cells.

This helps maintain a healthy balance in normal, healthy individuals, yet researchers have found that cancer cells can use these checkpoint molecules to evade the immune system. Building on research advances, scientists are now looking to turn the tables by developing drugs that block the activity of these checkpoint molecules, which has the effect of enabling the immune system to go after cancer cells more aggressively.

Some positive results have already been gained from the use of these drugs. PD-1 inhibitors like Pembrolizumab and Nivolumab have been shown to be effective in treating several different

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types of cancer, including kidney cancer and some types of head and neck cancers, while Atezolizumab can be used to treat bladder cancer and is currently undergoing further clinical trials as a therapy against certain types of solid tumour.

There is a high level of interest in this research among physicians, patients and investors, yet some researchers have urged caution, suggesting that further investigation is required before immunotherapy techniques can be more widely applied. One major concern is that by allowing the immune system to attack cancer cells more aggressively, the checkpoint inhibitors also enable it to attack healthy organs, causing potentially serious side-effects.

These include fatigue, nausea and appetite loss at the less severe end of the scale, through to more serious problems affecting a number of organs, including the lungs, kidneys and liver. Work is ongoing into how this potential toxicity can be limited or even reversed, but much remains to be learned in this area. Clinical trials are ongoing for several different checkpoint inhibitors, while researchers are also looking at combination trials, where two drugs are used simultaneously.

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CAR T-Cell therapy A second major area of cancer immunotherapy research is CAR T-Cell therapy, in which T-cells from the patient’s own blood are collected and then genetically engineered to enhance the immune system’s ability to recognise and kill tumour cells. The re-engineered T-cells have a specific type of receptor on their surface called a Chimeric Antigen Receptor (CAR), which now allow the T-cells to recognise an antigen on targeted tumour cells.

These modified cells can eventually be re-infused into the patient, with the hope that the T-cells will then multiply and attack cancer cells with that specific antigen. At the moment, CAR T-Cell therapy is only available to patients participating in a clinical trial, but the early results of trials on patients with blood cancers have been positive, leading to a great deal of optimism among researchers about the long-tern prospects for using this approach more widely.

It is important to place these early trials in context however, as so far studies have only been conducted over relatively short time-frames, and participants will need to be followed for a longer period to really build a deeper understanding of the long-term efficacy of the treatment. One important attribute is that the CAR T-cells may remain in the body long after the infusion has been completed, guarding against the recurrence of the disease, but there is more to learn in this respect.

There is also a wider acknowledgement of the existing limitations of CAR T-Cell therapy and the side-effects of this approach. The vast majority of patients treated with CAR T-Cell therapy experience flu-like symptoms, such as a high temperature and muscle pain, while the treatment can also have more serious side-effects, among the most concerning of which is cytokine-release syndrome (CRS), in which there is a rapid and massive release of cytokines into the bloodstream.

This can have serious effects beyond the emergence of flu-like symptoms, with some patients experiencing delirium, confusion and seizure while undergoing treatment. The patients with more severe disease are the most likely to experience these serious side-effects, and researchers are investigating ways to reduce these side-effects and manage them effectively.

The results from recent clinical trials are encouraging in this respect. Trial investigators have reported that the side-effects of CAR T-Cell treatment are relatively mild for most patients, and can be managed with standard drugs, while it was found that those patients who experienced a more severe reaction could be treated with etanercept and tocilizumab, two drugs which helped manage the toxicity of treatment.

An acknowledgment of these side-effects has to be balanced against the side-effects of more conventional treatment when assessing the efficacy of immunotherapy as a method of treating cancer. While the use of immunotherapy is not completely without risk, standard treatments like radiation and chemotherapy also have side-effects, and some researchers have suggested that immunotherapy would in fact be less toxic over the long-term.

Further research A great deal of research attention is now focused on immunotherapy, with many clinical trials ongoing into both CAR T-cell therapy and checkpoint inhibitors. Some therapies are already available; the Food and Drug Administration (FDA) in the US has so far cleared four checkpint inhibitors for use by adults; Yervoy, Keytruda, Opdivo and Tecentriq, while several more are in the pipeline, and data continues to emerge on the efficacy of CAR T-cell therapy.

The early results show significant promise in this respect.

Studies show that CAR T-cell therapy could be an effective treatment option for patients with acute lymphoblastic leukemia (ALL) who had suffered a relapse following treatment with more conventional therapies. Research into the use of CAR T-cell therapy on other blood cancers, including chronic lymphocytic leukemia (CLL) and some types of non-Hodgkin lymphoma (NLL) have also shown positive results.

This research is being undertaken in both the public and private sectors, with a great deal of interest among investors in biotechnology companies. Clinical research company Juno therapeutics raised $304 million when they went public in December 2014, and the company is currently involved in several trials aiming to bring CAR T-cell therapies to the clinic.

Recent research suggests that immunotherapy could be used in treatment against more than two dozen cancers, and potentially more, with new drugs showing significant and extended effectiveness against even rare and previously intractable tumours caused by viruses. Viruses and other pathogens are thought to be responsible for more than 20 percent of all cancers, reinforcing the wider potential of immunotherapy.

While there is still a great deal left to learn, Louis Weiner, director of the Georgetown Lombardi Comprehensive Cancer Center, believes immunotherapy will be a central element in cancer treatment in future. “We are in the midst of a sea change in how we are treating cancer,” he said. “We’re really seeing the fruits of many years of research into what drives cancer and how it interacts with the immune system to defeat it and survive.”

We are in the midst of a sea change in how we are treating cancer. We’re really seeing the fruits of many years of research into what drives cancer and how it interacts with the immune system to defeat it and survive

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Specific regions in the chromosome are commonly lost in the development and progression of cancer, yet much remains to be learned about the role of these deletions in the disease. Researchers in the DelCancer project are using gene editing techniques and experimental models of cell transformation to shine new light on the development and progression of breast cancer, as Dr Anna Sablina explains

Understanding the impact of chromosomal deletions The loss of

DNA in the genome is a common feature of the development and progression of cancer. While alterations and changes to some regions of the genome are thought to play a role in tumourgenic transformation, much remains to be learned about the loss of heterozygosity that is commonly observed in cancer genomes, an area that forms the primary research focus for the ERC-backed DelCancer project. “The main goal of the project is to investigate the consequences to patients of large-scale chromosomal deletions,” says Dr Anna Sablina. This is not an easy question to study, as typically multiple genes are lost simultaneously when large areas of chromosome are deleted. “Some of those genes can suppress the proliferation of cancer cells, but others can confer a selective growth advantage.

That’s why it’s really difficult to define the role of these large-scale deletions in the development of cancer,” explains Dr Sablina.

Genetic engineering tools The development of sophisticated new genetic engineering tools is an important step forward in these terms. The project is using both TALEN and CRISPR technologies, which allow researchers to cut DNA at specific locations and manipulate the genome of human cells.

“We can mimic the situations that we can

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see in cancer patients. So we can introduce the same large-scale deletions that we see in cancer patients, then assess the role of these deletions on cancer development and progression,” outlines Dr Sablina.

Researchers are working mainly with patient cells derived from mammaplasty procedures, and genetically engineering these cells to model the alterations associated with cancer. “We use the TALEN or CRISPR gene-editing techniques

project is using experimental models of cell transformation to investigate the impact of deleting specific chromosomal regions. “We introduce these chromosomal alterations into the model, then we try to figure out what is going on in the cells by looking for different assays and different pathways,” explains Dr Sablina. “We look at whether these large-scale chromosomal deletions can lead to the formation of cancer.”

We can mimic

the chromosomal abnormalities that we can see in cancer patients. These model systems allow us to assess the role of these deletions on cancer development and progression to introduce the genetic alterations that we commonly see in breast cancer patients,” continues Dr Sablina.

Researchers are deleting an entire region of the chromosome, rather than a smaller area or specific parts of the chromosome, aiming to establish a protocol for editing the genome on a large scale. The goal then for Dr Sablina and her colleagues is to assess how disrupting the chromosomal network in this way affects cells. “If we have such a large-scale chromosomal deletion, how will it affect gene expression? And will this contribute to cell transformation?” she outlines. The

This research relates to both the early stages of cancer development and its later progression.

Some chromosomal alterations may occur at an early stage of cancer development, while others may take place later, an issue which Dr Sablina and her colleagues are investigating.

“First of all, we are looking at the cancer genomes. We aim to figure out which alterations recur, to define the border of the deletions, and to define whether the specific deletion is an early event or a late event,” she says. Data from the cell models can also lead to new insights into the molecular mechanisms behind cancer

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At a glance development. “We can look at whether a specific alteration is associated with drugresistant or metastatic phenotypes for example. It’s then easier for us to figure out which phenotypes we should look at in our models,” continues Dr Sablina.

Diagnosis and prognosis This work also holds wider relevance in terms of diagnosis and prognosis for breast cancer patients. Breast cancer is a highly complex condition, and it is currently classified across several different categories in order to identify the best course of treatment for each individual case; Dr Sablina says deeper knowledge about chromosomal aberrations could bring real benefits in this regard.

“We can see that some of these chromosomal aberrations could serve as prognostic marker for certain therapeutic decisions. Some of them could act as indicators of sensitivity to a particular type of therapy,” she says. These prognostic markers could potentially be used in the clinic in future; Dr Sablina plans to investigate this further, using tissue taken from patients during surgery. “We will introduce these pieces of tissue into a mouse, so we can look at a primary tumour Loss of chromosome 8p governs tumor progression and drug Response by altering lipid metabolism.

in a humanized mouse. Then we will characterise the different chromosomal alterations we observe in this tumour, which will affect the response to specific drugs,” she continues.

The wider goal in this research is to investigate how particular chromosonal deletions lead to the initiation and progression of cancer. While the project is focused primarily on breast cancer, Dr Sablina says this approach could potentially be used to investigate other forms of cancer.

“I’m mainly familiar with breast cancer, but this could be applied to any other kind of tissue,” she says. Researchers will continue to investigate the underlying mechanisms behind cancer development over the coming years, which could also help in the identification of new therapeutic targets to help improve treatment. “With effective drug screening, we can really identify compounds or drugs to reach our modified cells. Then we can go back to the patient data, and see which chromosomal organisation can be used as a predictive marker for sensitivity to a particular type of therapy,” outlines Dr Sablina.

Full Project Title The role of loss-of-heterozygosity in cancer development and progression (DelCancer) Project Objectives One-fourth of a typical breast cancer genome is affected by chromosome arm deletions. By genetically engineering human cells, we generated clinically relevant models of large-scale chromosomal deletions. Our results demonstrate that experimental models mimicking cancerassociated deletions provide a powerful system for functional annotation of the cancer genome. The generated models also represent a platform to identify drugs that selectively kill tumor cells harboring a particular chromosomal abnormality.

Project Funding ERC Starting Grant DelCancer Contact Details Dr Anna Sablina VIB Laboratory for Mechanism of Cell Transformation KU Leuven O&N Campus Gasthuisberg Herestraat 49 bus 602 3000 LEUVEN T: +32 16 37 69 27 E: anna.sablina@cme.vib-kuleuven.be W: http://www.vib.be/en/research/ scientists/Pages/Anna-Sablina-Lab.aspx

Dr Anna Sablina

Dr Anna Sablina is a Group Leader in the VIB Laboratory for Mechanism of Cell Transformation at the University of Leuven. Her main research interests are focused on understanding the cooperative interactions that conspire to promote tumorigenic transformation.

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Exploring the causes of cancer metastasis Evidence suggests that the progression of breast cancer depends on interactions between cancer cells and the surrounding microenvironment. Researchers in the BONEMETTNC project aim to dissect the role of the microenvironment in breast cancer metastasis, work which could open up new therapeutic avenues, as Dr Thordur Oskarsson explains The most common

form of cancer in women, accounting for around 25 percent of all female cases across the world, breast cancer causes more than 500,000 deaths a year. The vast majority of these deaths are caused by metastasis, the process by which malignant cells spread to distant organs, a topic that lies at the core of the BONEMETTNC project. “We are trying to dissect the role of the surrounding microenvironment in breast cancer metastasis,” says Dr Thordur Oskarsson, the project’s Principal Investigator. The consequences of mutations and other changes in cancer cells are frequently context-dependent, underlining the importance of research into the surrounding microenvironment, or metastatic niche, which supports the continued growth of the cancer. “Over the last few years we have focused in particular on the extracellular matrix, which is the non-cellular component of the microenvironment,” outlines Dr Oskarsson.

Extracellular matrix The extracellular matrix fills the space between cells within tissues and performs a number of key functions, including providing structural support and regulating cellular communication. In cancer, the extracellular matrix is distinct from healthy tissue and resembles the matrix that is produced during wound healing. The development of a cancer

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associated matrix is a complex process, however it is recognized that reactive stromal fibroblasts, a type of connective tissue cell, play a prominent role in matrix production and maturation. This is an area of great interest to Dr Oskarsson. “We aim to dissect the molecular cross-talk between these stromal cells and cancer cells,” he says.

These interactions are highly dynamic and the resulting extracellular matrix niche may not form instantaneously.

Therefore, when disseminated cancer cells arrive at a distant site, the microenvironment may not be welcoming, leading to the elimination of most of the cancer cells. The continuous cross-talk

fluids of breast cancer patients. These are patients with systemic metastasis, so we think that these samples may provide a window to look at the most aggressive cancer cells in metastasis,” says Dr Oskarsson. One of the reasons that Dr Oskarsson is interested in molecules like TNC and other matricellular proteins is that while they do not contribute significantly to the scaffolding structure of the extracellular matrix, they are important for cell regulation and the modulation of signalling pathways. “They can determine cell fate, particularly under stress, and we think that this is very important for the metastatic colonisation,” he outlines.

Stem cell properties are likely to be important for the maintenance and progression of breast cancer between cancer cells and stroma induces changes in the microenvironment, which may generate a supportive niche that promotes cancer growth. “Moreover, we have observed that the cancer cells that can bring their own niche components have a selective advantage in secondary organs,” explains Dr Oskarsson.

The extracellular matrix protein tenascin C (TNC), a type of matricellular protein, is an essential component of the metastatic niche in breast cancer. “We’ve observed that TNC is expressed in cancer cells that we isolated from the pleural

A second major reason for studying TNC and other matricellular proteins is their expression in the normal stem cell niches of a number of different tissues. This could indicate that TNC plays a role in regulating the properties of normal stem cells, properties which have increasingly been shown to be important in the development and progression of cancer.

“In a tumour, stem cell attributes, such as self-renewal and the ability to resist stress, have essentially been hi-jacked by the cancer cells, and during metastatic progression, cancer cells express their

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At a glance Full Project Title Analysis of Tenascin C function in breast cancer metastasis to bone (BoneMetTnc)

Tenascin-C expression in breast cancer. Immunostaining of tenascin-C protein in a primary breast tumour (left) and metastasis (above).

own TNC to maintain some of these properties,” explains Dr Oskarsson.

The interaction between the tumour cells and the metastatic niche continuously evolves as the metastasis grows, and cells manipulate the microenvironment to promote their own fitness. The project is investigating the role of TNC during this process, looking at the underlying mechanisms behind signalling and cell functions. “We are identifying the receptors that mediate TNC induced metastatic colonization. This is very important and may expand the possible strategies to target the TNC axis in metastasis,” outlines Dr Oskarsson.

Another major area of research is the role of TNC in resistance to cancer therapy.

“We generate tumours that are deficient in tenascin C, and treat with commonly used chemotherapy to look at whether we can sensitise cancer to the current therapeutic options by eliminating tenascin C,” continues Dr Oskarsson.

“Moreover, using conditional knockdown methods, we can eliminate tenascin C at distinct stages during the progression of the disease, and compare different intervention strategies.”

Mechanistic research Alongside their research into TNC, Dr Oskarsson and his colleagues are also starting to analyse other molecular components of the metastatic niche as well as the cells that produce these components.

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“We’re looking at the fibroblasts and endothelial cells that are recruited to metastatic foci, and analysing the molecular changes that occur during disease progression. We’re studying the cross-talk between these stromal - or niche - cells, and the cancer cells themselves,” he outlines. This will help researchers build a deeper understanding of metastatic process. “There are many things that we still need to dissect and analyse within the metastatic niche, a lot of work needs to be done in that area,” says Dr Oskarsson.

While at this stage the project is primarily focused on mechanistic analysis, the research holds important clinical implications, potentially offering insights that may help to inhibit metastatic relapse. “An important part of our work is to clinically validate any findings from the model systems that we are using, both 3-D cell culture models and mouse models,” continues Dr Oskarsson. The findings from these model systems can then be related back to clinical parameters.

The project has access to clinical samples from partners in Heidelberg and Mannheim, from which researchers can then look to draw links and learn more about extracellular matrix proteins. “We can stain these extracellular matrix proteins in patient derived tumours and look to associate their expression with numerous clinical parameters,” explains Dr Oskarsson.

Project Objectives The aim of the project is to dissect the function and molecular mediators of the extracellular matrix protein tenascin C (TNC) within the metastatic niche in lung and bone. Furthermore, we want to identify and analyze the surface receptors to which TNC may bind and promote signaling and metastatic progression. Finally, we aim to analyze the potential role of TNC in resistance to cancer therapy.

Project Funding Marie Curie Actions CIG Dietmar Hopp Foundation German Cancer Consortium (DKTK) Project Partners • Professor Andreas Schneeweiss, National Center for Tumor Diseases, University Hospital Heidelberg • Professor Marc Sütterlin, Department of Gynecology and Obstetrics, University Medical Center Mannheim • Dr Saskia Spaich, Department of Gynecology and Obstetrics, University Medical Center Mannheim • Professor Peter Sinn, Institute of Pathology, University Hospital Heidelberg Contact Details Thordur Oskarsson, PhD Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) German Cancer Research Center (DKFZ) Im Neuenheimer Feld 280 D-69120 Heidelberg, Germany T: + 49 (0) 6221/ 42-3903 E: t.oskarsson@dkfz.de W: http://www.hi-stem.de W: https://www.dkfz.de

Dr Thordur Oskarsson Dr Thordur Oskarsson is a group leader at the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) and the German Cancer Research Center (DKFZ). He received a PhD from the Swiss Institute for Experimental Cancer Research (ISREC) in Lausanne in 2006 and pursued a postdoctoral training at the Memorial Sloan-Kettering Cancer Center in New York, between 2006 and 2011. The research in the Oskarsson laboratory focuses on the role of the microenvironment in cancer metastasis and therapy resistance.

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Figure 1. An extra copy of Ink4/Arf and p53 attenuates NSCs function decline in SVZ with aging (C) Expression of several NSC markers is elevated in SVZ from aged (24-30 months) transgenic mice. (D) Neuroblast and neuronal markers of are also elevated in olfactory bulbs of aged transgenic mice.

Investigating the transformation of neural stem cells Glioma stem cells play a significant role in the initiation, maintenance and development of certain forms of tumour, including glioblastoma multiforme, a highly malignant form of brain cancer. New strategies to directly target these cells could lead to great improvements in treatment, as Dr Ander Matheu of the SOX-BMI1 project explains The body’s population

of neural stem cells plays a central role in generating, maintaining and repairing the central nervous system throughout life. However, as we age the number of neural stem cells declines, a process which has been associated with a decline in cognitive activity and neurodegenerative diseases and the emergence of certain mutations, which can have significant consequences for personal health. “Mutations in these cells induce cell transformation, which can lead to tumour formation and glioblastomas,” says Dr Ander Matheu.

Based at the Biodonostia health research institute in the Spanish city of San Sebastian, Dr Matheu is the Principal Investigator of the SOX-BMI1 project, an initiative investigating the transformation of neural stem cells and their role in certain pathologies, including glioblastomas and neurodegenerative disease. “We aim to discover whether a general mechanism affects the different pathologies associated with aging,” he outlines.

Cancer stem cells A key focus in this research is the development of cancer stem cells and the maintenance of their characteristics.

Mutations in neural stem cells can lead to their transformation into glioma stem cells,

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a rare subpopulation of tumour cells, which leads to the development of glioblastoma, a highly aggressive form of brain tumour. “It has been established that specific mutations in neural stem cells induce tumours and glioblastoma, in part by affecting the TP53 protein,” says Dr Matheu. Indeed, results generated within the project and published in the journal Aging Cell demonstrates that mice carrying a combined extra copy of p53 and Ink4/Arf display elongated lifespan, delayed neural stem cell

Established therapies like chemotherapy and radiotherapy are not very effective and the location of the tumour often makes surgery complicated, underlining the importance of continued research. Dr Matheu and his colleagues are investigating the underlying mechanisms and factors behind the maintenance and function of both neural stem cells and glioma stem cells; two specific transcriptor factors – SOX9 and BMI1 – are known to play an important role in these terms. “If

Glioblastomas are very aggressive, and they are resistant to commonly used therapies. The prognosis for patients is poor, as established therapies like chemotherapy and radiotherapy are not very effective, and the location of the tumour often makes surgery complicated exhaustion and enhanced resistance to cellular transformation and tumor formation (Carrasco-Garcia et al., 2015).

Glioma stem cells are not only involved in the initiation and maintenance of the disease, but also its progression and later resistance to therapy. “Glioblastomas are very aggressive, and they are resistant to commonly used therapies, so the prognosis for patients is poor” continues Dr Matheu.

neural stem cells lack SOX9 or BMI1 then they differentiate. They don’t maintain the characteristics of stem cells and they cannot proliferate,” he explains.

Researchers in the project are investigating the significance of both SOX9 and BMI1 in regulating the population of cancer stem cells, using both animal models and cell samples from human patients. “We have been able to isolate and generate cultures of human glioma stem cells. We also have

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Hallmarks of aging. López-Otín et al, 2013

cultures of neural stem cells, from both mice and humans,” outlines Dr Matheu.

This approach allows Dr Matheu and his colleagues to study both the initial cause of a tumour, and the mechanisms behind its maintenance, progression and recurrence.

With the mouse models that are being used in the project, researchers are able to study the initiation of glioblastomas, whereas the tumour is already established in human tissue samples, from which new insights can be drawn into its maintenance and progression. “There we can study the maintenance of a tumour and the factors behind resistance to therapy,” says Dr Matheu. Researchers manipulate the expression of SOX9 and BMI1 in glioma stem cells to try and characterise their role

in the regulation of these cells. “We know that high levels of both of these proteins are expressed in the cell lines that we have generated,” continues Dr Matheu. “We modulate their activity through lentiviral infections, and we then characterise what is happening at the cellular level.” Interestingly, we have found that SOX9 genetic inhibition significantly impairs the activity and malignant features of glioma stem cells. This work has been recently published in Expert Opinion On Therapeutic Targets journal (Garros-Regulez et al., 2016).

Researchers are studying cell differentiation and tumour activity, aiming to build a fuller picture of the role of SOX9 and BMI1 in the development and maintenance of cancer, work which could

Expression of SOX9 in GBM and gastric cancer biopsies

eventually yield important therapeutic insights. One area of particular interest to Dr Matheu and his colleagues is the role of SOX9 in resistance to therapy. “We have found that the activity of SOX9 is responsible for resistance to Temozolomide, the form of chemotherapy most commonly used in the clinic,” he says. Researchers are working to identify drugs that inhibit the activity of SOX9, and significant advances have been achieved. “We have found that Rapamycin inhibits the general function of glioma stem cells through the inhibition of SOX2 and SOX9. Rapamycin is an agent that inhibits mTOR activity, one of the main activated pathways in glioblastoma,” explains Dr Matheu. “The effects of Rapamycin are extensive, so we aim to find a drug to directly inhibit these glioma stem cells.”

Cancer therapy This holds important implications for cancer therapy. Evidence suggests that targeting SOX9 or BMI1 could block the characteristics of cancer stem cells, which could represent a new avenue for treating not only glioblastoma but also additional types of cancers such as colorectal and gastric cancers where the group of Dr. Matheu identified that SOX9-BMI1 axis plays a relevant role in the maintenance of cancer stem cells. These works have been recently

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At a glance High levels of SOX9 in glioma stem cells correlate with tumor progression

Full Project Title Role of SOX9-BMI1 in adult neural stem cells and in glioma stem cells (SOX-BMI1) Project Objectives The goals of this translational research project are to investigate the clinical relevance of SOX9-BMI1 in glioblastoma, to characterize its role in the regulation of glioma stem cells and to determine whether Sox9-Bmi1 concomitant overexpression is sufficient to induce neural stem cell transformation and cause gliomas. To achieve our aims, we will generate a unique set of cellular and animal models to study in vitro and in vivo the biology of neural and glioma stem cells.

Project Funding Funding provided by Marie Curie Career Integration Grant CIG 712404.

Project Partners • Nicolas Sampron (Donostia Hospital) • Robin Lovell-Badge (The CRICK Institute) Contact Details Head of Neuro-Oncology Group Leader, Biodonostia HRI Pº Dr. Beguiristain s/n 20014 Donostia – San Sebastián Gipuzkoa T: +34 943 00 6073 E: ander.matheu@biodonostia.org W: www.biodonostia.org/en

published in Scientific Reports (CarrascoGarcia et al., 2016) and Cancer Research (Santos JC et al., 2016) journals. Dr Matheu and his colleagues plan to investigate this therapeutic potential further. “We also aim to identify small molecules that can inhibit this protein and try to translate that to the clinic,” he says. This of course is central to therapeutic development, and while translating laboratory research into clinical

Both SOX9 and BMI1 are commonly overexpressed in several forms of cancer, which Dr Matheu says was an important part of the original motivation behind the project. “We’ve postulated that inhibition of this pathway would help not only reduce or eliminate brain tumours and glioblastoma, but also other types of tumours. There is clear evidence that this will be a good therapeutic strategy in other

If neural stem cells lack SOX9 or BMI1 then they differentiate. They don’t maintain the characteristics of stem cells and they cannot proliferate developments can be a complex process, Dr Matheu is keen to investigate potential anticancer therapies. “We are trying to directly target cancer stem cells. The preliminary data from the project suggests that this is possible,” he says.

The project’s research also holds wider relevance beyond the specific example of glioblastoma to encompass other forms of cancer and neurodegenerative disease.

types of cancer, including colo-rectal, breast, and gastric cancer,” he outlines.

Since SOX9 and BMI1 are involved in regulating stem cells and a decline in stem cell activity occurs with aging, this opens up further avenues of investigation. “We are also planning to study the impact of SOX9 and BMI1 on aging associated disorders such as neurodegenerative diseases,” continues Dr Matheu.

Dr Ander Matheu

Dr Ander Matheu’s main research interests are cancer and the process of ageing. He gained his Ph.D. under the supervision of Dr. Manuel Serrano, and he currently prioritises translational research, in order to ensure that basic discoveries have practical applications and help to improve human health.

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New approaches to get to the heart of membranous nephropathy A rare disease which affects the kidney, membranous nephropathy is the second-most common cause of nephrotic syndrome. The OSAI project is using novel technological approaches to shed new light on the disease, research which could lead to the development of rapidly acting new therapies, as Principal Investigator Professor Pierre Ronco explains A rare disease which affects structures inside the kidney, membranous nephropathy is caused by a thickening of the base membrane of the glomerulus, a filtering unit in the kidney. This thickening is caused by the accumulation of immune deposits, as Professor Pierre Ronco explains. “There are deposits of antibodies and of antigens. The consequence of that is the development of proteinuria – loss of proteins through the urine – and the decrease of the albumin serum in the blood,” he says. Based at the INSERM Institute and University Pierre et Marie Curie in Paris, Professor Ronco is the Principal Investigator of the OSAI project, an EC-backed initiative investigating the pathophysiology of membranous nephropathy, which he coordinates with his co-worker, Dr Hanna Debiec (Research Director at INSERM). “The disease can evolve in three ways; spontaneous remission, persistent proteinuria, or endstage renal failure,” he says. “It has been shown that this disease is auto-immune in nature – in most cases the antigen is localised in the glomerulus. The patient produces antibodies directed to this antigen, which become deposited in the glomerulus and this induces the disease.”

Triggering events The project’s primary objective is to understand the triggering events that lead to the disease and the pre-disposing factors behind positive or negative outcomes. This builds from the current understanding of how the disease develops and progresses. “The first step is the presentation of the antigens to the immune system by the HLA class 2 molecules – for instance HLA-DQA1,” explains Professor Ronco. The immune system produces antibodies which circulate in blood and are then deposited in the glomerulus, where Professor Ronco says they react with the antigens. “This activates a

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Figure 1. Mechanisms of immune mediated podocyte injury in MN and pathogenesis based therapeutic approach. complement cascade, leading to the formation of the membrane attack complex of complement. This induces injury to the podocyte, and to the capillary wall, which in turn induces proteinuria and can eventually lead to nephrotic syndrome,”

This forms a key element of the project’s research agenda.

Membranous nephropathy is a complex disease, and typically develops as the result of a sequence of events. “We are interested in each step of the disease. We are interested

It has been shown that membranous nephropathy is auto-immune in nature – in most cases the antigen is localised in the glomerulus. The patient produces antibodies directed to this antigen, which becomes deposited in the glomerulus and induces the disease he outlines. “What is not known is the trigger event which induces the production of antibodies in patients with predisposing variants. Molecular mimicry with microbes or toxic agents could play an important role.”

in the first step, in the triggering event that stimulates the production of antibodies. We are also interested in the last step, the formation of the complex of complement, which attacks the podocyte membrane, and the development of

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proteinuria,” says Professor Ronco. One major area of interest is the gene variants which could be involved in complement activation. “We think that there are maybe genetic variants in the complement cascade, which are responsible – to varying degrees – for activation of the complement, and which thus may regulate formation of the membrane attack complex of complement, resulting in varying severity of disease,” continues Professor Ronco. “We aim to find new drugs that could potentially block the formation of this complex of complement.”

The disease does not invariably progress to a point where treatment is required though, as while in some cases patients require dialysis, around a third of patients will go into spontaneous remission. “Most patients present with nephrotic syndrome and a third of them will undergo remission,” says Professor Ronco.

Researchers are also interested in the mechanisms that induce spontaneous remission of nephrotic syndrome. “It could be the disappearance of the triggering event, or possibly another mechanism is involved,” says Professor Ronco.

Membranous nephropathy is known to be the second most common cause of nephrotic syndrome, underlining the wider importance of research in this area.

“There are different causes of nephrotic syndrome. Some are immunological in nature and others are metabolic, including diabetes,” explains Professor Ronco.

New technological approaches Researchers are using cutting-edge techniques to investigate the successive steps of membranous nephropathy. The first technique is called HLA peptidomics, a method which is being used to identify epitopes, the relevant immune response targets. “Our objective is to identify T-cell epitopes of the major antigen PLA2R, that are recognised by the T-lymphocytes,” outlines Professor Ronco. A T-cell epitope is the part of a complex formed with HLA class-2 molecules that is presented to the immune system, which leads to the production of antibodies. “These HLA class-2 molecules can circulate in blood in combination with the epitope, which is recognised and presented by this molecule.

However, the amounts of circulating HLA epitope-complexes are very low. So we have embarked on a collaboration with our colleagues in Zurich (Tim Fugmann, Dario Neri), who are very experienced in peptidomics,” continues Professor Ronco.

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Figure 2. Schematic description of the new diagnostic methodology based on analysis of plasma soluble HLA peptidome.

“They are trying to set up a very sensitive method to identify the epitopes combined to HLA class-2 molecules in the blood.”

This technique has never previously been used to study auto-immune disorders where antigens or epitopes are presented

by HLA class 2 molecules. While the technique is relatively untested, Professor Ronco says the early signs are promising.

“Our collaborators have reached the first step, where epitopes complexed with HLA class-2 molecules can be identified. We are now starting a second step, where we will try to identify these complexes in patients with membra漀渀us nephropathy or other immunological glomerular diseases,” he outlines. This approach will help researchers to monitor the progression of the disease and predict patient outcomes.

“We think that the patients with active disease will have circulating HLA epitope complexes in the blood, whereas those patients in remission will probably have a very low amount of these complexes, or no complexes at all,” says Professor Ronco.

The second key technique being used within the project is molecular modelling of the membrane attack complex of complement. This is a highly complex molecule, with multiple components, and once assembled it can damage key structures within the kidney. “When assembled, this complex induces injury to podocytes and increases the permeability of the capillary wall to proteins,” explains Professor Ronco. Project collaborator Bogdan Iorga at CNRS in Gif-sur-Yvette, a

research campus close to Paris, has developed a dynamic model, encompassing each step of the assembly process. “With this model, we will be able to identify each of the possible intermediate steps of the membrane attack complex assembly. Then we can potentially propose new compounds for the treatment of membranous nephropathy,” continues Professor Ronco.

“The objective will be to block the assembly of the membrane attack complex of complement, and consequently prevent the onset of proteinuria.”

The current methods of treating membranous nephropathy rely primarily on immuno-suppressive agents, such as corticosteroids, cyclosporine and cyclophosphamide. However, Professor Ronco says that alongside the toxicity of immuno-suppressive agents, there are two main problems with this method of treatment. “The first is that a maximum of only around 70 percent of patients will enter remission of proteinuria. The second is that the effect of the treatment is delayed,” he explains. The project aims to develop alternative new therapies that will work more rapidly. “We want to develop new drugs that can block complement assembly on the surface of the podocyte in the glomerulus, because we hope that this new treatment will be active very rapidly,” outlines Professor Ronco. “Also, for those patients who are resistant to immuno-suppressive therapy, we hope to at least limit the level of inflammation in the glomerulus.”

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At a glance Full Project Title Membranous nephropathy : a model for solving organ-specific auto-immunity (OSAI)

Figure 3. The MAC, C5b-9 complex formation. C5b-6 initiates pore formation via the sequential recruitment of homologous proteins: C7, C8, and 12–18 copies of C9. The C5b-9 complex forms transmembrane pores in cell membranes. Red arrows: designed inhibitors that blocks assembly and membrane insertion of the terminal complement complex.

This research could also hold implications beyond membranous nephropathy, as the condition is considered to be a paradigm of organ-specific autoimmune disease. However, while these approaches could potentially be used to study autoimmune conditions affecting other organs, Professor Ronco says the project’s current focus is very much on membranous nephropathy. “We hope to deliver additional biomarkers, especially T-cell epitopes, as identified by the

peptidomic approach, that are associated with the disease,” he says. Cases of membranous nephropathy can vary in severity, so Professor Ronco says it’s important to identify those patients who need treatment and those who don’t. “A major objective is to propose predictive biomarkers to the clinicians, in order to determine those patients who will need treatment with immuno-suppressive agents and complement antagonist drugs, and those who won’t,” he says.

Project Objectives Membranous nephropathy (MN) is a paradigm of organ-specific autoimmune disease which affects the kidney glomerulus, resulting in the formation of immune deposits, complement-mediated proteinuria, and renal failure. My group has recently identified 2 causative antigens (neutral endopeptidase and bovine serum albumin) in children, and 2 predisposing genes HLA-DQA1 and PLA2R1 coding for another antigen in adult MN. Project Funding ERC-AG - ERC Advanced Grant Contact Details Project Coordinator, Pierre Marie Victor Ronco Institut National de la Santé et de la Recherche Médicale T: + 33 1 56016639 E: pierre.ronco@tnn.ap-hop-paris.fr W: http://cordis.europa.eu/project/ rcn/108575_en.html

Pierre Marie Victor Ronco

Pierre Ronco was appointed full Professor of Nephrology at UPMC in 1986. He became head of the Renal division in 1995 and director of the INSERM research unit in 1998. He was appointed senior member of the prestigious Institut Universitaire de France in 2008. He served as President of the Scientific Councils of Medical Faculty Saint-Antoine and Francophone Kidney Foundation, President of the Francophone Society of Nephrology, councillor of the International Society of Nephrology (ISN) and of the European Society of Nephrology ERA-EDTA and President of the 49th ERA-EDTA congress in Paris (May 2012, 8600 delegates). He is currently Vice-President of the Francophone Kidney Foundation, and member of the NIH supported network on rare kidney diseases (Neptune).

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How do you recognise that face?

The human brain has a remarkable ability to recognise and remember faces, even in different situations and across large time gaps. How do we do it? Professor Bruno Rossion tells us about his work in investigating how the human brain builds a visual representation of a face, research which could lead to new insights into how the brain functions The field of cognitive

and systems neuroscience offers enormous scope for research, with scientists using a wide variety of techniques to build a deeper understanding of how the human brain functions. As the Principal Investigator of the FACESSVEP project, Professor Bruno Rossion is looking at one specific aspect of brain function. “We specifically focus on a brain function that we think is fundamental: Perceptual Categorisation – how the brain organises sensory information and labels the world, for instance to tell apart cats from

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dogs, and do so for all instances of these animal species. We are concentrating on vision, the dominant modality in humans” he outlines. “Within the field of vision, we use the human face as our favourite model.

We want to understand how the brain recognises people by their face – that’s the main goal of the project, it’s the model for us to understand brain function.”

Facial identity This is a very rich model, as the visual system extracts a lot of sensory

information from an individual’s face to categorize it according to gender, emotion, age and a whole host of other things. The main focus for the project however is facial identity. “How do we use the face to identify people?” says Professor Rossion.

The human brain has a great capacity to recognise and remember faces, even in different situations and across large time gaps, and there are no animal species that have developed such a level of expertise.

“We’re able to clearly individualise faces, draw distinctions between faces, and are

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able to recognise that it’s the same face across changes of views and different lighting. Maybe you haven’t seen a person for five years but you still recognise them – how does the brain do it?” asks Professor Rossion.

There has been a great deal of research into whether we use specific facial features such as the eyes or the mouth to recognise an individual’s face. However, Professor Rossion believes the primary question is elsewhere: how we integrate an individual’s facial features into a visual image. “It’s a perceptual process – we generally call it “holistic” or “configural” processing. It’s really the ability of the human brain, of the visual system, to extract a single, unified representation of all these features at a glance,” he explains.

“When you look at a face and recognise it, you don’t usually fixate on any of the features. Your first fixation, where your eye gaze will land, is on the top of the nose of the face, usually in the middle – in between these features.”

This is thought to be because the top of the nose is the best position to extract information on all the features at once and construct a holistic representation.

This is the case both for people that we know well and those we are meeting for the first time; in fact, there is little evidence to suggest the visual system treats people differently on the basis of familiarity. “What is clear is that if you

know somebody, the representation is richer and you’re able to recall a lot of semantic information about that person,” says Professor Rossion.

“However, I’m interested in the extraction of the first perceptual image, an image that is sufficiently detailed to individualise the face, to make it a unique pattern in your brain. How do we do that?”

The visual system, broadly defined as the system that deals with the visual modality, plays a central role in this process. While the eye, the optic nerve and the primary visual cortex were long thought to be the main regions of the

understand how the visual system works, then we can gain deep insights into the working of the whole brain,” says Professor Rossion.

FPVS This is a powerful source of motivation for the project’s work, with researchers using a method called fast periodic visual stimulation (FPVS) to investigate how humans build a visual representation of a face. This method involves repeatedly stimulating the visual system at a fixed frequency and recording the brain’s response using an electroencephalogram (EEG). “The idea is pretty old: if you

We’re able to clearly individualise faces, draw distinctions between faces, and are able to recognise that it’s the same face across changes of views and different lighting.

Maybe you haven’t seen a person for five years but you still recognise them – how does the brain do it? brain that dealt with vision, it is now known that a much larger proportion of our brains are involved. “It’s estimated that up to 30-40 percent of the human brain deals with vision, either directly or indirectly,” outlines Professor Rossion.

Enormous mental resources are required to deal with the complexity of the visual world, underlining the wider importance of research into the visual system. “If we

stimulate the brain with a light flickering on and off at say ten cycles per second, 10 Hertz – then the brain synchronises its activity exactly to that frequency,” explains Professor Rossion. “So if you put an electrode on an individual’s scalp, or inside their brain, you will see that after a few hundreds of milliseconds, populations of neurons will synchronise exactly to that frequency.”

Fig 2 (a & b). A face picture presented at a fast rate of 5.88 Hz through sinusoidal contrast modulation, ensuring that the visual system is constantly stimulated for about one minute. Every 5 pictures (1.18 Hz), a new face identity is presented. Stimulation sequences can be presented at upright or - as a control - at inverted orientation, since the human brain finds it very difficult to identify inverted faces. c. An EEG spectrum gives responses at 1.18 Hz and harmonics (2.36 Hz, etc.), reflecting the discrimination of facial identities at this rate. This response is prominent over right occipito-temporal sites. d. Despite interindividual variability, the face identity discrimination response is obtained in a few minutes of stimulation in all individual participants tested (from Liu-Shuang, Norcia & Rossion, 2014, Neuropsychologia).

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Fig 3. a. Sinusoidal contrast modulation of natural images at a fast 12.5 Hz rate (80 milliseconds between image onset). Faces embedded every 7 stimuli leads to large faceselective responses in the EEG spectrum (b) at the exact frequency rate of 12.5/7 = 1.78 Hz and harmonics (3.56 Hz, etc.). This right occipito-temporal face-selective response is obtained in a few minutes of stimulation in every individual brain. c. EEG signals over time reveal an ongoing synchronization to stimulation rate at 12.5 Hz, which can be selectively filtered out to reveal the specific complex response to faces. This response is made of 4 components from about 100ms onset to 500ms, revealing a prolonged selective processing of faces in the human brain (Retter & Rossion, 2016, Neuropsychologia).

This property offers a way to control brain activity, from which researchers can investigate which regions of the brain deal with visual information. “If I show you a light flickering at 10 Hertz, I get an electrical response from the brain at 10 Hertz, but I don’t get it from regions of the brain that don’t deal with vision. So the FPVS method is extremely specific,” says Professor Rossion. This phenomenon is fairly well-known, described in a paper published as long ago as 1934, but it has been relatively under-used; now Professor Rossion is using it in research with complex images. “We simply started by presenting images of different faces at 3.5 Hertz, for a duration of a minute,” he explains.

Researchers found that regions of the brain that deal with facial processing started to synchronise to that frequency.

From here, Professor Rossion has been able to directly relate external stimulations to brain activity. “This is a major goal in research, we aim to develop intelligible relationships between the visual world and brain activity,” he says. By synchronising

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the brain to a specific frequency, researchers are able to almost take control of the brain. “We are able to concentrate all brain activity – everything that we are interested in – in that specific frequency.

So it’s a very objective tool to understand brain function and it gives us enormous power, because we can just concentrate on the electrical response to that specific frequency,” explains Professor Rossion.

Different frequency rates of stimulation are being investigated within the project, as Professor Rossion believes it’s important to take the rate of stimulation into account when testing brain function. For instance, researchers have found that the best frequency to individualise faces, to build a visual representation, is at 6 hertz. “If I give you a second, and there are a number of faces to recognise in a crowd, we have found that you’re able to individualise up to six faces. If you have more faces you can’t do it in a second – it’s too many,” outlines Professor Rossion. “This is why we call 6 Hertz the optimal frequency for individualizing faces.”

This research is primarily centred on adults, but there are also workpackages in the project investigating facial recognition in children and infants. One of the great advantages of the FPVS technique is that researchers get a significant brain response in a very short amount of time, which means it can be used with infants, who might be rapidly distracted when other techniques are applied. “We’ve been able to test infants between 4-6 months old. We have studied their ability to tell various natural images of faces apart from complex natural images of objects. We have shown that they are able to do it at a single glance, that is when 6 images are presented every second,” says Professor Rossion. “In children, we have also started to look at the development of the ability to recognise the identity of faces.”

The question of whether adults, infants and children all recognise faces in the same way is still a source of debate.

Professor Rossion believes the FPVS technique holds clear potential in this regard, yet it will be important to maintain a common standard across different populations in research, taking the typical adult system as the model. “If adults are able to individualise faces at 6 Hertz, we should not slow down the frequency when we test infants and children, we should also test them at 6 Hertz,” he stresses. “If they cannot respond at 6 Hertz it just means they cannot do it. So when we talk about facial identity recognition, we need to incorporate the rate at which you are able to do it in the definition of the function proper.”

A lot of cognitive processes are still evolving in infants and children, and debate continues over the age at which the facial identity recognition system becomes fully mature. There are differences in the way children and adults recognise faces, and our facial recognition abilities do change over time, but the underlying nature of these changes are unclear. “We don’t know if it’s a qualitative or quantitative change. Is the process the same in children and adults, and it improves? Or does a fundamentally different process take place?” says Professor Rossion. The application of new techniques could help answer these questions in future, believes Professor Rossion. “I’m very optimistic on this because we have a sensitive, objective and implicit measure of brain activity in our hands. But at the moment this question is unresolved,” he says.

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Clinical population The project’s research also extends to investigating clinical populations, whose facial recognition processes have been disturbed. Researchers are looking at facial recognition processes in patients with a deficit called prosopagnosia, where the ability to recognise faces is impaired following brain damage; Professor Rossion says this work has uncovered new potential avenues of investigation. “With the FPVS technique I gained facial identity recognition measures from every individual I tested outside the clinical setting, within a few minutes of testing.

Then when I tested patients with prosopagnosia I got no response,” he says.

This demonstrates that the technique is valid as a diagnostic tool, now researchers are looking to use it on other populations.

“We intend to test a population with autism spectrum disorder,” outlines Professor Rossion.

This condition is characterised in some cases by an impaired ability to use facial

relevant, including dyslexia. “We would like to test children who are suspected of having reading disorders, to see if we can develop diagnostic tools for dyslexia,” he outlines. Another area of interest is recording signals inside the brain; Professor Rossion says the development of a method of treating epilepsy refractory to medication offers a unique opportunity to gain new insights. “Clinicians are considering removing the part of the brain that generates an epileptic seizure. These patients are implanted with electrodes to test which part of the brain should be removed or not,” he explains.

This provides a great opportunity to investigate the brain, as signals recorded from within the brain are thought to much richer than those from outside. It is of course essential to get the consent of the patients first; with this proviso, Professor Rossion is keen to explore this further. “We have a unique opportunity to understand the brain by testing these individuals with this new approach,” he says.

If I show you a light flickering at 10 times a second, I get an electrical response from the brain at 10 times per second, but I don’t get it from regions of the brain that don’t deal with vision. So the FPVS method is extremely specific cues to interact with people. It is not known whether this is a perceptual problem, in that they fail to extract the information from the facial cues, or if they are in fact able to extract the information but they are not interested and don’t make use of it. “With the FPVS technique we should be able to answer that question.

We’re not going to ask them anything, we’re just going to measure how their brain reacts to facial changes,” explains Professor Rossion. The technique has also just been applied to other processes, including reading. “Instead of presenting faces we present words and letters at a fixed rate, and measure the brain’s response at that rate,” says Professor Rossion. “While faces are processed primarily in the posterior region of the brain’s right hemisphere, visual letters primarily engage the left hemisphere, as soon as children learn these letters.”

Researchers are looking to build further on this work in future. With the project set to conclude in January 2017, Professor Rossion is keen to explore other areas in which the FPVS technique could prove

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At a glance Full Project Title Fast Periodic Visual Stimulation to Understand Human Brain Function (FACESSVEP) Project Objectives The overarching goal of this research project is to understand how the human brain recognizes people by their face, a function for which artificial systems or other animal species can’t match human adult performance. The specific project is based on the visual stimulation of the brain with complex images presented at a fast periodic rate (e.g., 6 images/second) and the recording of electrophysiological brain activity exactly synchronized to this rate.

Project Funding • Main funding of the project: European Research Council (ERC) – Starting Grant (Consolidator scheme) 2012-2017. • Fonds National de la recherche scientifique (FNRS) • Belgian Federal Grant Agency (BELSPO) • Louvain Fundation • Communauté Française de Belgique, ARC grant.

Main Project Partners • Anthony Norcia, Stanford University, USA • Louis Maillard, Centre Hospitalier Universitaire (CHRU), Nancy, France Contact Details Professor Bruno Rossion, IPSY/IONS Place Cardinal Mercier 10 bte L3.05.01 à 1348 Louvain-la-Neuve T: +32 1047 8788 E: bruno.rossion@uclouvain.be W: http://face-categorization-lab. webnode.com/research/steady-state-facepotentials-ssfp-/

Professor Bruno Rossion

Professor Bruno Rossion is director of research at the National Research Fund in Belgium (FNRS), University of Louvain in Belgium. He graduated from the University of Louvain and spent postdoctoral years at Brown University, USA. He has authored over 150 scientific publications in international peer-reviewed journals on the topic of face perception, using a diversity of approaches in systems and cognitive neuroscience.

Fig 4.

Inside the brain.

The fast periodic stimulation technique is applied while recording electrophysiological signals inside the brain of patients implanted for clinical monitoring of epileptic seizures. This rare approach allows identifying and quantifying the neural basis of face perception, with fast periodic visual stimulation (Jonas et al., 2016, PNAS)

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Recent global history is marked by several instances of civil conflict, where people of the same nationality have taken up arms against each other. The role of the disease environment in outbreaks of civil war has so far been largely overlooked, says Professor Uwe Sunde of the DISCON project, an EU-backed initiative taking a fresh look at the topic

Exploring the links between civil conflict and disease The last fifty years have been marked by regular outbreaks of civil violence across the world, where citizens of the same nation have taken up arms against each other. While issues like ethnic tensions, resource allocation and political representation have often been major factors behind these outbreaks, the role of the disease environment has been largely overlooked, now researchers in the DISCON project are taking a fresh look at the subject. “The basic idea of the project is to bring health into the picture, and find out whether variation in health threats, or the outbreak of epidemics, can have a causal effect on the outbreak of civil violence,” says Professor Uwe Sunde, the project’s Principal Investigator. In some cases external actors have become involved in civil violence, yet Professor Sunde says the project is focused on civil conflict between people of the same nation. “We have different data sources.

We’re most interested in intra-state conflicts that are fought among sections of the same nation without external interventions,” he outlines.

There have been many examples of such conflicts over the last fifty years, and Professor Sunde and his colleagues have access to a wealth of data from across the

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globe in their research. This is combined with further epidemiological information to help researchers build a deeper picture of the role of disease in civil violence. “We use data sources that collect data on conflicts worldwide at a high level of temporal resolution on an annual basis. We combine that with information from epidemiological databases, that measure

Disease exposure A key step in the project is to establish whether there is a potential causal effect of disease exposure on outbreaks of civil conflict. Professor Sunde and his colleagues have been working on a research paper in this area. “We look at civil war as an outcome, and we use an identification strategy based on exposure

We essentially look at droughts or heat waves, and whether they have a different impact in terms of the outbreak of civil conflict if they happen in an area with few diseases or many diseases disease exposure in terms of infections and diagnosis of certain disease conditions,” says Professor Sunde. Typically a wide range of factors are involved in outbreaks of civil violence, so Professor Sunde aims to exclude other causes aside from the disease environment. “We control for as much we can, including factors like income and ethnic polarisation,” he stresses.

“Essentially all measures of potential determinants of civil conflict highlighted in previous research are accounted for in our empirical framework.”

to particular diseases that are essentially non-eradicable, non-preventable, and that cannot be communicated or spread through conflict,” he explains. These diseases are called multi-host vector transmitted diseases (MHVD), examples of which include dengue fever and malaria. “These diseases cannot be transmitted human-to-human – a vector is required. The vector in the case of malaria is a mosquito,” continues Professor Sunde. “This means that in areas where the disease isn’t present, or that aren’t

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suitable for that vector, you’re not going to transmit the disease just because troops are coming in. Then you can exploit variations in weather conditions that may or may not suit the vector, to look at variations in exposure to disease.”

This approach allows researchers to look at the causal relationship between disease exposure and outbreaks of civil conflict within a country, rather than the other way round. In a first step, the researchers are investigating variation in time-invariant conditions that affect the population of these vectors. In a second step, they look at the relationship between climatological shocks and the disease environment, exploiting variation within a country over time. “We essentially look at unusual events like heatwaves, droughts, and periods where the temperature was substantially above the mean for a particular area, and then look whether they have a different impact in terms of the outbreak of civil conflict if they happen in an area with few diseases or many diseases.” outlines Professor Sunde. Certain areas are known to have a high exposure to disease, in large part due to geography and climate, while in others exposure is more irregular, another topic of interest to Professor Sunde. “We can look at areas where many MHVDs are endemic and compare them to areas with few MHVDs and look at the effects of particular weather conditions that don’t happen every year,” he says.

“In areas with many MHVDs, suitable weather conditions for vectors lead to more violence than in areas with few endemic diseases.”

In a next step, the project investigates the hypothesis that people in areas

regularly exposed to a mosquito-borne disease tend to develop a level of immunity after they were first bitten, so that subsequent infections have much more moderate effects.

Weather fluctuations that affect disease exposure year-by-year or month-by-month might therefore be an important aspect to consider. “Certain weather conditions in terms of temperature and precipitation clearly influence the development of disease vectors.” explains Professor Sunde.

Heighten awareness A prime objective in this research is to heighten awareness of the importance of disease as a factor in outbreaks of civil conflict. While this area of research has been relatively unexplored until now, Professor Sunde and his colleagues have reached some clear findings. “We have found that high exposure to these MHVDs, both in terms of the presence of a lot of pathogens and in interaction with particularly suitable weather conditions, actually leads to an increase in the probability of an outbreak of civil conflict,” he says. The next step in research will be to analyse much more fine-grained data sets, and then take a closer look at public health policies. “We can look at whether health policies have an impact in reducing conflict – the first indications suggest that might be the case,” says Professor Sunde.

“We also plan to look again at issues around global warming, which are extremely interesting in that context, because global warming is expanding the habitat for these vectors. Asian Tiger mosquitoes have recently been found in Germany, and southern England.”

At a glance Full Project Title Disease Environment and Civil Conflict (DISCON) Project Objectives The goal of this research project is to investigate the role of the disease environment as a new, so far largely overlooked, determinant of civil conflict, using data at the national and subnational level.

Project Funding European Commission, Marie SklodowskaCurie Career-Integration Grant, FP7-MCCIG 618641 DISCON Project Partners • Matteo Cervellati • Simona Valmori Contact Details Project Coordinator, Professor Uwe Sunde Ludwig-Maximilians-Universität Seminar für Bevölkerungsökonomie Schackstr. 4/IV Stock, Raum 413 D-80539 München T: +49 (0)89 2180 1280 E: Uwe.sunde@econ.lmu.de W: http://www.popecon.econ.unimuenchen.de/personen/professoren/ sunde/index.html Cervellati, M., Sunde, U. and Valmori, S. (2016), Pathogens, Weather Shocks, and Civil Conflicts.

Economic Journal, forthcoming, doi:10.1111/ecoj.12430

Professor Uwe Sunde

Professor Uwe Sunde holds a chair in population economics at LMU Munich.

His research interests include long-term economic development, population economics, and political economy. He obtained his PhD from the University of Bonn and was director of the Swiss Institute for Empirical Economic Research at the University of St.Gallen prior to his current position.

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The creative power of chemistry lies in the ability of scientists to shape matter in unprecedented ways and generate new substances and materials with unique and advantageous properties. Now, researchers in the Light4Function project are looking to the next step, aiming to use light to control the timing and location of chemical and physical processes, as Professor Stefan Hecht explains

Researchers shine new light on chemical processes

There is a

long history of chemists designing sophisticated molecules to create new pharmaceuticals and novel materials.

This work has underpinned a great deal of technical and industrial development, but the level of sophistication is still way behind mother Nature’s machinery. Now researchers in the Light4Function project are looking to the next step, aiming to develop new methods to remotely yet precisely control chemical processes. “We are investigating the use of light as a trigger to control where and when chemical reactions take place,” explains Professor Stefan Hecht, the project’s Principal Investigator. The project aims to design and implement new functional photoswitchable systems, drawing inspiration from the natural world. “Nature uses stimuli – such as the presence of a messenger molecule, for example a hormone, or light – to trigger an event. The latter offers great advantages since light can be applied with exquisite spatio-temporal as well as energetic resolution – it’s the ideal remote-control,” says Professor Hecht.

This work is inspired by observations of the natural world, where light triggers and drives important processes. Professor

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Hecht points to the example of photosynthesis. “In photosynthesis, light generates a proton gradient across a membrane, and that drives synthesis of adenosine triphosphate,” he explains. With modern spectroscopy techniques, it is now possible to pulse light at very high frequencies, which allows researchers to control the timing of a chemical reaction using light. “Nowadays you can pulse light

Photoswitches Light can also be applied externally, in a non-invasive manner, offering a way to precisely control the outcome of a chemical reaction without adding a chemical.

However, one component has to interact with the light; Professor Hecht and his colleagues hold deep expertise in this area, particularly in the design of a specific type of molecules, so-called photoswitches.

We are investigating the use of light as a trigger to control where and when chemical reactions take place at the atto-second frequency (10 -18 seconds). Even fast chemical processes occur on a timescale longer than 10 -15 seconds and typically chemistry is much slower as it is limited by diffusion, which occurs at 10 -10 seconds. So light gives you absolutely exquisite control over time and we can initiate a reaction very precisely,” outlines Professor Hecht. “For spatial resolution, light is inferior to techniques such as Atomic Force Microscopy and Scanning Tunnelling Microscopy, but with state-of-the-art equipment you can go well below the so-called diffraction limit.”

“These molecules can exist in two different forms. Light can turn the molecules from one form into another. We want these two forms to behave very differently – like Dr. Jekyll and Mr. Hyde – because we want to exploit their differences to regulate various chemical and physical processes,” he says.

The project’s agenda includes fundamental research into these photoswitches, of which there are several different types. “We are looking to both design new photoswitches and improve existing photoswitches. We want them to switch reliably and very efficiently, ideally upon exposure to

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Figure 1 (Left). Photoswitches, which allow for modulation of their reactivity in exchange reactions (top left) as well as for locking adducts (bottom left), can be employed as crosslinkers to enable light-controlled glueing (top right) and local scratch healing (bottom right) of polymers. Related publications: Angewandte Chemie International Edition 2016, 55, 13882-13886 and Nature Communications DOI: 10.1038/ncomms13623.

Physical processes

sunlight,” continues Professor Hecht. “This is important for people working in photopharmacology in particular. We want to push the wavelength very far into the red part of the spectrum, so that it can penetrate the skin.”

Using the different properties of the two switch forms, it is possible to precisely modulate local chemical reactivity. This should impact a number of fields, including medicine. “In treatment, you want to make sure that a drug only kills unhealthy cells and not the healthy ones – this selectivity is a big problem in chemotherapy for example,” explains Professor Hecht. With precise spatial control over the location of a chemical reaction, the drug in its inactive form could be located close to a tumor, at which point the drug could be optically switched into its active form. “However,” notes Professor Hecht “There is no such universal molecule that can be used across all different chemical processes. We always need to optimize the photoswitch for its intended purpose.”

Researchers in the project aim to target several different processes using these photoswitches, alongside their fundamental research into improving their properties. The first aspect that researchers investigated was control over chemical connections, so bond-making.

“Here we follow two conceptually different approaches: in the first, we employ the switch itself as a starting material in the chemical reaction. But then for every connection that you want to make, you have to use one photon. So if you want to connect one thousand molecules, you will need at least one thousand photons,” explains Professor Hecht. In the second area of the project, the researchers are investigating lightcontrolled catalysis. “In this case, the switch would be integrated in the catalyst, and because the catalyst can turn over more than one substrate molecule, we get a regime where we can make a thousand molecules while only using a few photons,” says Professor Hecht. “This is the main difference between these two project areas.” The researchers have already exploited this fundamental work on light-controlled bond-making and bond-breaking to prepare polymeric materials which can be glued and healed - they even self-heal upon exposure to sunlight (Figure 1).

Beyond chemistry, the project is also trying to control various physical processes with light, most importantly charge transport.

Professor Hecht collaborates closely with Professor Paolo Samori of the University of Strasbourg. “He is an expert on electronic devices using transistors made from organic molecules,” says Professor Hecht.

In this case, photoswitches have been integrated into so-called organic thin film transistors (OTFTs), which are used in several different electronic devices, including computers, mobile phones, and television screens (Figure 2). “Some companies are working on optical memories that use this kind of technology,” continues Professor Hecht. “Here we can exploit the very different electronic properties, not chemical properties. In one form, they would trap a charge, while in the other the switch doesn’t interfere with charge transport. Thus, we can turn the transistor on and off at the speed of light.”

A fourth area of investigation in the project centers around light-driven molecular motion, where the researchers try to convert light directly into motion. The key challenge here is translating light-induced molecular changes into macroscopic movements. “We developed molecules that were very good at changing their shape under sunlight. Then, we collaborated with Professor Albert Schenning and his colleagues at TU Eindhoven and they integrated these molecules into a special

Figure 2 (Right). Photoswitches, which allow to modulate current flow through organic semiconductors and transistor devices made thereof (left), enable the design of fast and flexible optical memories (right). Related publications: Nature Chemistry 2012, 4, 675-679 and Nature Nanotechnology 2016, 11, 769-775.

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Figure 3 (Left). Photoswitches, which undergo large geometrical changes upon exposure to visible light (bottom left), can be aligned in polymer films (bottom right) that oscillate in sun-light (top right). Related publication: Nature Communications 2016, 7, 11975.

plastic film, in which the switch molecules are now aligned and hence organized, such that they all change their shape and work in concert. If you put these plastic films in sunlight, they chaotically bend up and down

bring significant benefits is in biomedical applications. “We have made some molecules that are highly relevant for people who want to go in the biological direction. We have successfully made these molecules that switch using visible light and red light, and beyond this we have even achieved two-photon induced switching,” outlines Professor Hecht.

This latter area represents a way of improving the resolution in space, using non-linear optical effects. “The idea is that a process only happens when a certain light

Light can turn the molecules from one form into another. We want these two forms to be behave very differently – like Dr. Jekyll and Mr. Hyde – because we want to exploit their differences to regulate various chemical and physical processes - they oscillate,” outlines Professor Hecht.

These properties could prove useful in selfcleaning surface coatings, for example for solar cells, notes Professor Hecht (Figure 3).

“The efficiency of solar cells declines over time simply because they get dirty,” he explains. “Cleaning them costs money and can destroy them, so it would be very exciting if we could use part of the light hitting the solar cell to brush away dust because of a smoothly vibrating surface.”

Potential applications The primary focus of the project has been on the development of new photoswitchable systems, but Professor Hecht is well aware of the wider potential of this research, and is keen to explore applications outside the academic sphere. One area in which these new photoswitchable molecules could

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intensity threshold has been reached,” explains Professor Hecht. “You could then think about two laser beams intersecting each other in a very small, very precise spot, and only in this tiny spot would the intensity be high enough that the molecules could absorb two photons.” Recently Professor Hecht and his colleagues have developed photoswitches which could be switched with two photons. “In the biological context, our basic research is about laying the molecular foundation for the areas in which photoswitches could eventually be used. This work is highly relevant for the bio community,” he outlines. “We don’t use photoswitches in the project to regulate drug action for example, it’s not our primary focus, but that’s one promising area in which they could eventually be applied.”

At a glance Full Project Title Light-controlled and Light-driven Molecular Action (Light4Function) Project Objectives Light4Function aims to develop and optimize photoswitchable molecules as tools to utilize light to control and drive various chemical and physical processes.

These range from remote-controlling bond making and breaking and catalysis, relevant for the creation of adaptive materials, to optically programming charge transport in electronic devices and light-driven actuation.

Contact Details Professor Stefan Hecht Laboratory of Organic Chemistry and Functional Materials, Department of Chemistry, Humboldt-Universität zu Berlin Brook-Taylor-Str. 2 12489 Berlin Germany T: +49 (0)30 2093 7365 E: sh@chemie.hu-berlin.de W: www.hechtlab.de Göstl, Senf, & Hecht: “Remote-controlling chemical reactions by light: Towards chemistry with high spatio-temporal resolution” Chem.

Soc. Rev. 2014, 43, 1982-1996.

Bléger & Hecht: “Visible-Light-Activated Molecular Switches” Angew. Chem. Int. Ed. 2015, 54, 11338-11349.

Professor Stefan Hecht

Professor Stefan Hecht is heading the Laboratory of Organic Chemistry and Functional Materials at the Department of Chemistry of Humboldt-Universität zu Berlin.

His research interests range from synthetic macromolecular and supramolecular chemistry to surface science, with particular focus on utilizing photoswitchable molecules for remote-controlling materials, devices, and processes.

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The Next Generation of Green Planes is About to Take Off The aviation industry is a major contributor of the pollutants responsible for climate change. There is now a high demand to focus on innovative aircraft designs that would not only cut emissions dramatically but would create more efficient and quieter airplanes for us to fly in. This is why NASA is now leading the way to ‘greener’ designs, by funding an exciting new range of X-Plane projects

L

et’s start with the problem. Look up, almost anywhere in the world and sooner or later you’ll see long sunlit contrails diffusing out into the sky. The emissions from an airplane will carry in them a cocktail of carbon dioxide, hydrocarbons, carbon monoxide, water vapour, nitrogen oxides, sulphur oxides and black carbon – all of which have an impact on the atmosphere.

Air travel has been a very successful growth industry, so emissions have escalated on a tremendous scale. In the EU countries alone, gas emissions from aviation ramped up by 87% from 1990 to 2006.

In 2015, worldwide, a total of 781 million tonnes of C02 was produced from flights alone, not surprising perhaps, when 8.3 million people fly every day. What’s more, civil aviation consumes more than 5 million barrels of oil per day. This is therefore a major commercial sector that’s causing significant environmental pollution and is impacting on natural resources – but let’s face it,

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we are not prepared to give up air travel any time soon. In fact, air travel is predicted to double in size within the next 10-15 years. So what can be done?

Luckily, the problem is on the radars of key stakeholders.

Everything from light weight composite materials, improvements for better propulsion systems and techniques for reducing noise have become the subjects of research by academics and companies working together to make aviation cleaner and greener.

NASA invests in X-planes NASA, in particular, is working on creating new experimental aircraft and technology that will dramatically reduce fuel consumption, emissions and noise too. The overarching aim is to cut emissions by more than 50 percent and reduce noise levels to half of the current level of the quietest aircraft currently in operation.

NASA has launched the New Aviation Horizons programme – which is a 10-year accelerated research plan. Part of this is to

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investigate new design concepts, which has led to the organisation investing its substantial budget into six month long contracts, handed out to four companies that can contribute, each tasked to work out the technical details, cost and approach of making new super-efficient, subsonic *‘X-Plane’ designs based around green objectives.

Those four companies are now engaging in work that is rewriting the script on plane designs, which in turn could herald a new era of air travel.

So, what are these new plane concepts that could reduce emissions and transform the industry?

Not just flights of fancy Here’s an insight into each new conceptual design, currently on the drawing board: • The Aurora D8 ‘Double Bubble’ – By Aurora Flight Sciences Corporation of Manassas, VA. With an investment from NASA totalling $2.9 million, the D8 is a twin hulled aircraft, proposed by Aurora Flight Services and Massachusetts Institute of Technology (MIT). In 2015, the US Federal Aviation Administration (FAA) also contributed funding for the D8’s Lower Energy, Emissions and Noise Program.

Aurora has been a pioneering company in manufacturing and innovative technology in the aerospace industry for nearly 30 years and the D8 is a conceptual commercial aircraft that is tantalising the sector with possibilities for future changes in airliner design.

Aurora claims to have ‘rethought and reconfigured every part of the air vehicle to maximise efficiency and minimise operating costs as well as improve passenger experience’. There is an expectation that it could go into service by 2027.

The design is a departure from the traditional way of putting a plane together. Instead of making the plane a composite of

thousands of parts, with a traditional tube and wing design, it will have one integrated system and a ‘double bubble’ fuselage with twin lobes and aisles within them, with small wings and jet engines mounted on the top near the tail.

As the jets are mounted at the rear, thrust requirements are less than usual from something known as Boundary Layer Ingestion (BLI) – which increases propulsive efficiency. Tests in the wind tunnel for the D8 suggest 15% fuel savings just for having the engines embedded in the aft of the fuselage.

The radical integrated design means that there is more lift which reduces drag, resulting in less fuel required for flight.

It’s proposed that the D8 configuration could achieve a 71% reduction in fuel burn, a 60 EPNdB reduction in noise, and an 87% reduction in LTO NOx – all relative to a best-in-class Boeing 737-800 narrow-body aircraft. This aircraft would typically fly at speeds estimated at 582mph / 936kmph.

Analytical tests have been conducted by the team that have verified the design benefits. Next up in the panning, is to conduct flight research using a demonstrator that can simulate accurate flight conditions.

• Blended Wing Body (BWB) – Dzyne Technologies Incorporated of Fairfax, VA. There is a similar focus on the aforementioned lift to drag ration design advantage here, this time geared toward a smaller aircraft than the D8. The wing and body act as one component – seamlessly joined together with an improved aerodynamic shape to traditional aircraft, thus reducing drag and increasing lift. There will be no clear dividing line between the body and the wings.

This plane design will not look conventional – it has a sciencefiction feel to it – like all those planes you see on movies about the future. Interestingly – BWB has usually been seen to be a design that suits larger planes and is not so suited for smaller jets but Dyzne’s design has changed this stance.

There are two concepts that Boeing is looking into.

Firstly, Boeing’s very own BWB design – some versions of which have already been flight tested. The other is a Truss-Braced Wing concept

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The design for this Hybrid Wing Body concept will be capable of carrying the same cargo as the giant Lockheed C5 plane with the advantage of burning 70% less fuel

Dyzne is looking at the potential for a lightweight material called Prseus composites technology for the structure of the plane. The plane design (we’re talking about a 110-130 seater regional plane) has a single deck, centralised body with thin wings. The landing gear is stored outwards (not under the cabin) and the cargo and baggage is held in the wing roots. The way the plane is put together will create a 20% saving on fuel burn.

• Hybrid Wing Body (HWB) – Lockheed Martin Aeronautics Company of Ft. Worth, TX. The design for this Hybrid Wing Body concept will be capable of carrying the same cargo as the giant Lockheed C5 plane with the advantage of burning 70% less fuel. Over-wing nacelles make it possible to install large, fuel efficient very-high bypass engines

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– which prove 5% more aerodynamically efficient than underwing engines. The overall design is a little more conventional than that proposed by Dzyne – more T shaped in the tail.

The hybrid wing body would have a combination of blended wing and fore-body which would be a benefit for aerodynamic efficiency but it would have a conventional aft fuselage as well as the tail, in order to be compatible with standard cargohandling equipment. This design should have a bright future as a basis for a commercial plane and it could also be used in the military for airlifts.

• Blended Wing Body (BWB) & Truss-Braced Wing Concept – The Boeing Company of Hazelwood, MO. There are two concepts that Boeing is looking into. Firstly, Boeing’s very own BWB design – some versions of which have already been flight tested. The other is a Truss-Braced Wing concept. This is a long wing that performs very aerodynamically – the wing is held up by trusses connected to the fuselage. To look at this, it is perhaps the most conventional looking of the X-Plane concepts presented here.

The plane has a wing not unlike a glider’s in appearance that spans a lengthy 170 ft (as opposed to the norm of 118ft) and is attached to the tubular fuselage. Wind tunnel tests have been promising according to NASA. This design can reduce fuel burn by up to 10% compared against traditional 180 seat narrow body airliners.

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From design to reality The challenge for each of these company’s research teams is to come up with a detailed technical plan demonstrating how to pilot one of these planes for up to two to three hours in subsonic flight.

Ed Waggoner, NASA’s Integrated Aviation Systems Program Director, explained in a statement: “Engaging these contractors now to gather this information will help us move forward efficiently and expeditiously when we’re ready to commit to building the X-planes themselves.”

In as little as five years’ time from now, the first experimental aircraft could be built from the research that is currently taking place in facilities around the US, into how these X-Planes would behave.

It’s highly likely we may see versions of these kinds planes in our skies in the future and they would make our current airliners look dated by comparison. There will be so many benefits from using them, from less noise pollution, more comfort, less costs for carriers but most of all it is essential that the industry acts on cutting emissions and burning less fuel. We are now at the beginning of a new age for aviation.

* X-Planes is a term for a class of experimental aerospace plane model that requires research.

New Measures Agreed in International Aviation for Emissions Reduction On 6 October 2016 in Montreal, Canada, at the 39th meeting of the International Civil Aviation Organisation, a total of 191 countries came together to reach a landmark agreement, to take measures to alleviate global climate change, by reducing emissions from the aviation industry.

More specifically, Government, industry and civil society representatives have agreed on a new global market-based measure (GMBM) to control CO2 emissions from international aviation.

“It has taken a great deal of effort and understanding to reach this stage, and I want to applaud the spirit of consensus and compromise demonstrated by our Member States, industry and civil society,” said ICAO Council President Dr. Olumuyiwa Benard Aliu. “We now have practical agreement and consensus on this issue backed by a large number of States who will voluntarily participate in the GMBM – and from its outset. This will permit the CORSIA to serve as a positive and sustainable contributor to global greenhouse gas emissions reduction.”

ICAO’s Carbon Offsetting and Reduction Scheme for International Aviation (CORSIA) is designed to complement the basket of mitigation measures the air transport community is already pursuing to reduce CO2emissions from international aviation. These include technical and operational improvements and advances in the production and use of sustainable alternative fuels for aviation.

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Powering the future of aviation Reducing carbon emissions is an increasingly urgent priority for the airline industry, while operators are also investigating ways to improve operational efficiency and reduce maintenance costs. The I²MPECT project aims to develop an innovative power converter which could have a significant impact on the airline industry, as Karl Weidner and Oliver Raab explain The airline industry

is under pressure to reduce its carbon footprint and improve efficiency in line with wider goals around limiting the impact of climate change.

Making greater use of electrical technologies could have a significant impact in these terms, an issue that researchers in the I²MPECT project are investigating. “One of the core aims of the I²MPECT project is to improve the efficiency of the airline industry. One possible way to achieve this is by moving away from burning fossil fuels towards greater use of electrical power,” explains Oliver Raab, the project’s coordinator.

Funded under the Horizon 2020 programme, the project brings together nine partners from across Europe, aiming to develop next generation power electronic converters for use in aircraft.

“We’re looking at the components of the converter itself and how we can improve the efficiency of those parts,” says Karl Weidner, principal engineer at Siemens.

A number of factors need to be taken into consideration into this work, with researchers in the project looking at each of the building blocks of the electrical converter. The shared goal is to develop efficient power converters and demonstrate their effectiveness even in harsh environments, while also looking to reduce the cost of production. “In reducing the cost of these building blocks, we can reduce the cost of manufacturing the system overall,” points out Raab. Based himself at Siemens, Raab says one of his

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company’s key roles within the project is to investigate the reliability of each of the different components within the power converter, which is of course a key issue in terms of their potential applicability in aircraft.

“We compare different semiconductors, as well as packaging and assembly techniques in terms of their performance and durability,” outlines Raab. “Coming from that point, we’re looking to make the power modules, the heart of a converter, more efficient, more safe and more reliable.”

he outlines. A third key point is that these chips can withstand higher temperatures, leading to a less heavy cooling system, which is an important issue in terms of the eventual application of a power converter in an aircraft. “A converter has to be very reliable, very safe and lightweight to be used in an aircraft. This is something that we are working on – together with Safran Electrical & Power who are furthermore responsible for assembling and testing the overall converter system,” Raab states.

improve the efficiency of the airline industry. One possible way to achieve this is by moving away from burning fossil fuels towards greater use of electrical power One of the core aims of the I²MPECT project is to

Semiconductor components The project’s agenda also includes research into novel semiconductor components for the power module, especially silicon carbide (SiC). These offer some significant benefits in comparison to conventional silicon chips, according to Weidner. “The main reason for using these new semi-conductor technologies is that they are much more efficient than conventional silicon chips.

You can drive those chips at a much higher frequency – so you can transform electrical energy in a much smoother way, and therefore improve the efficiency of the overall energy conversion system,”

The project’s work in developing an innovative planar technology holds clear potential in these terms. Raab and his colleagues are closely involved in building up a planar interconnect technology, part of the wider goal of developing a compact and intelligent power electric converter. “The modules which we at Siemens and Dynex Semiconductors are developing are very compact, offer low inductivity and a good thermal behaviour” he explains. Different circuit topologies will be considered as researchers look to identify the best approach in terms of power density, efficiency and robustness. This down-selection process is supported by specialists of Airbus Group

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At a glance Full Project Title Integrated, Intelligent Modular Power Electronic Converter (I²MPECT)

Innovations, central R&T entity of Airbus Group. All this is done bearing in mind the challenging requirements that have been defined by Airbus and that have to be met for an eventual use in the target application onboard aircraft. “A further thing to consider is that the control and driving circuits have to be very specialised and very precise. They have to be very close to the switching elements – otherwise you get inductive disturbances,” outlines Raab. “We have to integrate the electronic components with each other very effectively – there’s a lot of research at the project partner ETH Zürich on precisely triggering those wide band gap chips.”

A high level of symmetry in the system is essential to achieving efficient switching, which is the basis for transforming a voltage to another voltage, and a frequency to another frequency. The switching characteristics also offer a means to monitor the health and functioning of the power module, a core element of the project’s work, which is being investigated at the University of Sheffield.

“When you switch a semiconductor chip you get a response, and from this answer you can derive insights into the health status of the SiC chips and the power module itself,” explains Raab. This has important implications in terms of monitoring the state of the converter, and also can help reduce maintenance costs. “For example you can calculate the remaining life time of a power module by combining simulation

models and experimental results together with profound calculation algorithms.

Such a so called life time model is being developed by the Institut national des sciences appliquées de Lyon (INSA) in close collaboration with the other project partners,” outlines Raab. “From there, you can assess the likely performance lifespan of the power module.”

This leads into an enhanced ability to forecast when a converter will come to the end of its lifecycle, and hence predict maintenance intervals, which will have a significant impact on the expenses for aircraft operators. Accelerated reliability tests are being applied in the project to assess the performance of the converter. “In the project we’re using both physical methods and simulations to speed up the aging process of power modules,” says Raab. These tests, such as driving the power modules at very high temperatures, in some ways expose them to harsher conditions than the actual operating environment, which allows researchers to find defects in the modules in a very short period of time.

“Together with our partner INSA, we are trying to identify failure mechanisms, and from that learn how we can modify the manufacturing process to prevent them if possible,” continues Raab. “If this is not possible, then we aim to find out after which period of time, and under which conditions, those failures will occur and how we can prevent those conditions.”

Project Objectives Modular power electronic converters are the key technology enabling a “more electric” aviation. A more electrically driven aircraft has the potential to significantly reduce the airplane weight and therefore to reduce fuel consumption and the carbon footprint of today’s airplanes.

The I²MPECT project will demonstrate important advances in power converters for harsh environments. Innovative 3D device packaging based on planar interconnect technologies with new integrated cooling technologies will be implemented for wide band-gap wire-bond free power semiconductor devices.

Project Funding Funded by the European Commission Grant No. 636170: 6,734,627.00 euros.

Project Partners Airbus Group (FR/DE), Dynex Semiconductor Ltd. (UK), Eidgenössische Technische Hochschule Zürich (CH), Institut national des sciences appliquées de Lyon (FR), K&S Projektmanagement (DE), Safran Electrical & Power (FR), Siemens AG (Coordinator, DE), University of Sheffield (UK).

Contact Details Project Coordinator, Oliver Raab Siemens AG Corporate Technology CT REE PEM SPT-DE Otto-Hahn-Ring 6 81739 München, Deutschland T: +49 89 636-634366 E: oliver.raab@siemens.com W: http://www.i2mpect.eu/

Karl Weidner

Oliver Raab

Oliver Raab is project manager and research scientist at Siemens Corporate Technology with his background lying in micro-electro-mechanical systems. Before he has put his research focus on power electronics he has been developing assembly solutions for different areas of application ranging from photovoltaics and printed electronics to detectors for computed tomography.

Karl Weidner is a Principal Key Expert Engineer and experienced project leader in the field of future packaging technologies and innovative products for a broad range of technology fields.

He has 27 years of experience and is focused on creating specific solutions in the area of electronic packaging and system integration.

I²MPECT Siemens wirebond-less planar power module.

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Creating Efficiencies in Aircraft Design Two EU funded projects, ALPES and AeroGust, coordinated by the University of Bristol, are developing new methods to speed up and improve the accuracy of key processes involved in the design of more environmentally friendly aircraft. The aim is determining how loads, such as those caused by gusts of wind, interact with aircraft. Professor Jonathan Cooper explains the methods and the objectives of the projects that will lead to more efficient and cost effective aircraft designs A key job in the design of an aircraft is to make sure it can cope with the stresses arising in flight or from manoeuvres on the ground. For instance, when an aircraft is buffeted by strong winds, this will affect all the parts of the plane’s structure as well as impacting on passenger comfort, so calculating the way that each component and also the entire aircraft reacts to gusts is essential knowledge before a plane can be built.

“Say you’re flying and the pilot says, ‘buckle up, we’re going through bumpy weather’,” explains Professor Cooper, illustrating the challenge. “This is an example of loads, in this case due to socalled gusts or turbulence. Aircraft need to be designed to cope with those loads and also those resulting from manoeuvres as a plane flies around, or during take-off and landing, turning and braking. So the loads department, in conjunction with the aerodynamicists, will compute the hundreds of thousands of different loads that might be encountered during a flight, and stress calculations then need to be performed for many different parts of the aircraft.”

A massive computation The computational task has to account for the effect of loads on every element of the aircraft design, in every possible situation.

In practical terms, this means calculating all possible combinations of fuel and passenger weights in different situations such as flying high or low, or flying fast or slowly. The number of variables is vast.

From these calculations it is possible to reveal a complete picture of all the stresses on the structure of the plane and to determine the critical cases. Only when

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Aircraft flying in a vertical gust field. you have that information, can you understand where you might be able to make adjustments in the design, such as making parts thicker where the stress is too high, for example.

“Some parts of the aircraft will be most affected by gust loads, and others by landing, or turning on the runway and so on, and these critical cases are determined from all the simulations. Once you’ve done one entire set of simulations, the structures department can work out where they may be able to change the structure in some way to make it safer and also lighter in weight – and then the process starts over again.”

The problem is, as it takes so long to process each set of variables, the time and expense to rethink major aspects of design may not always be practical. It would be hugely beneficial therefore, if the time and effort it takes to compute loads early on in the design phase, was made more efficient. New approaches need to be explored to see where

efficiencies can be made, whilst maintaining accuracy.

This is where the five researchers in the ALPES project come in, working on solutions that will streamline processes whilst improving accuracy.

The engineers are all engaged in PhDs, conducting new research, whilst dividing their time between the University of Bristol, Siemens in Belgium and Airbus.

“We are doing some brand-new science but we are doing it with an industrial focus,” said Professor Cooper.

“We are doing things that Airbus are interested in, that are going to help improve their aircraft designs. It takes 8-10 years to develop a new design but if we can bring that down to five years, you get a tremendous competitive advantage. So we are looking at creating efficiencies – if we’ve got 500,000 different cases that we need to look at and we can reduce that to 50,000, or even 5000, we immediately speed the process up dramatically.”

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At a glance

Improving Aircraft Design If researchers can make new aircraft design concepts faster and easier to process and evaluate, it will lead to more refined aircraft and possibly novel configurations.

For example, by exploiting more flexible and lighter materials and new aerodynamic designs, it will be possible for planes to burn less fuel. This is the ultimate goal, to make aircraft more environmentally friendly and more cost effective at the same time. “It is important in this process to try to get the aircraft the right shape in-flight. Part of what we’re looking at is how we design the wings taking the

to reduce the drag. A lot of aircraft now have winglets, which are the parts at the end of the wing that bend upwards. The reason for having winglets is that they help to improve the aerodynamics. One of the students in the ALPES project is looking at how we can use the wing tips to reduce the loads due to gusts.

By working closely with industrial partners, Airbus and Siemens, the PhD students have a unique opportunity to affect an industry by improving simulation. The project sits right on the edge between academia and industry and has the potential to make big differences in a competitive market.

Some parts of the aircraft will be most affected by gust loads, and others by landing, or turning on the runway and so on, and these critical cases are determined from all the simulations Once you’ve done one entire set of simulations, the structures department can work out where they may be able to

change the structure in some way flexibility into account. The other aim is to reduce weight; if you can find ways of reducing the loads, you can therefore reduce the weight.”

“The use of carbon-fibre composites is becoming increasingly important, because you can use less weight but still carry the same amount of load, and also control the wing deflection in-flight ” says Professor Cooper. “In addition you’re always trying to do things with the aerodynamic shape

“Hopefully some of these methods will eventually find their way into Airbus.

Siemens’ role is developing software packages, so a win-win would be that we develop methods with Airbus and then our PhD’s code is used in collaboration with Siemens to make software, which does what Airbus wants it to do. If our methods are used, then it’s a success. The other bonus is that the five researchers from ALPES go and work in the industry.”

Full Project Title Aircraft Loads Prediction using Enhanced Simulation (ALPES) Project Objectives ALPES is an EC FP7 Marie Curie European Industrial Doctorate Training Network which runs from 1 October 2013 to 30 September 2017. The aim of the network is to improve the prediction accuracy and efficiency of the loads experienced by an aircraft in-flight and on the ground.

Project Partners The ALPES network involves five PhDs combining a novel research programme with a highly industrially focused training schedule, including placements at Airbus in the UK and/or France.

Key Participants • University of Bristol: Professor Jonathan Cooper, Dr Ann Gaitonde, Dr Dorian Jones, Professor Mark Lowenberg, Sarah Hassall.

• Siemens PLM Software: Dr Yves Lemmens, Dr Jens de Boer, Els Tops.

• Airbus: Tom Wilson, Murray Cross, Simon Coggon, Etienne Coetzee Contact Details Professor Jonathan Cooper RAEng Airbus Sir George White Chair in Aerospace Engineering Queen’s School of Engineering, University Walk, Bristol BS8 1TR T: +44 (0)117 33 15819 E: j.e.cooper@bristol.ac.uk W: http://www.bris.ac.uk/aerodynamicsresearch/projects/alpes/

Professor Jonathan Cooper

ALPES Early Stage Researchers Professor Jonathan Cooper is the Royal Academy of Engineering Airbus Sir George White Chair of Aerospace Engineering at the University of Bristol. His prime research areas are in aeroelasticity and loads, and he is also co-author of the Wiley textbook “Introduction to Aircraft Aeroelasticity and Loads”.

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At a glance Full Project Title Aeroelastic Gust Modelling (AeroGust) Project Objectives AeroGust aims to investigate and develop improved simulation methods for gusts by responding to three main areas of work: 1) Investigations using Computational Fluid Dynamics (CFD).

2) Creation of a numerical gust loads process that does not require wind tunnel data for early design stages.

3) Development of efficient reduced order models for gust prediction that account for aerodynamic and structural complexity at an acceptable cost.

Project Funding Funded by the European Union’s Horizon 2020 Research and Innovation programme under grant agreement number 636053.

Project Partners University of Bristol (Coordinator), Inria, NLR, DLR, University of Cape Town, NUMECA, Optimad Engineering S.r.l., University of Liverpool, Airbus Defence and Space, Dassault Aviation, Piaggio Aerospace and VALEOL. Contact Details University of Bristol, Queen’s School of Engineering, University Walk, Bristol BS8 1TR T: ​+44 (0) 117 33 15015 E: AeroGust-project@bristol.ac.uk W: www.aerogust.eu

Dr Ann Gaitonde (left)

Dr Dorian Jones (right)

Dr Ann Gaitonde is joint Head of the Fluid and Aerodynamics Research Group at the University of Bristol, working alongside Dr Dorian Jones. She was awarded her PhD in 1991 and subsequently worked in the Department of Aerospace Engineering as a post-doctoral researcher developing computational methods to calculate unsteady fluid flows.

Dr Dorian Jones is joint Head of the Fluid and Aerodynamics Research Group at the University of Bristol along with Dr Gaitonde. He was awarded his PhD in 1995 following his studies into the Direct Numerical Simulation of turbulent ducted flows. His research concerns the development of numerical methods for the prediction of unsteady fluid flows.

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The AeroGust Project Another project, under the leadership of Dr Ann Gaitonde and Dr Dorian Jones, that links to ALPES is AeroGust, which focuses on the interaction of gusts with aircraft. As with ALPES, this project is aiming to scale down the bulk of work in the design process, by creating new efficiencies in simulations and reducing the reliance on expensive and time consuming wind tunnel testing. It is also intended that the AeroGust research will transfer into renewable wind technology, aiming to reduce the loads on wind turbines.

generated in AeroGust will streamline the processes of tests and simulations.

“One of the advantages of simulation is that once you’ve got everything working, you can make design changes – you can make things longer, or change any aspect of design just by changing a couple of lines of code. Whereas, normally, you’ve got to go through the whole process again and again of building another model every time you try something out.

AeroGust is looking at better modelling techniques for gusts. With CFD, it means

With CFD, it means we have sophisticated

methods of modelling the air flow over the wing for example, to discover how those airflows interact with the wing “A wind tunnel is used to drive air around a fixed aircraft model rather than flying it through the air. There are very few wind tunnels worldwide that are able to accurately reproduce the conditions for a full size aircraft in flight, and such testing is really expensive, in the region of tens of thousands of euros a day.”

Both computer simulations and model testing are required in conjunction to generate and validate designs but if there was a bias towards accurate computer simulations in initial design experiments, the process can be speeded up dramatically.

Reducing the number of experiments save costs and time.

A key tool at the disposal of the researchers working on the AeroGust project is Computational Fluid Dynamics (CFD) software, which is used to produce accurate models of the aerodynamic gust flows around the flexible aircraft structure which, in turn, is modelled using Finite Elements (FE). The new computer codes

we have sophisticated methods of modelling the air flow over the wing for example, to discover how those airflows interact with the wing. CFD for gusts is still an area that is very much a current research topic. The methods that have been used before are much less sophisticated.”

Using better simulation techniques will lead to more efficient time use and high levels of effectiveness and accuracy in the resulting designs which can be made lighter. Entirely new kinds of design, including the use of different structural materials can be explored easily.

Summary Both AeroGust and ALPES have objectives that can be used to make future aircraft designs more environmentally efficient and to be evaluated much quicker. The work being conducted from both these projects could be pivotal for shaping the future of aircraft design.

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The road to better safety standards Strict application of two specific EC directives leads to a fragmented approach to road safety inspections, which has important safety implications. Adewole Adesiyun spoke about the Ecoroads project’s work in establishing a common approach to road safety infrastructure inspections and tunnel safety management The Sierre coach crash in a Swiss road tunnel in March 2012 was a traumatic event, causing 28 deaths and leading to a renewed debate on how the safety of European roads could be improved. The work of the Ecoroads project, an ECbacked initiative bringing together researchers from a number of European countries, will make an important contribution to the debate. “The general objective of the Ecoroads project is to overcome the barrier established by the interpretation of two directives – 2008/96/ EC and 2004/54/EC,” says Adewole Adesiyun, the project’s Coordinator. These two directives relate to road safety standards in tunnels (2004/54/EC) and standards on the open roads (2008/96 EC); Adesiyun says this leads to a fragmented approach to road inspections, which may have safety implications. “We are investigating whether, if the barrier between these two directives had not existed, the accident in the Sierre tunnel could have been prevented,” he explains.

“We’re looking at how we could develop a uniform approach to road safety inspection and road safety audits, both in tunnels and on the open road.”

Road safety This is not currently the case, contrary to what many drivers may believe. While road travel is a relatively safe mode of transport, regular inspections are required to maintain and improve standards, and there are many factors to consider. “When we talk about road safety inspections, we are talking about infrastructure, the pavement, the emergency parking facilities in tunnels, and other issues,” points out Adesiyun. Car manufacturers of course consider safety measures in vehicle development, while information on road conditions is also available to drivers; the project’s focus however is the road infrastructure. “We looked at how do tunnel experts and road experts understand safety operations in these two different environments?” says Adesiyun. “Currently, the people that do tunnel inspections are often not the same people as inspect open roads – it’s typically

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two separate teams. Instead of having two separate teams, why don’t we have one team that conducts inspection both on open roads and tunnels?”

The first step in this is bringing the two groups together to share expertise and best practice. From there, experts can discuss key issues and look to establish a common approach to road safety inspections. “We discussed, for example, mitigating the risks associated with lay-bys and the transition between tunnels and open roads,” says Adesiyun. The project aims to provide recommendations for road safety audits and road safety inspections; pilot joint safety operations will be conducted on five sections of road in Europe, featuring both tunnels and open roads. “We have an international team comprised of road and tunnel safety experts that conduct these road safety inspections and audits on these five sections of road. Currently, most of the people who inspect a road are from the home country, but in this project we have an international team,” continues Adesiyun. “We’re bringing together expertise and experience from different parts of Europe.”

This will form the basis for guidelines and recommendations on road safety inspections.

The ultimate goal is to help improve road safety; Adesiyun hopes the project’s work will have an impact in these terms. “We are hopeful that the project will enhance the application of road safety audits and inspections in tunnel safety, through the joint road safety operations,” he says.

ECOROADS (Effective and COordinated ROAD infrastructure Safety operations) The ECOROADS project aims to establish a common enhanced approach to road infrastructure and tunnel safety management by using the concepts and criteria of Directive 2008/96/CE on road infrastructure safety management and the results of two related European Commission (EC) studies. Directive 2008/96/EC covers open road safety management, and Directive 2004/54/ EC covers tunnels.

Dr Adewole Adesiyun FEHRL, Boulevard de la Woluwe 42 1200 Brussels Belgium T: + 32 2775 8234 E: adewole.adesiyun@fehrl.org W: www.ecoroadsproject.eu

Dr Adewole Adesiyun is the Deputy Secretary General of FEHRL. He is responsible for the management of FEHRL research and project activities as well as monitoring the financial aspects of such projects. He provides support to FEHRL member institutes wishing to participate in cooperative research.

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Communication is key to road efficiency Robust, reliable communication between trucks could enable new vehicle applications in order to both greatly improve fuel efficiency and reduce congestion on European roads.

The ROADART project aims to improve robustness of wireless communication on hardware, software and also at the application side, as Dr Christos Oikonomopoulos explains A huge number

of trucks and heavy duty vehicles travel on Europe’s roads every day of the year, carrying enormous volumes of goods and products to destinations across the continent.

Effective communication between these trucks could help improve road transport efficiency and reduce congestion, a prime motivation behind the work of the ROADART project. “The main objective of ROADART is to investigate and optimise Intelligent Transport System (ITS) communication units with respect to their use in trucks. We are focusing on truckto-truck (T2T), and truck-to-infrastructure (T2I) communications,” outlines Dr Christos Oikonomopoulos, the project’s Principal Investigator.

While communication technologies are in general widely used in cars, the size of truck-trailer combinations means that new architecture concepts are required for trucks and heavy duty vehicles. “We aim to develop and evaluate new architecture concepts, in order to ensure a sufficient quality of service for trucks and heavyduty vehicles,” continues Dr Oikonomopoulos.

Robust communication The key objective here is to make the wireless communication system for T2T/ T2I services more robust and reliable. “We are developing new components for these

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communication systems,” explains Dr Oikonomopoulos. This work is built on research across a number of areas of ICT, including measurement campaigns to investigate a variety of radio channels as well as CACC (Cooperative Adaptive Cruise Control) applications. “ROADART will create a large database of available wireless signal propagation measurements, for various antenna positions. This database can be used as a tool and a reference point for a range of innovative actions on vehicular communications and especially T2T links,” says Dr Oikonomopoulos.

“The measurement campaigns will be used to define scientifically and experimentally verified radio channel models suitable for T2T and T2I communications. Full reports and analysis on channel behavior and quality parameters for the specific channels will be extracted.”

This will help lay the foundations for the project’s work in developing robust and reliable new architecture concepts.

One major area of research is the development of distributed multiantennae systems. “For example, the large dimensions of a truck and its trailer mean that if you have an antenna on the roof of the driver’s cabin it may not be sufficient to cover the rear of the truck,” points out Dr Oikonomopoulos. This means it is necessary to look for alternative positions

for the antenna. “Distributed antennae systems are not located just in one place – they could be located in side mirrors for example,” continues Dr Oikonomopoulos.

“Other architectural concepts are also being considered, including beamswitching and beamforming.”

Improving the robustness of wireless communication with respect to packet loss and latency directly improves the availability of wireless communicationbased applications. Especially in case of safety- and time-critical cooperativedriving applications like CACC, reliability of the inter-vehicle wireless communication is of the essence. It allows for short intervehicle distances, which can lead to a reduction of fuel consumption by 10-20 percent. Nevertheless, to cope with potentially dangerous situations arising from link impairments, it is necessary to improve the robustness of both the communication and the application layer.

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While the project is using existing communication standards like WiFi IEEE 802.11p and ITS-G5, Dr Oikonomopoulos says this is not sufficient in terms of the project’s wider goals. “There are not enough existing standards, so we need to supplement them, using for example diversity or MIMO techniques in order to improve communication,” he says. A key priority in this area is improving reliability. “Diversity or co-operative techniques are important aspects of the project, where we try to combine more than one communication technique to improve the performance,” outlines Dr Oikonomopoulos.

Channel models The project’s research agenda also includes developing novel radio channel models for T2T and T2I communication. These channel models are effectively realistic representations of traffic environments, which provide a framework to investigate certain scenarios. “We have defined critical scenarios, like trucks driving into long distance tunnels. We will perform some measurements in certain test environments, and we will try to model them,” explains Dr Oikonomopoulos. This research holds important implication for

several different traffic scenarios in the project. “The T2T scenario in critical environments like a long range tunnel is one aspect of ROADART. We are also looking at different applications and use cases like crossroad and suburban/rural environment scenarios,” says Dr Oikonomopoulos.

Researchers aim to investigate and optimise ITS communication units with respect to these specific applications. A number of Key Performance Indicators (KPIs) have been defined within the project, setting out the technical targets for the research activities, including beamforming gain, reliability and availability. “The reliability indicator relates to the required Bit Error Rate (BER) for uncoded transmission in order to establish a reliable link for a given coverage area. We set this value of BER at 10-3, meaning an error rate of one bit in every thousand bits,” explains Dr Oikonomopoulos. “A low Packet Error Rate (PER) ensures that information becomes available at the receiver. We expect an improvement of the throughput due to diversity/multi-antenna techniques over existing ITS G5 standard (of about 10-20 percent) and with IEEE 802.11p standard modifications of about 30-50 percent.”

T2T communication we have defined critical scenarios like long range tunnels. We will perform some measurements in certain test environments, and demonstrate CACC with trucks For

the way trucks are driven on motorways, an issue which Dr Oikonomopoulos and his colleagues plan to investigate in the project. “A demonstration goal of the project is to show reliable and robust T2T communication by means of using CACC in trucks. The first truck will be the leading truck, then behind there will be more trucks following using the CACC application,” he outlines.

This approach could help both reduce the environmental impact of trucks and heavy duty vehicles and also improve the efficiency of European roads. Effective communication will also help trucks find the best possible route in situations where other modes of communication may not be available, such as in tunnels. “You can transmit information about traffic jams, accidents, or roadworks in real-time, so the truck driver can change their route and not worsen traffic congestion,” points out Dr Oikonomopoulos. Researchers are looking at

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There are also further potential use cases for these communication units outside those that have already been identified. This will form an important part of Dr Oikonomopoulos’s future research agenda. “We think that some architecture concepts will be unique to some use cases, or can be matched to the current situation. We will try to identify more use cases, and to determine which concepts should be investigated further,” he says. The architecture concepts that have been developed so far will be able to cope with changing traffic levels, and will provide a solid foundation for continued research. “It is our hope that the concepts we envisage realising within the ROADART project will not need further work for optimisation, since they can be deployed regardless of the amount of vehicles on the road. They would be scalable and could operate even in heavy traffic situations,” says Dr Oikonomopoulos.

At a glance Full Project Title Research On Alternative Diversity Aspects foR Trucks (ROADART) Project Objectives ROADART focuses in the investigation of ITS communication units integrated into trucks that assure a sufficient Quality of Service (QoS). At the end of ROADART a demonstration under critical conditions in a real environment (highway, tunnels) as well as platooning of several trucks driving close behind each other is envisaged.

Project Funding Funded under the European Union’s Horizon 2020 research and innovation programme under grant agreement No 636565.

Project Partners • IMST GmbH • MAN Truck & Bus AG • TNO NL • University of Piraeus Contact Details Dr Christos Oikonomopoulos-Zachos IMST GmbH Antennas & EM Modelling Carl-Friedrich-Gauss-Str. 2-4 47475 Kamp-Lintfort T: +49-(0)2842-981-371 E: oikonomopoulos@imst.de W: www.roadart.eu W: www.imst.de

Dr Christos Oikonomopoulos-Zachos

Dr Christos Oikonomopoulos-Zachos studied Electrical Engineering at the RWTH Aachen University, Germany, (Dipl.-Ing. 2003, Dr.-Ing. 2010). Since 2009 he is with the department of Antennas and EM Modelling of IMST GmbH, where he is responsible for all automotive antenna activities. He is involved in several automotive projects which include MIMO antenna systems, LTCC technology and mobile communications antennas.

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Europe is home to an extensive network of inland waterways, yet they are relatively underused in some areas of the continent. Energy-efficient technologies could help reduce the environmental impact of inland waterway transport, providing an efficient alternative to road transport, as Prominent project coordinator Jaap Gebraad explains

Green technologies for Europe’s inland waterways There are around 37,000 kilometres of inland waterways in the European Union, and the network has long been used to transport cargo and people throughout the continent. While it still plays an important transport role in some countries, particularly in Belgium, France, Germany and the Netherlands, the network is relatively under-used in other parts of Europe according to Jaap Gebraad, the coordinator of the Prominent project.

“There is a lot of under-used potential in some countries with an inter-connected waterway system, for example those countries that lie on the River Danube,” he says. Funded under the EU’s Horizon 2020 programme, the Prominent project is addressing technical issues around inland waterway transport (IWT), part of the wider goal of promoting inland navigation as an alternative to road transport.

“Within the Prominent project, we will standardise greening technologies which have the potential to be taken up by the IWT market, or have already been partially taken up,” outlines Gebraad.

The starting point in this work is identifying the vessels that use Europe’s inland waterways and analysing typical usage patterns. From this, researchers can then look to address the key technical development priorities in the IWT sector, a central element of the project’s agenda.

“Before you can identify what technologies are applicable to the fleet, you first have to be aware of what the

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fleet is and how it is used. How many of the same types of vessels are there? What are the engine characteristics?” points out Gebraad. The project is working to reduce the environmental impact of both newly-built vessels and older vessels, which tend to be less environmentally friendly. “In general, the older the vessel, the more polluting it is,” says Gebraad.

“We have identified a number of options to reduce the environmental impact of IWT. One is modifying diesel engines, which is applicable to existing vessels.

Another one, applicable to both new and existing vessels, is energy-efficient navigation. How can you sail as efficiently as possible?”

Liquid natural gas Researchers are developing an energyefficient navigation system to help skippers sail their vessels more efficiently, while a number of other technologies are being investigated within the project.

One major area of research is the use of liquid natural gas (LNG), a more environmentally-friendly alternative to conventional fuels; only a relatively small proportion of vessels in inland waterways currently use LNG, in large part due to logistical and financial factors. “First of all, there are hardly any facilities to ‘bunker’ the fuel, then there’s the cost of investment,” explains Gebraad.

Researchers in the project aim to support the introduction of LNG on a wider basis,

part of the wider goal of reducing the environmental impact of IWT, which Gebraad believes could have a positive impact on the sector. “If we can prove that IWT is less polluting than other transport modalities, this might help the sector to increase its market share in the transport chain,” he says.

This work in promoting new, energyefficient technologies will be key to meeting targets set out in legislation limiting the emissions of certain pollutants, in particular nitrogen oxides (NOx) and particulate matter (PM). The project is developing certification and monitoring procedures, designed to get the full picture of a vessel’s emissions.

“You can do a test where the engine is produced, but does this test give you the same results as when a vessel is sailing on a particular stretch of water? Here, we are also developing the concept of on-board monitoring. What does the vessel really pollute, when it is sailing on a river?” outlines Gebraad. Until now, a lot of tests have been done in the factory, but the recent scandal where a car manufacturer circumvented emissions tests underlined the need for a highly rigorous, reliable approach.

“After the recent scandals around road transport, emissions requirements are likely to grow more stringent, particularly because IWT vessels often sail through densely populated areas,” says Gebraad.

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There is potentially also an economic incentive for operators to reduce the environmental impact of their vessels.

Some ports may decide to reduce tariffs to more environmentally-friendly vessels, in which case operators need to demonstrate that their vessel meets those requirements. “This doesn’t mean the measurement will take place in the port, but rather on-board the vessel, to prove that the vessel meets emissions requirements,” explains Gebraad. The needs of industry are a key consideration in this research, and Gebraad is keen to ensure that the project’s work has a wider impact. “The project consortium brings together research institutes and commercial companies, and we also have

Onboard measuring equipment.

Picture provided by TNO.

Full Project Title Promoting Innovation in the Inland Waterways Transport Sector (PROMINENT)

NRMM directive (non-road mobile machinery) laid down new emission requirements, which influences our research agenda,” he says. “Cooperation between the legislative field, industrial end-users and manufacturers, and other potential stakeholders is required.”

Within the Prominent project, we will standardise greening technologies which have the potential to be taken up by the IWT market, or have already been partially taken up an advisory board which convenes twice a year to discuss the progress of the project,” he says. “When the project finishes we want to ensure that the results are taken up by the market, so we have involved the market from the beginning.

What are their requirements?”

A workpackage within the project is dedicated to deploying these technologies in real-life scenarios, giving potential users the opportunity to provide feedback and identify potential improvements. From these foundations, researchers can then look towards rolling these technologies out on a wider basis. “What is needed to support mass implementation? What does it cost, what is required?” asks Gebraad. The wider legislative environment is of course an important consideration, and Gebraad believes that close cooperation between the relevant stakeholders is essential to promote the ‘greening’ of IWT. “The recent

At a glance

Alternative transport The wider goal in this research is to demonstrate to industry that IWT represents an efficient and environmentally friendly alternative to road transport.

Many inland navigation vessels are capable of carrying thousands of tonnes of cargo, far more than a typical truck, and the interconnected nature of Europe’s inland waterway network means it’s possible to directly reach a wider range of destinations than might have been thought. “Nowadays you can even load a vessel in Rotterdam and deliver cargo to Constanta in Romania, the gateway to the Black Sea,” outlines Gebraad. Nine core transport corridors have been identified across Europe, and research continues into utilising them more effectively. “The European Commission is funding continued research to support the integration of IWT into the transport chain,” continues Gebraad.

Project Objectives PROMINENT will address the key needs for technological development, as well as the barriers to innovation and greening in the European inland navigation sector.

PROMINENT thereby is fully in line with the objectives of the European action programme NAIADES-II. PROMINENT is ultimately aimed at providing solutions which make inland navigation as competitive as road transport in terms of air pollutant emissions by 2020 and beyond. In parallel PROMINENT aims to further decrease the energy consumption and carbon footprint of IWT, an area where IWT has already a strong advantage compared to road transport.

Project Funding Funded by the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No 633929.

Project Partners • Please see website for full details.

Contact Details Jaap Gebraad Project Coordinator PROMINENT Stichting STC-Group T: +31 104 486 018 E: prominent@stc-r.nl W: www.prominent-iwt.eu

Jaap Gebraad

Jaap Gebraad is board secretary and senior project manager at the Stichting STC-Group. Since 2008, he has coordinated numerous European funded projects regarding harmonisation and modernisation of professional qualifications in inland navigation. He plays a central role in encouraging cooperation between industry, educational institutes and competent authorities on a European level.

Signing of the Green Deal agreement, by the Dutch Minister of Infrastructure and Environment, on the 12th September 2016.

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Strengthening the foundations of community policing Effective community policing programmes are built on close communication between citizens and law enforcement agencies (LEAs), as they work together to solve crime. Dr George Leventakis, co-ordinator of the INSPEC2T project, tells us about their work in developing a new solution for community policing, including a mobile application for two-way communication Effective communication is

central to community policing programmes, helping build trust between citizens and law enforcement agencies. While that can still mean a friendly chat with your local policeman while out shopping, the authorities are also keen to apply modern technology to community policing, an issue that lies at the core of the INSPEC2T (Inspiring CitizeNS Participation for Enhanced Community PoliCing AcTions) project’s research agenda. “The project aims to provide a comprehensive tool to facilitate communication between law enforcement and the community, especially in the framework of the various community policing programmes that are being implemented in different EU member states,” outlines Dr George Leventakis.

The level of citizen involvement varies across these different community policing programmes, ranging from simply providing information right through to influencing local strategic priorities, as Dr Leventakis explained during his interview with EU Researcher. The common thread across these programmes is the need for efficient communication between citizens and the police, which can help ensure the police operate in a way that reflects local priorities. “When law enforcement agencies establish more efficient and effective channels of communication with local communities, then they can assess risks, and build a deeper understanding of what is happening in that community.”

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Community policing This forms the backdrop for the project’s work in developing a sustainable community policing framework, aiming to design, develop and test a set of technology applications. One important component is a mobile application for twoway communication, based on existing social media platforms, which will provide an effective way of reporting information.

“With our mobile application people won’t have to ring an emergency number, they can instantly text the details of an event, or send a picture or video.” The application also offers protection against hoaxers providing misinformation. “We can correlate events and information. In order to validate information, we need proof from other people and other sources,” explains Dr Leventakis.

Researchers are also developing several other technology applications and modules to further enhance community policing.

This includes a public portal with almost the same functionalities as the mobile application, a private portal for LEAs, and interface to Computer Aided Dispatch (CAD) systems for bidirectional information The INSPEC2T team

exchange; the project’s work provides a solid foundation for efficient reporting and analysis of information. “We’re also working on Case Based Reasoning and Multimedia Analytics, aiming to provide tools to the Police for analysing information. For instance, the pictures to be analysed from the Multimedia Analytics component may come from an uploaded picture from the public portal (accessed via the internet on a PC), not just from the Mobile App.” This allows the police to target their resources more efficiently, an important consideration at a time of economic uncertainty when law enforcement budgets are being squeezed. One of the main advantages of the platform is its modularity.

For instance, if a police department owns a sophisticated CAD system, this could be easily plugged in to the platform and used to exchange data. With more data available, police can build a more detailed picture of crime and disorder in the local community, and potentially even identify threats to law and order before they occur. “The system has the ability to identify the geo-location of an event, whether the information has been provided by text, or if it’s in a picture, image or video. The police can then analyse that data and identify the areas that are more vulnerable to crime, and reorganise their strategy and operating plans.”

There are clear operational benefits for the police from this system, yet this must also be balanced with a respect for civil liberties. Alongside their technical work in developing the system, Dr Leventakis says

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At a glance Full Project Title Inspiring CitizeNS Participation for Enhanced Community PoliCing AcTions (INSPEC2T) the project also considers the wider social and legislative context in which it will be used. “We are trying to develop an effective solution, based on existing legislation in EU Member States around protecting individual liberty and freedom of expression,” he says.

It’s also important that people can provide sensitive information without fear of being identified and potentially subject to reprisals, an issue of which the project is well aware. “People can provide information related to threats or incidents without giving any personal data.”

The overall solution will be tested and validated in five cities in four different counties across Europe, each with different policing traditions, priorities and Community Policing maturity levels. In some cities, volunteers and NGOs already play a major role in policing, while in others citizenry are less engaged; this diversity will be a strength in terms of testing, evaluating and improving

community policing programme should be aware of these issues and address them appropriately.”

Encouraging citizens to get involved in community policing programmes and communicate with law enforcement agencies is an important element of this wider agenda.

Serious games and gaming platforms are being used in the project to raise awareness of community policing and deepen community engagement. “We’re trying to pass key messages about interaction between law enforcement and citizens,” continues Dr Leventakis. This also acts as a way of training citizens and police in the use of social media and smart mobile applications, further strengthening relationships between the community and LEAs. “The more transparent you are, and the more information that you can pass to your stakeholders, the greater the levels of trust.”

User consent is crucial to the consortium.

The project aims to provide a comprehensive tool to facilitate communication between law enforcement and the community, especially in the framework of the various community policing programmes that are being implemented in different EU member states the system, believes Dr Leventakis. “There are different community cultures, there are different legislative environments, and there are different community policing programmes”, he says. A range of stakeholders will be involved in testing and validating the project’s technological tools.

“Municipalities, local police, relevant NGOs and local organisations will be involved in our test cases.”

New communities The issue of community policing takes on even greater importance in the context of the high levels of migration that some European cities have experienced over recent years, from both inside and outside the EU. People arriving from different countries may have different perspectives about the rule of law and the role of the police. “They have different perceptions of the police and different religious, social and cultural backgrounds. A local community looking to implement an effective

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This is the foundation of effective policing, and underpins much of the project’s work.

Alongside providing the means to report incidents, the system also encourages regular communication between citizens and police. “We offer community engaging communication where virtual communities can be created, including both citizens and police, to discuss issues, plan activities and raise awareness.” Rewards can provide a further incentive to citizens to pass on relevant information. “The system can provide information about active citizens, where they pass information that help the police solve crimes; a reward system can then be used.”

Researchers are now looking to move forward with the development of the system. “We have prepared and presented our prototypes and some mock-ups of our solution to our stakeholder advisory group and the external expert panel, now we are moving into the development and implementation phase.”

Project Objectives INSPEC2T projects’ scope is to develop a sustainable framework for Community Policing that effectively addresses and promotes seamless collaboration between the police and the community.

Project Funding The project is funded by the European Commission, under the “H2020-FCT-2014 Ethical/Societal Dimension Topic 2: Enhancing cooperation between law enforcement agencies and citizens - Community policing” call.

Project Partners http://inspec2t-project.eu/en/partners-2 Contact Details Project Coordinator, Dr Georgios Leventakis P. Kanellopoulou St 4 10177 Athens Greece T: +30 210 7710805 E: gleventakis@kemea.gr W: http://inspec2t-project.eu/en/

Dr Georgios Leventakis

Dr Georgios Leventakis (PhD - MBA - MSc.), is a qualified Security Expert. He holds a PhD in the area of Risk Assessment Modeling in Critical Infrastructure (CI) Protection, an MBA and an MSc in Risk Management. He has 22 years of professional experience in the public sector, of which 16 years in Security Management. He has participated in several National, European and International projects and initiatives regarding Physical Security of Critical Infrastructures, Border Management, (Land and Sea Border Surveillance), Civil Protection / Homeland Security technology & operations. He has participated as Senior Researcher in more than 45 EU research projects, authored several academic papers published in respective Journals or presented them at Academic Conferences.

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©Alperia SpA (pictures of District Heating plants in northern Italy).

The next generation of energy networks Energy efficiency is a prominent global issue, with researchers looking to both develop new technologies and manage existing resources more effectively. Dr Roberto Fedrizzi tells us about the FLEXYNETS project’s work in developing a new generation of District Heating and Cooling networks that will reduce energy losses during transportation, while also facilitating waste heat recovery The current generation of District Heating and Cooling networks play a crucial role in modern society, helping to transport energy to residential buildings and businesses. However, existing networks are prone to significant heat losses, says Dr Roberto Fedrizzi. “The current third generation networks work at higher temperatures – around 90° C – than the ground level temperature. There are energy losses of around 10-20 percent during transportation,” he explains. Based at the EURAC research centre in Bolzano, Dr Fedrizzi is the Principal Investigator of the FLEXYNETS initiative, a Horizon 2020 project which aims to develop a new, intelligent, more efficient generation of District Heating and Cooling networks.

“We aim to dramatically reduce the distribution temperature, and as such to reduce thermal losses through the pipeline to nearly zero,” he outlines.

These fifth generation networks will be designed to work at ‘neutral’ temperatures of between 15-20°C, close to the groundlevel temperature, which is in the range of 10ºC. While this will help reduce energy losses, with obvious benefits for energy companies and other utilities, thermal energy delivered at such low temperatures is not well-suited to household purposes.

“You cannot have a shower with that, or wash dishes,” acknowledges Dr Fedrizzi. A reversible heat pump will be used to increase the water temperature to a level where it can be used for domestic purposes; while this shifts the initial costs slightly 58

towards households, it will lead to longterm savings. “Where you can save money is in the energy bill that you pay, as you can reduce the amount of electricity that you use to warm up a building through a very effective operation of the heat pumps.

So that’s an economic saving from the new generation of district heating and cooling networks,” explains Dr Fedrizzi.

The network is also designed to deliver effective cooling, alongside this heating capability, while waste heat is recovered for heating purposes. These two aspects of

the network can work together simultaneously on the same pipeline, so that the network can operate in a way that reflects local climate conditions and seasonal demands. “There is a central unit balancing hot and cold loads. So in the summer months there will be a centralised chiller that would balance between warm and cold loads, while in winter there would be a centralised boiler,” says Dr Fedrizzi. The reversible heat pumps and chillers have proved effective in exchanging heat with the network, now

Flexynets concept of a DHC network.

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the main priority is integrating the key technologies with the network. “We are trying to understand how to integrate the heat pumps at a local level with the network. Then we are investigating how to manage the network itself as a whole,” continues Dr Fedrizzi.

Energy efficiency This work very much fits in with the wider goal of improving energy efficiency. While a great deal of research attention has focused on developing new technologies to harvest renewable sources of energy, Dr Fedrizzi believes it’s also important to manage the solutions currently available on the market more effectively. “First of all, we aim to manage thermal energies – both cold and warm – more efficiently. Secondly, we aim to integrate as much of the wasted energy or heat as possible in the network,” he outlines. This historically has proved to

management and integration of the network could open up opportunities for companies to recover waste heat and sell it back to the network; Dr Fedrizzi points to the example of a supermarket. “A supermarket using refrigeration units could recover the waste heat normally rejected into ambient - with associated electricity costs - and use it as a business opportunity,” he points out.

Researchers are investigating the potential to develop a ‘feed-in’ scheme similar to existing plans where householders with solar photovoltaic panels on their roofs can sell excess energy back to the grid. In the case of a supermarket, this kind of scheme would require an initial investment in connecting to the network, but again it would pay dividends over the long-term. “You have a payback due to the fact that the utility company would pay you for the energy that you put back into the network. This is a win-win situation,”

manage thermal energy available more effectively. Secondly, we aim to integrate as much of the wasted heat as possible in the network First of all, we aim to

be a difficult task, as previously networks operated at higher temperatures. “There are not really many energy sources that can be integrated at higher temperatures, since there are not really many processes that can provide continuous thermal fluxes at higher temperatures, where you need it,” explains Dr Fedrizzi.

The next generation of District Heating Networks will be designed to integrate heat from a variety of sources, including biomass, photovoltaics and cogeneration.

Researchers also aim to integrate waste heat, further helping improve energy efficiency.

“Refrigeration units at supermarkets, air conditioners and launderettes all waste heat for example.

That waste heat could be conveniently recovered into these new generation networks due to the lower temperature. The network is a long pipeline, and you can recover waste heat along it where it is available,” continues Dr Fedrizzi. Effective

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says Dr Fedrizzi. “The city re-uses energy that would otherwise have been wasted into the ambient, and the utility company can provide heat to users at a lower cost.”

This research has attracted the interest of the commercial sector, with companies looking for innovative solutions to deliver heating and cooling. Researchers are developing simulation models to identify the optimum operation of these fifth generation networks, and Dr Fedrizzi is keen to establish closer links with utility companies. “We want to work with utility companies who could be interested in demonstrations of these kinds of solutions,” he says. The project’s concepts will be tested in a laboratory currently being constructed at EURAC, which will closely mimic the conditions in practical applications, so that the needs of the commercial marketplace can be taken into account. “We want our research to have an impact in the real world,” stresses Dr Fedrizzi.

At a glance Full Project Title Fifth generation, Low temperature, high EXergY district heating and cooling NETworkS (FLEXYNETS) Project Objectives FLEXYNETS will develop and demonstrate a new generation of intelligent DHC networks that reduce energy transportation losses by working at “neutral” (15-20°C) temperature levels.

Reversible heat pumps will be used to exchange heat with the DHC network on the demand side, providing the necessary cooling and heating for the building.

Project Funding 2 million euros Project Partners Please see website for details Contact Details Dr Roberto Fedrizzi Coordinator of the Sustainable Heating and Cooling Systems research group, EURAC research Institute for Renewable Energy Via G. Di Vittorio 16, I-39100 Bolzano T: + 39 0471 055610 E: roberto.fedrizzi@eurac.edu W: http://www.flexynets.eu/en/

Dr Roberto Fedrizzi

Dr Roberto Fedrizzi is Coordinator of the Sustainable Heating and Cooling Systems team since 2009. EURAC research.

His expertise is in development and management of national and international research projects, laboratory testing of sorption and compression heat pumps, design of hybrid heating and cooling systems exploiting solar energy and heat pumps.

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District heating and cooling (DHC) networks play a crucial role in distributing energy to homes and buildings, yet there is scope for improvements in energy efficiency and market deployment. Johan Desmedt tells us about the H2020 STORM project’s work in developing, deploying and demonstrating a generic DHC network controller, which can be applied across both existing and new networks

STORM Generic controller spans the generations A great deal

of research attention has focused on district heating networks over recent years, aiming to improve energy efficiency and increase the use of renewable energy. While progress has been made, there is still scope for further improvement, an issue which researchers in the STORM project are addressing. “The project tackles energy efficiency at district level. We aim to develop, demonstrate and implement a smart district heating and cooling network controller, that can reduce the peak in a district heating network by 20 percent,” says Johan Desmedt, the project coordinator. The controller is designed to be applicable in both existing and new systems. “The idea of the STORM controller is that it will be applicable in both what we call third generation network systems and also fourth generation network systems,” explains Desmedt. “So fourth generation network systems are characterised by a lower supply temperature, and also by improved energy efficiency.”

Generic controller The project is aiming to develop a generic controller, looking towards its wider deployment across Europe in different district heating and cooling networks. The network controller will be demonstrated at two pilot sites; the network of Mijnwater BV in the Dutch city of Heerlen, and Rottne in the Swedish city of Växjö. “In Rottne, we have a third generation district heating system. This type of system is quite common in Europe,” outlines Desmedt. This network makes up about 10,300 metres with a total volume of about 64 m³. The production is based on two wood chip boilers, complemented with a traditional oil boiler. The purpose of the STORM controller here is to minimize the oil usage. The system of Mijnwater BV by contrast is more advanced; the differences between the two sites will help demonstrate the wider applicability of the network controller in Europe. “The network of Mijnwater BV is a highly advanced, innovative fourth generation district heating and cooling network,” says Desmedt. “Flooded

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mine galleries act as renewable energy sources and provide a total of 500,000 m² floor area connected to a low temperature district heating and cooling network. The purpose of the STORM project is to develop a controller in order to go towards a selfsufficient district in terms of energy.”

A number of different sources are used to generate the energy distributed within these different networks, varying according to the local climate. The network in Rottne utilises a biomass boiler, combined with an additional fuel boiler; Desmedt says the latter is an expensive

The idea of the STORM controller is that it will be applicable in both what we call third generation network systems and also the fourth generation network systems.

So fourth generation network systems are characterised by a lower supply temperature, and also by improved energy

efficiency

form of energy, a prime motivation in the project’s work in developing three specific control strategies, the first of which involves controlling demand. “We want to exclude the fuel boiler by a technique called peak shaving, by reducing peaks in the network system, and controlling the distribution,” he explains. Researchers are also investigating market interaction. In the last control strategy the DHC network provides balancing services to the electrical grid, later called the ‘market interaction’ control strategy. As explained above the clue in smart electrical grids lies in the creation and application of flexibility. When both grids are coupled, for example by means of a heat pump and/

or a CHP, the intrinsic flexibility in the DHC network can be used to control these heat pumps or CHPs depending on prices on the day-ahead and intraday market, and therefore increase the production unit owner’s profit. Another advantage is that this control strategy supports a productionmix with a high share of renewable energy at system level in this way.

The third business feature is that researchers aim to balance the supply and demand of heat in a cluster of buildings. In this way, the use of excess heat or renewable heat in a cluster is maximized, making the cluster self-sufficient and minimizing the consumption of additional primary energy, which Desmedt says is one of the project’s major objectives. “We can do this by using the thermal inertia of the building’s mass, or by demand-side management measures,” he explains. A key element in this work is the use of self-learning algorithms to more closely match supply to demand. “The algorithms learn from data – so the controllers also record the data from the network. Based on that data, you can forecast energy demand,” continues Desmedt. “And there we reached an accuracy of around 7-8 percent, so we are able to predict the total demand on a district heating system with an accuracy of 7-8 percent.”

Renewable energy Researchers also aim to increase the use of waste heat and energy from renewable sources, which is of course a major priority given widespread concerns about energy sustainability. “One of the aims of the project is to increase the amount of energy from renewable sources that is supplied via district heating and cooling network systems. For example, we want to increase biomass use in Rottne,” says Desmedt.

Europe is home to a wide variety of district heating and cooling networks, utilising different sources of energy and with different legal frameworks, yet Desmedt says the controller will be widely applicable.

“We’re not targeting one specific type of

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At a glance Full Project Title Self-organising Thermal Operational Resource Management (STORM) Project Objectives The objective of this project is to develop and demonstrate a generic district heating and cooling network controller. Generic in this sense means that the controller will be applicable to all generations of networks, including widely spread 3rd generation networks, but also very innovative 4th generation networks.

Project Funding 1.97 million euros. The STORM project is funded by the European Union’s Horizon 2020 Programme under Grant Agreement no. 649743.

Project Partners VITO, EnergyVille (EV) [a cooperation between VITO, the University of Leuven and R&D center Imec], Mijnwater, Euroheat & Power, NODA, VEAB, and Zuyd.

Contact Details Johan Desmedt Unit Energy Technology VITO/EnergyVille Genk, Belgium T: + 32 14 335 841 E: Johan.Desmedt@vito.be W: http://storm-dhc.eu/

@Nathalie Belmans - EnergyVille.

Johan Desmedt energy supply or type of network. It can also be applicable in the geo-thermal area, or solar district heating network systems, or biomass, or many others,” he stresses.

A large amount of data has been gathered so far on not only energy consumption patterns, but also behaviour and network temperatures. This will provide solid foundations for evaluating the performance of the controller. “We measured a whole district heating system.

So we looked at the temperature in the network, the flow in the networks, the energy consumption of the buildings, and more. So we measured all the data without the presence of the STORM controller,” explains Desmedt. Soon the smart controller will be implemented at the pilot sites, then its performance and impact on energy efficiency will be assessed. “It will be able to communicate with the district heating and cooling network systems.

Then we will evaluate and compare it with measurements before the controller was implemented,” continues Desmedt.

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From this, researchers can also look to add further elements to the controller, fully maximising the benefits of increasingly advanced self-learning algorithms. Desmedt and his STORM colleagues are also laying the foundations for further research in this area, with educational activities planned for PhD and Masters students and professionals. “We want to extend this work with additional features, for instance in sub-station control, where quite a lot of work is still needed ,” he says. The project is also working on replication activities, looking towards potentially implementing the controller more widely across Europe. “We are now discussing how we can do this in an easier way, maybe by developing a new concept,” says Desmedt. “With STORM, we want to contribute to the deployment of district heating and cooling networks across Europe, and the controller is one of the features which we can replicate.”

Johan Desmedt received his degree in electrical engineering in 1993 from the BME, Belgium. He is currently with the Energy Technology department of the Flemish Institute for Technological Research (VITO) and EnergyVille, Belgium. After conducting research in the field of energy efficiency in buildings, building simulation and modelling, and underground thermal energy storage, he became project manager in 2009. He is currently project manager of national and international research activities in the district heating and cooling.

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Providing energy to small, remote communities like the Greek island of Tilos can be a complex task, which is often reflected in the price. We spoke to Dr Dimitrios Zafirakis about the TILOS project’s work in establishing a smart energy microgrid on the island of Tilos which, together with communityscale battery storage, will help more closely match renewable energy supply to demand

Local scale energy storage – challenging conventional supply and demand models The Greek island of Tilos is located in the southern Aegean Sea, roughly midway between its larger neighbours Kos and Rhodes. Currently, Tilos’s electricity is supplied via an undersea cable that carries oil-based generated power from Kos to Tilos, via the island of Nisyros, but now researchers in the TILOS project are investigating an alternative approach. “We’re going to establish local scale battery storage which interacts with renewable energy sources (RES) – wind and photovoltaics (PVs) – on the supply side, together with work on demand-side management (DSM) aspects on the consumer side. We’re going to install smart meters and DSM devices into local residences on Tilos and develop a centralized energy management system (EMS) that will allow communication between the supply and the demand side, with the support of an advanced battery storage system,” says Dr Dimitrios Zafirakis, the project’s Coordinator.

The smart microgrid on Tilos will maintain communication with the main electricity system of Kos, in order to increase the security of supply and also offer guaranteed energy exports through the battery storage system. This energy scheme challenges conventional thinking.

“Previously it was thought that you had to decide between having an interconnector and a storage asset. We are trying to prove that they can in fact be complementary,” says Dr Zafirakis, who stresses that “this is also in line with the fact that the electricity demand of Tilos presents considerable fluctuation over the course of a year and thus energy trade with the host grid of Kos could be really meaningful.”

Tilos has a population of around 500, which swells to between 1,000-1,500 during the summer tourist season, leading to increased energy consumption.

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“Overall, Tilos has an annual energy consumption of around 3 GWh and an average load demand of 250 kW, which however rises to 1 MW during the peak summer period,” outlines Dr Zafirakis.

Measuring instruments installed on Tilos island.

Below Image: Solar Radiation Station.

Battery storage The battery storage system is based on FIAMM technology NaNiCl2 batteries, comprising two battery containers with a total energy capacity of 2.88MWh and nominal power of 800kW. This is projected to last for a total of 4,500 full cycles, potentially providing more than 15 years of guaranteed operation. “The system promises efficiencies in the order of 85 percent round-trip, allowing also for deep discharges. So they are quite an advanced battery storage technology,” continues Dr Zafirakis. With the energy balancing abilities of the battery system, the project is looking to maximize the local penetration of RES, in particular wind and PVs. “We’re going to install an 800 kW wind turbine on Tilos, plus PVs of 160 kW, trying also to minimise the environmental footprint of the installation, expecting to achieve annual RES penetration of more than 85 percent for the entire island,” says Dr Zafirakis. Furthermore, it is also planned that the battery system will provide guaranteed energy exports to the host grid of Kos, which suggests a valueadding energy stream for the storage asset and the community-scale smart microgrid.

Demand side management Additionally, researchers plan to install 150-200 smart meters at local residences, public buildings and pumping stations on Tilos, generating more data on consumption patterns. “We will be able to monitor local consumption, and at the same time control some of these energy loads based on the residents’ consent,” says Dr Zafirakis. DSM devices will handle three different electrical loads per house, supporting the operation of the smart

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microgrid through communication with the central EMS. “We’re going to control water heaters, refrigerators and air conditioning. For example, water heaters will be automatically turned off when we don’t have sufficient energy and the batteries are empty, so we won’t allow the consumer to turn it on. Then when there’s an energy surplus, the water heater will be turned on, and we can store electrical energy in the form of hot water,” explains Dr Zafirakis.

Researchers have been working closely with the local community to both train local people on the effective operation of the smart microgrid and listen to their concerns and feedback. This is essential to the effective operation of the smart grid. “If you’re not actively engaged, you’re not going to be able to run the smart microgrid effectively,” points out Dr Zafirakis.

System operation strategies Three different operational strategies will be investigated within the project, with researchers looking to evaluate the performance of the battery storage system and the entire smart microgrid in each scenario. “In the first, we will eliminate the energy supply from the island of Kos, and see if we can achieve 100 percent penetration of RES. This approach will be tested during winter, when energy consumption is lower,” explains Dr

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Zafirakis. “The second strategy involves interaction with the host electricity grid of Kos, with the undersea cable mostly used to cover energy deficits when they occur.

So that’s going to be a conventional part of the operation of the system, mainly during the summer months when local consumption peaks.”

In the third strategy, the storage asset will be used to both support local energy autonomy and provide the host grid of Kos with guaranteed amounts of energy.

“We’re going to consider the system as a kind of market – the microgrid will interact with the market,” continues Dr Zafirakis. “On the one hand, we want to provide energy autonomy to the people of Tilos. On the other, if surplus energy is generated, we aim to send it to the host grid of Kos under guaranteed terms.”

Researchers aim to evaluate the performance first of the battery storage system and then of the entire microgrid, assessing also the value produced in each of these scenarios. This can then provide the basis for investigating the respective market value and potential applications, especially for the battery storage system.

“Is the battery just going to satisfy some local demand? Do we want to stress the battery so that it also provides guaranteed exports to the host grid of Kos? What are the implications? We’re looking at how the value of the battery varies across these three scenarios,” says Dr Zafirakis.

The integrated smart meter & DSM prototype solution.

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At a glance Full Project Title Technology innovation for the Local Scale, Optimum integration of Battery Energy Storage (TILOS) Project Objectives TILOS aims to demonstrate the optimal integration of local scale energy storage in a fully-operated, smart island microgrid that will also communicate with another, main electricity grid. The main objective of the project will be the development and operation of a prototype battery storage system, based on NaNiCl2 batteries, provided with an optimum, real-environment smart grid control system and coping with the challenge of supporting multiple tasks, ranging from microgrid energy management, maximization of RES penetration and grid stability, to export of guaranteed energy amounts and provision of ancillary services to the main grid.

Project Funding This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 646529.

Contact Details Dr Dimitrios Zafirakis, Piraeus University of Applied Sciences 250, Thivon & P. Ralli St., Egaleo, 12244 Greece T: +30-2105381580 E: dzaf@teipir.gr W: http://www.tiloshorizon.eu/

Dr Dimitrios Zafirakis

Project progress and challenges On May 13, 2016, the Greek Regulatory Authority for Energy issued the production license for the first ever island-based, hybrid wind-PV-battery system in Greece and also among the first in Europe, in the context of the TILOS project. “This decision is a major breakthrough for the further development of RES-based battery storage schemes and for the gradual elimination of oil dependence for numerous island regions in Greece and elsewhere,” underlined Dr Zafirakis.

imported oil for power generation; however, while the project’s research holds clear relevance in these terms, Dr Zafirakis says there are still some issues to address. “A key challenge is to dramatically reduce the costs of installing batteries,” he stresses. The priority in any case is to demonstrate the technical feasibility of the Tilos system, from which researchers can then look to develop it further. “The island is a good test case, as the costs are high, and there is a vision at the European Commission

We are developing a smart microgrid based on RES and local-scale battery storage that can provide self-autonomy for numerous communities. At the same time, these communities can also interact with

the electricity market Dr Dimitrios Zafirakis is an Energy Engineer holding a Mechanical Engineering Degree from the Piraeus University of Applied Sciences - Greece, an MSc in Energy from the University of Heriot Watt - UK and a PhD in Business from the University of East Anglia - UK. His research interests include development of energy storage services’ portfolios, operational strategies for smart grids, mechanisms for achieving large-scale integration of RES and energy planning for remote areas and island regions.

In the same vein, the TILOS researchers argue that the project’s approach could significantly reduce the cost of energy production on small island communities like Tilos. Currently, the cost of supplying energy to smaller Greek islands is far higher than on the mainland, due to the need to use

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level to promote these kinds of systems” explains Dr Zafirakis.

This knowledge will also help inform the future development and possible implementation of smart grids on other islands; the project is engaging with the islands of Pellworm, La Graciosa and Corsica. “We are thinking about energy provision on other islands, building on earlier feasibility studies,” says Dr Zafirakis.

This research is relevant not only to islands, but also mainland communities.

“We are developing a smart microgrid based on RES and local-scale battery storage that can provide self-autonomy for numerous communities. At the same time, these communities can also interact with the electricity market,” outlines Dr Zafirakis.

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