EU Research Summer 2022 by Blazon Publishing and Media Ltd

EU Research Summer 2022

The necessity of science in uncertain times

Covid complacency: pandemic latest

War in Ukraine: its impact on science and research

The Brexit effect on the UK and Horizon

Mariya Gabriel on the future of European research

Disseminating the latest research from around Europe and Horizon 2020 Follow EU Research on www.twitter.com/EU_RESEARCH

Editor’s N S

ince Ukraine was invaded by Russia, the response by the West has been to isolate the aggressor and in doing so, science collaboration has been almost completely severed. This is huge. All shapes and sizes of projects have entwined over recent years between Russia, Europe and the US. Scientific research has always been a bridge between countries, common ground even when politics and values are not always aligned but the unprovoked invasion of this democratic, independent, European country has set a new precedent.

The outrage felt by Europe and the US has reshaped scientific borders as well as political ones. To say science will be damaged is true, science around climate change as one big example, but also around energy, diseases, space exploration and indeed every aspect of research you can think of. What the response demonstrates is how there are red lines in behaviour even when we often forgive differences for the greater achievements possible, and the unjust invasion of Ukraine is certainly one such red line. Europe has shown great resolve in taking action, despite the challenges of doing so. It’s a matter of priority, a matter of urgency. Before we innovate for a future world, we need to ensure that world is the one we want to live in.

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.

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It is right to cut off relations, investment and support to any nation that invades, attacks and murders people in their own streets. This is a new era, one less international, one more divided by sides and it will be the majority of forwardthinking, collaborative nations that will proliferate in the end, as they always do.

Hope you enjoy the issue.

Richard Forsyth Editor

Contents 28 18

Research News EU Research takes a closer look at the latest news and technical breakthroughs from across the European research landscape.

OBSERVE We spoke to Dr Pieter Vader, Diego Aguilar Rodriguez and Willemijn de Voogt about the work of the Observe project in developing extracellular vesiclebased systems to deliver RNA drugs into the body.

MATURE-NK

SIROCCO

We spoke to Dr Maria Moros about the work of the Sirocco project in developing functionalised magnetic nanoparticles to manipulate cell signalling pathways, which could open up new therapeutic possibilities.

BITRECS With the numbers of clinicianscientists in decline, the BITRECS programme has been established to help train the next generation and foster the scientific leaders of the future, as Elias Campo explains.

FluxWIN Recent research shows that decompositional processes in soil can still continue during the colder months. Dr Claire Treat aims to gain deeper insights into the processes behind Winter emissions of greenhouse gases

ReVeAL We talked to Bonnie Fenton from the EU ReVeAL project about using UVARs to improve accessibility, lower emissions, improve air quality and safety, and increase the overall quality of life in cities.

BIOELECTRIC Researchers in the BIOELECTRIC project are working to develop a biocompatible, soft bioelectric implant. This could open up new possibilities in the treatment of various medical conditions, as Professor Hagan Bayley explains.

CINCHRON Researchers in the CINCHRON project are investigating the circadian clock in different insects, work that has relevance for understanding daily rhythms in humans, as Professor Charalambos Kyriacou explains.

PP-MAGIC Researchers in the PP-MAGIC project are investigating how bacteria become persisters, which could lead to the development of more effective antibiotics, as Professor Henning Jessen explains.

Natural killer cells have the ability to kill tumour cells, now researchers are looking to harness their potential as to treat different forms of cancer, as Dr Erhard Hofer of the Mature NK project explains.

SignalingDynamics Cells use different languages to communicate with each other, while they can also vary these signals. This ultimately affects the fate and behaviour of cells, as Dr Katharina Sonnen and Sonja Weterings explain.

Could our global consumption of meat be the catalyst for environmental catastrophe, even our extinction? How could this be happening and what can be done? We have a big, meaty problem. By Richard Forsyth.

SNUGly The surface of virtually all bacteria are coated with sugar polymers, called glycans. Professor Emma Slack, Dr Milad Radiom, Dr Yagmur George Turgay and Suwannee Ganguillet are investigating how the immune system recognises these glycans.

Meat vs Climate

INSPECTr Dr Ray Genoe and his colleagues in the INSPECTr project are developing intuitive, easy to use tools and an intelligent platform that will help law enforcement agencies combat crime more effectively.

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EDITORIAL

iv4XR We spoke to Rui Filipe Fernandes Prada about the work of the iv4XR project in developing autonomous testing agents that promise significant benefits to developers of Extended (XR) reality systems.

ExPaNDS

MUSK2 We spoke to Professor Lassi Aarniovuori, Professor Juha Pyrhönen and M.Sc. Juuso Narsakka about the work of the MUSK 2 project in developing a megawatt class universal highspeed machine.

INVESTIGATING COLONIAL IDENTITY Greek colonies were established in different areas around the Mediterranean during the first millennium BC. Evidence shows that local people had a major influence on cultural development, as Professor Martin Guggisberg explains.

REACT Researchers in the REACT project are developing a chemical treatment process to enable the re-use of acrylic textile waste from awnings and outdoor furnishings, as Daniele Piga explains.

THE NEURO-ECONOMICS OF CONFLICT Professor Carlos Alós-Ferrer is bringing together insights from several different fields to work more effectively with random utility models, the standard approach for estimating preferences in economics.

We spoke to Dr Patrick Fuhrmann and Dr Sophie Servan about the work of the ExPaNDS project in creating a framework for effective data management and supporting open science.

PLANET The PLANET project aims to use ideas from the physical internet to help transport and logistics companies work in a smarter and greener way, as Dr Konstantinos Zavitsas explains.

Science a Casualty of War When Russia invaded Ukraine on 24 February 2022, it was a decision that would alter the world, not just in terms of loss, bloodshed and borders, but also in the dissolving of long-standing collaborations between the Western nations and Russia. For science, the conflict would bring about its own shockwave. By Richard Forsyth.

Fiscal effects of intermunicipal cooperation and mergers What is the fiscal effect of mergers between Swiss municipalities? What happens to tax rates and expenditures? These questions are at the heart of Professor Marko Köthenburger’s research.

Managing Editor Richard Forsyth info@euresearcher.com Deputy Editor Patrick Truss patrick@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 finance@euresearcher.com Senior Account Manager Louise King editor@euresearcher.com

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RESEARCH

NEWS

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

EU launches regional innovation support policy framework Mariya Gabriel, European Commissioner for Innovation, Research, Culture, Education and Youth announced the first 63 regions, seven cities and four countries. The launch of this pilot project aims to help regions coordinate regional, national and EU research and innovation policies, and to bridge the many gaps in Europe’s fragmented innovation ecosystems. “We would like to address two types of fragmentation in the European innovation ecosystems,” said Mariya Gabriel, EU research commissioner. “[These are the] fragmentation of funding instruments and policies within territories, and lack of connection between regional innovation players.” The new scheme, Partnerships for Regional Innovation, is part of the upcoming European Innovation Agenda (EIA), the European Commission’s new plan to promote innovation, due to be announced in early July. “It’s our wish to have these partnerships as one of the flagship initiatives of the new EIA,” said Gabriel.

The partnerships build on the Commission’s Smart Specialisation Platform, which aims to help regions develop a strategic approach to using EU cohesion funds. While that is seen as being effective, the new pilot goes a step further by setting out a methodology for navigating the various EU and national instruments as well, including the Horizon Europe research programme, and helping regions to deploy them. The one year pilot partnerships will help raise funds, but each region will cover its own participation costs, with activities tailored for each participant, including workshops, exchange of good practice, and in depth policy reviews.

The participants, 63 regions, seven cities and four countries, will share good practices, develop and test tools to leverage various funding and policy resources, and link regional and national programmes to EU initiatives. All this will be done with a focus on sustainability, tying the EU’s green policy to local innovation actions. Elisa Ferreira, EU commissioner for cohesion, hopes the partnerships will help regions tackle some of the asymmetric impacts of horizontal policies, and of the COVID-19 pandemic and the war in Ukraine. “If we don’t have a policy that rebalances this split, we won’t be able to have convergent growth,” said Ferreira. Closing this gap will also be at the centre stage of the new EIA, which aims to make Europe a powerhouse for deep tech start-ups and create a pan-European innovation ecosystem where innovators can seamlessly work together and expand business operations across borders. “These partnerships will make certain that this new wave of innovation spreads throughout Europe,” said Gabriel. To get the partnerships up and running, the Commission’s science hub, the Joint Research Centre, has drawn up a list of the more than 100 tools that are available to strengthen the coordination of regional, national and EU innovation policies. At the centre of the toolbox are local missions that coordinate actions, making it possible for regions to take advantage of different combinations of innovation policies and funding.

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DFG raises concerns as the EU looks to reform research publishing The Commission wants research institutions to reduce their dependence on journal metrics instead rewarding researchers for the quality of their work, not by the number of citations. In a position paper published in May, the German Research Foundation (DFG) says it is against a top down reform of the research assessment system in Europe, two weeks after an alliance of ten German research organisations, including the DFG, have warned they will not sign a draft agreement prepared jointly by EU member states, stakeholders and the Commission if the proposed reforms turn out to be binding. “The DFG is committed to an open publishing system and a culture of assessment that is geared towards content,” said DFG president Katja Becker in a statement announcing the publication of the position paper. The DFG says a change in the evaluation culture of research institutions is needed, but a reform cannot be successful if research managers do not fully trust the new system, which would discard publication metrics. “We want to promote confidence in this change so as to make it easier for academics to put quality first when it comes to the publication and assessment of scholarship,” said Becker. The Commission and a number of research associations across Europe say the current system of evaluating research is becoming outdated and reform is needed to make it more efficient. Instead of rewarding researchers for the number of papers published, citations and the prestige of the journals concerned, a new system should look at the quality of research, while reducing the reliance on journal metrics. These concerns are not new, nor limited to the EU.

In 2013, an international coalition signed the DORA declaration on research assessment in San Francisco, hoping to reduce the weight of publication metrics in the evaluation of researchers. The Commission has included a reform of research assessment in the policy agenda of the revived European Research Area plan for a single market for research in the EU. The Commission is now gathering support from a coalition of organisations to implement the assessment reform and to begin testing it out this year. The DFG acknowledges that assessing research by leaning heavily on publication metrics can have a negative impact on science and the humanities. Metrics such as the total number of publications and citations, as well as bibliometric measures such as the h-index, a metric for evaluating the cumulative impact of an author’s scholarly output and performance, are increasingly problematic. Researchers can exploit the system and advance their careers by chasing to score higher points in the publication game instead of focusing on the content of the research. DFG recommends that research organisations and funding agencies come up with new ways to assess the quality of publications. According to its position paper, it is the responsibility of funding agencies and foundations to accept a broader range of publication. “The reputation of publication venues and bibliometric indicators, where they exist, should be removed from the canon of official assessment criteria and kept to a minimum in practical use.”

EU blocks UK researchers from Horizon Europe funding amid Brexit tensions The EU has confirmed it is holding back the UK’s access to the €95bn ‘Horizon Europe’ programme as a response to Boris Johnson’s plans to tear up the Northern Ireland protocol.

João Vale de Almeida, EU ambassador to the UK, said British scientists would become “collateral damage” in the dispute with the country’s place in Horizon increasingly at risk of falling “victim of the political impasse”. He added: “It’s very regrettable.” The UK’s associate membership of Horizon was foreseen in the 2020 Brexit agreement but has been delayed by long-running disagreements between London and the bloc over Northern Ireland. The UK is preparing legislation that would clear the way for it to ditch parts of the protocol, which governs trade between the region and mainland Britain. The stand-off has alarmed the UK’s university leaders, who have written to British prime minister Boris Johnson pleading with him “to make a personal intervention to break the deadlock” before it is too late. The European Research Council (ERC) has written to 98 scientists and academics who were recently approved for €172m (£145m) in grants telling them that if the UK’s associate membership of the €80bn Horizon Europe programme is not ratified they will not be eligible to draw down the money. Scientists have said they are now

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scrambling to find alternative EU institutions to host the funding, with some already turning down the ERC money and hoping the UK government’s promise of replacement cash will be delivered. Cambridge University astrophysicist Dr Nicholas Walton had to leave his coordinating role in an upcoming European Space Agency project, as he was told UK scientists cannot hold leadership roles until the country’s Horizon Europe membership is ratified. Other UK scientists are facing dilemmas over whether to move to the EU or hand over leadership of projects to an EU institution, the Guardian reported. The European Commission faced pressure last November when a joint statement was issued by more than 1,000 universities, 56 academies of science and 33 rectors’ associations, urging it to finalise the UK’s association to Horizon Europe or risk “endangering current and future plans for collaboration”. In December, the Royal Irish Academy also urged Ireland’s Government to help finalise the UK’s involvement with Horizon Europe, saying the ongoing delays are putting research partnerships in jeopardy.

President Zelensky urges universities to help rebuild Ukraine’s higher education system He spoke of situation in Ukraine for students and universities and endorses partnerships with American higher education. President Zelensky, met virtually last week with presidents of members of the Association of American Universities. He gave an overview of Ukraine’s position on the war instigated by Russia and also answered questions about Ukraine’s interest in future partnerships with American colleges and universities. The address was also livestreamed to students at AAU institutions. Zelensky dedicated his talk to the students who were watching. He said all students face some key decisions: “Are you an actor or just an observer? Do you try to change anything or not?” These are life-changing decisions that shape students’ character, he said. He spoke of how when students encounter hate, they will film incidents on their phones and post the video to Instagram or YouTube. But to really change hate, in some circumstances, he asks whether the students who recorded the hate actually stopped a hateful act from taking place. Earlier this year, Ukrainian universities were planning a return to on-campus teaching and research after two years of COVID-19 enforced virtual operations. But the Russian invasion has now propelled the higher education system into a much bigger crisis. University buildings, including libraries and research centres have been destroyed by Russian bombs and now the government is looking for help abroad, not only for the money to pay for new buildings, but also for experts who can help the education ministry to reform university curricula once the war is over. “This is not just about money, this is about expertise,” Zelensky told a videoconference with representatives of the Association of American Universities (AAU) on Monday, the 82nd day of Russia’s invasion of Ukraine.

American university heads attending the meeting offered help immediately. “Count on us,” replied Kristina Johnson, president of Ohio State University. Barbara Snyder, president of the AAU said, “President Zelensky rightly understands that one of the best ways to guarantee a better, stronger, more prosperous Ukraine is rebuild its higher education system around world class research universities. Strong research universities not only educate a nation’s populace, they contribute immeasurably to innovation, health care, economic growth and cultural vibrancy, and they help retain domestic talent,” Ted Mitchell, president of the American Council on Education said universities stand ready to offer help beyond the immediate relief that is being offered to scholars. “We want to work with you to make sure that [fleeing academics] all feel that they are a part of the renaissance of Ukraine when they return,” said Mitchell. When the war cools off, Zelensky said, Ukrainian universities would welcome experts from the US and use their advice on how to build stronger university departments that would produce the knowhow needed to fend off future cyber attacks from Russia. Ukraine also needs to train future professionals who could contribute to the defence, aeronautics and healthcare sectors. “Life is coming back in Kyiv,” said Zelensky. Faculty and staff are slowly returning to campuses. For safety reasons students are still attending online classes, but everyone is, “sick of this idleness,” But it is still unclear how this aid would be delivered and what the US university sector, which is largely private, could do to help in the long term.

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Research shows climate change is stealing people’s sleep

It’s likely to get worse as the planet gets hotter with 50-58 hours of sleep per person being ‘eroded’ every year by 2099. The research, published in the journal One Earth, finds that warm night times steal an average of about 44 hours of sleep per person each year. And they cause the average person to suffer from around 11 nights of inadequate sleep, that’s less than seven hours in a night, each year. The researchers gathered billions of individual sleep measurements collected from more than 47,000 participants across 68 countries around the world. They then paired these observations with weather and climate data from the locations where they were gathered. It’s one of the largest studies of its kind to examine the links between climate change and sleep. “Our results indicate that sleep – an essential restorative process integral for human health and productivity – may be degraded by warmer temperatures,” Kelton Minor, first author of the study and PhD candidate from the University of Copenhagen, said in a statement. “In order to make informed climate policy decisions moving forward, we need to better account for the full spectrum of plausible future climate impacts extending from today’s societal greenhouse gas emissions choices,” he said. While previous studies have clearly shown hot days increase deaths and hospitalisations

and worsen human performance, researchers said biological and behavioural mechanisms underlying these impacts have not been well understood. The study relies on data from people who have access to sleeptracking wristbands. The majority of the data comes from higherincome countries and tends to skew toward middle-aged men. It’s likely that more data from other demographics, particularly lower-income participants, would indicate an even bigger effect. In particular, the study underrepresents participants from Africa, Central and South America, and the Middle East — places the authors note “already rank among the warmest in the world.” So while the study outlines yet another clear climate-related problem for human health, there’s still more work to be done. Future research, the authors suggest, should focus on the world’s most vulnerable populations. “The burden of future warming will not be evenly distributed,” the researchers said. “Taken together, our results demonstrate that temperature-driven sleep loss likely has and may continue to exacerbate global environmental inequalities.”

PRACE 24th Call for proposals supports high-gain scientific research and industrial innovations Half the applicants were successful and were awarded over 2 billion core hours of access to world class computing and data management resources. The Partnership for Advanced Computing in Europe (PRACE) is an international non-profit association with its seat in Brussels. They were first featured in the EU Research publication in our Autumn 2021 edition. The PRACE Research Infrastructure provides a persistent world-class high performance computing service for scientists and researchers from academia and industry in Europe. The computer systems and their operations accessible through PRACE are made available by 5 PRACE members (BSC representing Spain, CINECA representing Italy, ETH Zurich/ CSCS representing Switzerland, GCS representing Germany and GENCI/CEA representing France). The Implementation Phase of PRACE receives funding from the EU’s Horizon 2020 Research and Innovation Programme. The 24th Call for Proposals for PRACE Project Access received 62 eligible proposals, of which 31 were awarded, a total of 2.136 billion core hours. This brings the total number of Project Access projects

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awarded to 947 since 2010. Taking into account the four multi-year proposals from calls 20 and 22, and the 10.21 million core hours reserved for Centres of Excellence, the total amount of computing time awarded by PRACE to date has reached approximately 35 billion core hours. The proposals awarded under the 24th Call are led by principal investigators from 13 different countries including international collaborations with team members from countries like the USA and China. Among the awarded proposals, seven scientific domains are represented: 10 proposals are linked to the fields of Chemical Sciences and Materials, 8 to Fundamental Constituents of Matter, 3 to Engineering, 3 to Earth System Sciences, 3 to Universe Sciences, 2 to Biochemistry, Bioinformatics and Life Sciences, and 2 to Mathematics and Computer Sciences. Two projects are awarded under the “Industry Access Track”, which earmarks 10% of the total resources for proposals with principal investigators from industry.

Pfizer boss warns against Covid-19 complacency as cases rise Albert Bourla, Chairman and Chief Executive Officer of Pfizer predicts constant waves of COVID-19 because of complacency about the coronavirus and politicization of the pandemic. Albert Bourla pointed to complacency about the virus, politicization of the pandemic, and diminishing immunity from vaccines and prior infections, according to comments reported by the Financial Times. People are also growing “tired” of COVID-19 safety regulations, said Bourla, who was speaking at the World Economic Forum in Davos, Switzerland, where world leaders and members of the business elite are gathered for an annual summit. Though COVID-19 cases are falling globally, in the US they’ve been gradually rising since early April, data from Johns Hopkins University shows. In the week to May 22, the US reported 790,000 new cases, more than three times as many as were reported in the last week of March. Pfizer said on May 3 it expects 2022 revenue from Comirnaty, its COVID-19 vaccine, of around $32 billion. “What worries me is the complacency,” Bourla said in Davos, noting that fewer people were wearing masks and that even people who have already been vaccinated were less likely to get booster shots. The consequences would likely be seen in between three and six months, he predicted. Bourla said Pfizer believed that antiviral drugs would replace vaccines as the key weapon in fighting the coronavirus, at least until shots providing a longer period of immunity were developed. Pfizer was “doubling down” on producing its antiviral pill Paxlovid, Bourla added. On Pfizer’s “game changer” antiviral pill, Paxlovid, the head of Pfizer healthcare Ireland Peter Reid said it was up to the Health Service Executive to recommend who should benefit from the treatment. It emerged last week that 65 doses of Paxlovid had been administered in Ireland since the drug became available here last month.

The Irish government bought 5,000 doses of the pill which have been used to treat older, unvaccinated, high-risk and immunocompromised patients. “We’ve signed a bilateral agreement with the State, so that’s great. That means we’ve been able to make that treatment available to patients who may benefit from it,” he said. “We have the licence, but it is up to the HSE and the Therapeutic Advisory Group to recommend who should benefit from the treatment.” Vaccine manufacturers are under pressure to share vaccine technology to allow for the manufacture of generic vaccines that could potentially be made and manufactured in developing countries. However Mr Reid said supply is not the issue as Pfizer is “making the vaccine available in an equitable and affordable way across the globe”. Vaccine donations to developing countries is also impacted by infrastructural challenges. “A lot of it is down to their infrastructure to take in a vaccine. As you know, it’s refrigerated at very low temperatures. So do they have the infrastructure to take it in? Do they have the trained resources to administer the vaccine? And then there is also the culture in some countries where the uptake of vaccines has never been high and therefore it is going to be a challenge.” Ireland has committed five million doses, mostly through the WHO-backed Covax initiative, which is co-ordinating the supply of vaccines to less developed states. But only 1.8 million have been delivered. The Department of Health said vaccine donation activity has reduced substantially this year, and while millions of doses have been put forward by Ireland for donation, there is “a significant emerging supply and demand imbalance.”

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The genetic landscape of Europe New study gives ‘big picture’ of European population genetics. A new study by RCSI University of Medicine and Health Sciences examining population genetics across Europe has analyzed the diverse ancestries of people living in the UK. This knowledge has the potential to inform future health research on genetic factors leading to disease. The study, led by researchers at the RCSI School of Pharmacy and Biomolecular Sciences and the SFI FutureNeuro Research Centre, has been published in Proceedings of the National Academy of Sciences. The RCSI and FutureNeuro researchers used the UK Biobank, a database of genetic and health information of over 500,000 participants from the UK, to examine population genetics and ancestry across Europe. The study analyzed the genetic ancestry data of individuals in the UK Biobank who reported having a European birthplace outside of the UK – about 1% of the dataset. Researchers cataloged where individuals shared segments of their genome with other individuals, meaning they had a common ancestor within the past 3,000 years. With this information, the researchers could group individuals with more segments in common than on average into three branches, corresponding to southern, central-eastern, and northwestern Europe. By studying the patterns of the genome sharing, the researchers were able to infer historical patterns such as population size and how genetically isolated specific European regions are, relative to

each other. In general, people from southern Europe were found to have less in common genetically with each other than in other areas, due to the larger population sizes and therefore usually greater number of ancestors in the region. An exception to this was Malta which, being an island, was found to have a smaller pool of ancestors. This is the first large sample analysis of Maltese population genetics. Identifying European regions such as Malta with specific histories of genetic isolation could potentially aid the discovery of genetic factors contributing to disease. Professor Gianpiero Cavalleri, Professor of Human Genetics at RCSI, Deputy Director of FutureNeuro and senior author on the paper, commented: “This research has shown the diversity of European ancestries sampled by the UK Biobank and has enabled us show the “big picture” of the genetic landscape of Europe, including new insights into communities such as within Malta. This work suggests similar gains of knowledge could be found within non-European ancestry groups using the UK Biobank, groups that are typically excluded from genetic analyses.” The research was conducted using the publicly available UK Biobank resource. It was supported by the NUI Post-Doctoral Fellowship in the Sciences and Engineering and Science Foundation Ireland, via the FutureNeuro Research Centre and the Centre for Research Training in Genomics Data Science.

Gene edited tomatoes could help people ‘ketchup’ on the Vitamin D Tomatoes that boost the body’s vitamin D could be among the first gene-edited crops allowed on sale in England. Researchers at the John Innes Centre (JIC) said the breakthrough offers a “sustainable solution” to a global health problem - as millions of people are estimated to be deficient in vitamin D, needed for healthy bones and muscles. It is also know as the “sunshine vitamin” as it is produced in the human body from sunlight absorbed by the skin. But in winter, and in higher latitudes, many people need extra vitamin D from supplements or from a small number of foods including oily fish, red meat and egg yolks.Plants are generally poor sources, and while tomato leaves naturally contain very low levels of one of the building blocks of vitamin D, called provitamin D3, it is not normally found in ripe tomatoes.

high levels of provitamin D3, so these usually-wasted parts of the plant could be used for the manufacture of vegan-friendly vitamin D3 supplements or food fortification.

The researchers used new “gene editing” techniques to “switch off” a particular plant enzyme to allow provitamin D3 to accumulate in the fruit. This was then converted to vitamin D3 through exposure to ultraviolet (UVB) light. The JIC team said one edited tomato contained the same levels of vitamin D as two medium-sized eggs or 28g of tuna. The study, published in the Nature Plants journal, says the leaves also contained much higher

Gene editing is different to the controversial process of genetic modification (GM), as scientists can target and manipulate specific genes already present in an organism, rather than introducing DNA from different species. Later this week, the government is expected to introduce a bill aiming to speed up production of crops edited to be more resistant to disease and drought, and less reliant on chemical fertilisers, in a bid to improve British food security in the wake of the war in Ukraine.

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Dr Jie Li, first author of the study, said: “The Covid-19 pandemic has helped to highlight the issue of vitamin D insufficiency and its impact on our immune function and general health. “The provitamin D enriched tomatoes we have produced offer a muchneeded plant-based source of the sunshine vitamin. That is great news for people adopting a plant-rich, vegetarian or vegan diet, and for the growing number of people worldwide suffering from the problem of vitamin D insufficiency.”

Delivering on the potential of RNA therapeutics

RNA therapeutics hold great potential as a means of treating a range of diseases, yet they are also immunogenic and it is difficult to transport these molecules to specific locations in the body. We spoke to Dr Pieter Vader, Diego Aguilar Rodriguez and Willemijn de Voogt about the work of the OBSERVE project in developing extracellular vesicle-based systems to deliver RNA drugs into the body. The potential of

RNA therapeutics is enormous, with researchers investigating possible applications in vaccine development, cancer treatment and several other areas of medicine, yet RNAs are also difficult molecules to work with. These molecules are fragile and can be degraded by various different enzymes, while there are also further issues to overcome before they can be applied more widely. “They are immunogenic, while they are also large and negatively charged, so they cannot spontaneously enter cells, which is necessary for them to perform their function,” says Dr Pieter Vader, Associate Professor in CDL Research and the Department of Experimental Cardiology at the University Medical Center Utrecht. As the Principal Investigator of the OBSERVE project, in which he is working together with PhD students Diego Aguilar Rodriguez and Willemijn de Voogt, Dr Vader is investigating the possibility of using extracellular vesicles (EVs) as a way to deliver RNA therapeutics and help overcome the issues which are currently limiting their application. “These

EVs are vesicles that are secreted by the cell, towards the extracellular milieu,” he outlines.

Extracellular communication These EVs are thought to have a variety of roles, with Dr Vader primarily interested in their role in intercellular communication. Some EVs are able to deliver content including proteins, RNAs and other small molecules in a

it?” he explains. A tool based on the CRISPRCas9 machinery is being used in the project to study EV-mediated RNA delivery on the single cell level. “With this tool we can see which cells in a dish or an organoid have taken up RNA via our vesicles,” continues Dr Vader. “We can then try comparing different types of vesicles in terms of which deliver most efficiently. We can perhaps then modify them

We’re studying naturally occurring extracellular vesicles – we study what they carry, how they carry it, as well as how they deliver it. We’re really trying to map that – which vesicles can deliver RNA and how do they do it? functional manner to other cells, a topic that Dr Vader and his colleagues in the project are investigating. “We’re studying naturally occurring EVs – we study what they carry, how they carry it, as well as how they deliver it. We’re really trying to map that – which vesicles can deliver RNA and how do they do

a little bit and ask the question; does their delivery capacity improve?” This is an important issue in terms of using these vesicles therapeutically, an issue high on the project’s agenda. Researchers are using naturally-occurring vesicles, but certain changes are necessary in order to

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Microfluidic mixing for manufacturing hybrid nanoparticles. Synthetic lipids are dissolved in the organic phase prior to mixing with the aqueous phase containing extracellular vesicles. Upon mixing under controlled conditions, hybrid nanoparticles can be formed.

load them with exogenous, therapeutic RNA. “We need to modify the EVs in order to give them the ability to carry RNA, so we are applying certain tricks, including hybridization with synthetic nanoparticles and other approaches, to load sufficient amounts of exogenous RNA into them,” says Dr Vader. This is a significant challenge, as typically there is nothing inside the vesicle to ‘hold’ on to the RNA; Dr Vader is developing hybrid nanoparticles, comprised of an EV and a liposome, to address this. “The liposomes carry a bit of positive charge and the RNA is negatively charged, so we were able to get one of the lipid components to hold on to the RNA,” he explains. “We then essentially merged the two nanoparticles – the liposomes and the EVs – together through extrusion.” The liposome is a bi-layer structure, effectively a very simple model system of an EV. With the addition of a bit of charge to hold onto the RNA, these two nanoparticles are merged together through extrusion, resulting in a hybrid structure. “This structure resembles an EV, but we’ve added some exogenous lipids, and it can now carry this therapeutic RNA,” outlines Dr Vader. By modifying the amounts of liposome and EVs used in forming these structures, Dr Vader and his colleagues are able to change the way they function. “We see that if we use a higher ratio of EVs compared to liposomes, then the mechanism of uptake is dictated by the EVs. Whereas if we have a lower ratio of EVs, we see that the liposome dictates where they go,” he says. “The problem is that at the moment we can’t really increase the proportion of EVs in the hybrid nanoparticle any further, just from a practical standpoint. We want to go even higher and investigate what happens, but first we have to optimise our manufacturing process.”

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Microfluidic mixing This is an issue that is being addressed in the project, with researchers investigating other methods of producing these hybrid nanoparticles. One possibility that Dr Vader is looking at is microfluidic mixing, which involves performing rapid mixing in a highly controlled manner, using very small volumes. “This is done on a chip. You have an inlet of the vesicle components, an inlet of the synthetic lipids, and then a highly controlled, rapid, chaotic mixing, before we get our end product,” he explains. The ultimate objective here is to develop a hybrid structure that can be loaded with a

Super-resolution microscopy image (dSTORM) of single extracellular vesicles (EVs). EVs are labeled with the general membrane dye Memglow560 (cyan). Transmembrane proteins CD81 (magenta) and CD63 (yellow) are detected on the EVs through staining with specific antibodies. Imaging was performed on the Nanoimager S (ONI). Top right: Zoom-in of an individual EV containing both CD81 and CD63.

therapeutic RNA; while this approach could be used to treat a variety of conditions, the focus in the OBSERVE project is on heart failure. “The structure will be based on stem- or progenitor cell-derived vesicles, which hold intrinsic regenerative properties. We will evaluate those in a mouse model of heart failure, of ischemia re-perfusion damage,” outlines Dr Vader. “We believe that we can combine the RNA delivery properties of EVs with their natural properties.”

A more effective way of delivering RNA therapeutics into the body would represent a significant step towards realising their potential. The main benefits of RNA therapeutics are firstly that they are highly specific, and secondly that they target a disease at its source. “They target the genetic disorder, or a gene that is wrongly expressed for example,” says Dr Vader. The EVs could also be used to deliver different types of RNA molecules, opening up wider possibilities. “The general demand from the delivery system is very similar for these RNA molecules, because they all have to be delivered to the cytosol of the target cells. So in principle if you can deliver one RNA, you can also deliver another,” continues Dr Vader. “However the loading, and the strategy for loading, may be different for a small RNA in comparison to a large one. Ideally you would want to load as much RNA as you can into a single EV.” These EVs also represent a safer and more versatile approach to delivering RNA than synthetic lipid nanoparticles (LNPs), which have been used in Covid-19 vaccines. While synthetic LNPs work effectively in delivering vaccines, they can lead to adverse reactions in other applications, which is not the case with EVs. “As a natural vehicle, EVs may not cause adverse reactions, so they are a much safer option,” explains Dr Vader. There is more work to do before EVs can be applied more widely however, and at this stage Dr Vader is still working to improve the hybrid nanoparticles. “We’re looking at the liposome-EV hybrids, using microfluidic mixing. We’re also looking at other hybrid structures, using for example polymeric nanoparticles,” he outlines. “Once we have prototypes that work, and that we can make at sufficient scale for a mouse model, we can look to move on. We are hoping to start some very preliminary testing in mouse models in the coming year .”

OBSERVE Overcoming cellular barriers to therapeutic RNA delivery using extracellular vesicles Project Objectives

The OBSERVE project aims at exploring the potential of extracellular vesicles (EVs) as a means of delivering RNA therapeutics to cells. These EVs are secreted by cells into the extra-cellular milieu, and play an important role in inter-cellular communication. These EVs essentially transport different materials between cells, including proteins, RNAs, lipids and other small molecules. Researchers are probing how EVs deliver RNAs, and looking to explore the wider therapeutic possibilities.

Project Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme, Starting Grant (StG), LS7, ERC-2019-STG.

Contact Details

Dr Pieter Vader, PhD Associate Professor CDL Research & Department of Experimental Cardiology Room G03.644 University Medical Center Utrecht Heidelberglaan 100 3584 CX Utrecht The Netherlands T: +31 88 7557654 E: pvader@umcutrecht.nl W: https://www.umcutrecht.nl/en/research/ researchers/vader-pieter-p

Dr Pieter Vader, PhD

OBSERVE Project Research Roles Researchers in the OBSERVE project are investigating several issues around EVs, with the aim of eventually using them to deliver RNA therapeutics. We spoke to Diego Aguilar Rodriguez and Willemijn de Voogt, PhD students at UMC Utrecht, about their role in the project, the methods they’re using, and the wider possibilities of RNA therapeutics. EU Researcher: Could I ask you both about your respective roles in the project? Willemijn de Voogt: My role is on the fundamental part of the project. I’m trying to unravel the biology behind EVs – how are they taken up? Which proteins or RNAs are involved in functional EV transfer? I’m looking at the pathways of intra-cellular trafficking, and the pathways underlying the transfer of RNA molecules. Diego Aguilar Rodriguez: I’m focused more on the potential therapeutic applications of EVs, with the goal of developing novel therapeutic tools to deliver mRNA. We’re looking to harness the properties of these EVs and trying to apply them in drug delivery. We’re trying to learn about these EVs and the potential benefits of their use in terms of things like uptake, targeting and preferential accumulation. EUR: Could you then look to bring these attributes to synthetic drug delivery systems? DAR: This is what we’re trying to do. Both EVs and synthetic drug delivery systems have limitations - we’re trying to get the best of both worlds.

Pieter Vader is Associate Professor at CDL Research and at the Department of Experimental Cardiology at the University Medical Center Utrecht. His main research interests are in the field of therapeutic applications of extracellular vesicles, including unraveling the mechanisms underlying extracellular vesicle-mediated cargo transfer. In 2021, Pieter was award the Prix Galien Research Award for his work on drug delivery.

EUR: How does the relationship between basic and applied research work? Do you need to collaborate quite closely? WdV: Not yet, as the project is still at quite an early stage, but hopefully more so later on. For instance, if I find that certain proteins are essential for uptake or functional delivery in a certain cell type, then potentially Diego can design hybrids that contain specifically these proteins. EUR: How will you use microfluidic mixing to create hybrids? DAR: One of the phases is the organic phase, with synthetic lipids. In the aqueous phase we’ll have EVs with the therapeutic reagent, in this case mRNA. Then we will hybridise them with a microfluidic chip, then at the end we purify the sample. EUR: Do you see wider potential in RNA therapeutics? WdV: Very much so, we’ve seen the therapeutic potential of RNAs in recent times, for example with the development of vaccines against Covid-19. By exploiting these delivery vehicles, we can look to target specific diseases in multiple ways, such as by trying to express certain genes or knock down certain genes.

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Photograph displaying splitting and feeding of cells in the cell culture laboratory. © Fraunhofer IZI

Natural killer cells to target cancer Natural killer cells have the ability to kill tumour cells, now researchers are looking to harness their potential as a means of treating different forms of cancer. The Mature NK project provides training to early stage researchers, helping them develop the skills that could lead to the development of more effective anti-cancer immunotherapies in future, as Dr Erhard Hofer explains on behalf of Dr. Ulrike Köhl, the coordinator of the project. A type of

lymphocyte, natural killer (NK) cells are an important part of the innate immune system, with the ability to kill harmful cells. Researchers in the Mature NK project are exploring the possibility of manufacturing these cells for use in treating certain types of cancer, representing an attractive alternative to other options like T-cell therapies, which can lead to toxic side-effects. “We would not have this problem with NK cells. It has been shown that NK cells are usually very welltolerated when infused into patients,” explains Dr Erhard Hofer, part of the project’s scientific management team. The project brings together research groups and biotech companies from across Europe to provide training to early stage researchers (ESRs), who are conducting research into several different aspects of NK cells. “Some of the laboratories in the project are active in basic immunology, while others are more clinically-related. The project consortium includes several research institutions and biotech companies that are active in the development of NK cell therapy,” says Dr Hofer.

Mature-NK project The wider aim here is to help translate research advances into effective treatments, with the partners in the project investigating several

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different means of modifying NK cells and then manufacturing them for use in treating certain types of cancer. There are various methods by which NK cells can be manufactured, one of which starts with taking cells from a blood donor. “The primary white blood cells of donors can be taken and then amplified. You can select the NK cells using antibodies and amplify them in special cell growth media to get a limited number of batches for NK cell

of iPSC, that then can be frozen and stored. “Therefore off-the-shelf-strategies for NK cell products are possible,” says Dr Hofer. NK cells can then be genetically modified to enhance their effectiveness in terms of identifying and then killing tumour cells. “These NK cells can be equipped with artificial effectors that would help them directly identify and kill targets like tumour cells more effectively,” explains Dr Hofer. “For

Some of the laboratories in the project are active in basic immunology, while others are more clinicallyrelated. The project consortium includes several research institutions and biotech companies that are active in the

development of natural killer cell therapy.

infusions in patients. Another method involves using induced pluripotent stem cells (iPSCs). These can be prepared from small numbers of various cell types including fibroblasts or various blood cells The advantage is that the generated iPSC cells can be grown in an unlimited way and then can be triggered to differentiate into NK cells,” outlines Dr Hofer. This will allow repeated production of large numbers of NK cells from the same batch

example, antibodies have been prepared that target tumour cells, helping NK cell receptors bind to them more effectively.” Normally, these NK cells have a number of different surface receptors, proteins that bind to both normal cells and also tumour cells. One of the ways by which NK cells kill their targets – which differentiates them from T-cells – is that they look for the presence of normal, selfidentifying receptors on the surface of normal

appropriate tumour antigen on the cancer cells, using CAR technology or NK cell engagers, the tumour could be specifically targeted, NK cells would properly invade and then the right level of reactivity would develop. Further preventing inhibitory interactions of tumour cells with NK cells will be required.” he says. “A large number of clinical trials are ongoing into the use of NK cells. Most are on leukemia, but there are also some looking at solid cancers.”

Modify cells MATURE-NK group photo taken at the first Winter School.

cells. “When they see these kinds of receptors, the activity of NK cells is blocked. These are surface molecules from the family of the socalled major histocompatibility complex. Where a cell doesn’t have these normal surface receptors, the NK cells would react by killing all cells that do not display this molecule,” says Dr Hofer. The nature of these surface receptors, that vary between individuals in a population, is an important factor in matching the donor for the most reactive NK cells to the right recipient, and Dr Hofer says tools are available now to help achieve this. “If you take cells from a donor, they need to be selected in such a way that their reactivity towards the patient’s cell is as high as possible. There are now reagents around to do this,” he outlines. Furthermore, a number of different methods are available to enhance the reactivity of the cells. The easiest way is simply to activate cells using cytokines, natural triggers that increase the general activity of the cell, while Dr Hofer says there are also other options. “You could genetically modify the cell – one possibility is using so-called Chimeric Antigen Receptor (CAR) constructs, that would endow the NK cells to bind specifically to tumour antigens and to get activated for killing. Another possibility is to use soluble, multi-valent cross-linkers,” he explains. These cross-linkers would be constructed from single chain antibodies that bind to the tumour surface and NK cell receptors (NK cell engagers). “These are soluble reagents that could be infused into the bloodstream for example, or they could be bound to therapeutic NK cells before infusion. Then they could be used to increase the chance that the NK cell would find the target cells - in that case the tumour cells,” continues Dr Hofer. “The NK cells would then bind – via this reagent – to the tumour cell, and at the same time get activated by the agent.” Researchers in the project are looking to use these kinds of methods to develop treatment for acute myeloid leukemia, a type of cancer which affects white blood cells, while a lot

of attention is also being paid to multiple myeloma. The hope is that the project’s research will lead to new treatments against these and other types of leukemia, and also open up new possibilities in the treatment of solid cancers, which are currently quite difficult to treat using immunotherapies. “There has been progress recently with solid cancers, but a big obstacle is that you would need to get the cells on the one hand to properly invade the tumour mass and on the other hand to prevent them from being inactivated by the tumour,” explains Dr Hofer. Different approaches would be required for different kinds of cancer, a topic on which Dr Hofer hopes progress will be made. “The hope is that by linking the NK cells to an

The idea here is to modify the NK cells in such a way that they would specifically target tumour cells and get similar reactivity as has been achieved with CAR T-cells, another type of recently successful immunotherapy. If this can be achieved, then the prospect of applying NK cells more widely in cancer treatment would move a step closer, and Dr Hofer believes they would be more cost-effective than many alternatives. “NK cells would be a lot easier and cheaper to develop than T-cells, and also off-the-shelf NK cell products for the use in different individuals would be possible,” he stresses. While advanced biological knowledge and technical expertise are essential to the development of these types of treatments, business skills are also required to bring them to clinical application, a topic that is addressed in the project. “The students get training in business management. They are trained in patents, and they are taught

Manufacturing of GMP (good manufacturing practice) grade natural killer (NK) cells: A schematic overview of the automated process steps for the isolation of NK cells from peripheral donor blood and their 2 weeks expansion in ex vivo cell culture using CliniMACS Prodigy® equipment is presented. In short, leukapheresis (LA) products (PBMNCs - peripheral blood mononuclear cells) from healthy donors are depleted for CD3+ T lymphocytes followed by immunomagnetic enrichment of CD56+ NK cells (PF - positive fraction). Expansion of NK cells is then performed over 14 days using NK MACS growth medium supplemented with various interleukins (IL) as displayed. Samples are collected over the whole process (IPC - in process samples; QC - quality control samples) to establish cell number and several quality parameters. After 3 days of culture the NK cells are transduced with the CAR (chimeric antigen receptor) vectors and CAR expression on the surface of NK cells is separately monitored. Finally, the cytotoxic activity of the CAR NK cells towards the cancer cells of interest is tested. (Adapted from Oberschmidt et al., 2019, Human Gene Therapy Methods 30, DOI: 10.1089/hgtb.2019.039)

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how to write at least an initial stage patent application,” outlines Dr Hofer. “While some of the companies involved in the consortium could commercialise the project’s research, the intention is to help students develop their skills so that they would also be prepared to found their own companies in future.” There are positive early signs in terms of potential applications arising from the project’s research, with Dr Koehl and her colleagues looking into conducting an initial stage clinical trial protocol on one of the most promising reagents. This could then provide the basis for a follow-up clinical trial with one of the project’s clinical partners, while Drs Koehl and Hofer are also looking into the possibility of a successor

project. “It might also be possible to apply for a follow-up project. A future project could be more focused on clinical and commercial partners,” he says. The ESRs in Mature-NK also have the opportunity to share their findings with the different groups in the consortium, which is stimulating further research and opening up new avenues of investigation. “A satellite workshop to the NK2022 meeting will be held in May, at which all our students will present their data. The NK2022 meeting is a conference of the society of natural immunity, where all the major players in the field come together,” continues Dr Hofer. “We hope that all of the ESRs in the project will take the opportunity to participate.”

MATURE-NK MAnufacturing TUmor-REactive Natural Killer cells

Project Objectives

The MATURE-NK project is designed as a research training network for 13 early stage researchers (ESRs, PhD students) to perform research encompassing basic, translational and clinical aspects of tumor-reactive natural killer (NK) cells. Improved procedures for NK cell manufacturing for clinical application are developed. In a wider context the general objectives are i) to fortify NK cell anti-tumor cytotoxicity, ii) to develop NK cell-engineering technology and an improved manufacturing process for NK cell products and iii) to prepare for follow-up clinical trials.

Project Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska-Curie Actions.

Project Partners

CAR (chimeric antigen receptor)-modified NK cells.

http://www.mature-nk.eu/partners.html

The principal of the CAR technology to target NK cells towards cancer cells is displayed. The NK cells are modified by transduction with a viral CAR vector so that the NK cells express an artificial activating CAR on their cell surface that has the capacity to guide the cells to the cancer cell and to activate the NK cell for killing when it binds to the tumor antigen on the cancer cell. Depending on the cancer type CAR constructs mediating binding to different tumor antigens preferentially expressed on different cancer types are already available or can be generated.

Contact Details

Professor Erhard Hofer Medizinische Universität Wien Schwarzspanierstrasse 17 A-1090 Wien, Austria T: +43 676 5581928 E: erhard.hofer@meduniwien.ac.at W: www.mature-nk.eu/ : @MATURE-NK : MATURE-NK Erhard Hofe

Photograph displaying cell expansion in plastic bags in the clean room of a GMP facility. © Fraunhofer IZI

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Ulrike Köhl

Erhard Hofer has a focus of research in molecular immunology and vascular biology. He has been a professor at the Medical University of Vienna (MUW) from 1997 to 2014, when he retired. Since then he has been involved in the management of the EC-funded cancer immunotherapy projects NATURIMMUN and more recently MATURE-NK. Ulrike Köhl is Director of the Fraunhofer Institute for Cell Therapy and Immunology (IZI) in Leipzig and of the Institute of Cellular Therapeutics at Medical School Hannover since 2012 and 2017, respectively, and holds professorships at University of Leipzig and Medical School Hannover. Previously, she worked at MD-Anderson-Cancer-Centre (Houston/ USA) and at the University Hospital Frankfurt. Her goals are focused on the manufacturing of ATMPs and the development of cell-based immunotherapies.

Waking up our regenerative pathways Many cells in the body respond to mechanical stimuli by activating different types of signalling pathways, which then affects cell behaviour. We spoke to Dr Moros about the work of the Sirocco project in developing functionalised magnetic nanoparticles to manipulate these pathways, which could open up the possibility of enhancing wound healing and directing stem cell fate. Many of the

cells in our body sense mechanical stimuli, which they then respond to in different ways, for example by proliferating or differentiating. In order to maintain correct blood pressure endothelial cells sense the current situation and then respond accordingly. “When they sense pressure on the surface of the cells, they respond by activating different pathways. They may need to change the contraction or relaxation of cells, finally increasing or decreasing the arterial diameter,” explains Dr María Moros, Principal Investigator of the Sirocco project. A deeper understanding of how cells convert these mechanical stimuli into biochemical activity – a process called mechanotransduction – could open up interesting new therapeutic avenues, a topic that Dr Moros is investigating in the Sirocco project. “In the project we’re looking at wound healing on the skin, which is a relatively simple model,” she says. “If it works, we can then look at other structures, like the heart, liver and intestine.” This could represent a way to essentially activate regeneration pathways which have become dormant in humans over the course of evolutionary history. Some invertebrates are able to fully regenerate themselves, such as the fresh water Hydra vulgaris, but humans do not have the same capacity. “It is not that we don’t have these regenerative pathways, it’s more like they are asleep or are only activated on very specific occasions. These pathways are really active in some of our organs like the intestine – but in other tissues, they are nearly inactive,” says Dr Moros. The wider aim in the project is to provide researchers with a tool to study these pathways and to activate them artificially, which could in the long-term open up the possibility of controlling them in a spatiotemporal way and applying them in regenerative medicine. “These pathways are really powerful in regeneration,” outlines Dr Moros.

Magnetic nanoparticles A specific regeneration pathway which is known to ultimately lead to cell division has been chosen in the project, with researchers now looking to investigate how stimuli are

Fluorescence microscopy image showing magnetic particles (in red) attached to MDCK cells membranes expressing E-cadherin (in green). Nuclei are stained in blue.

Above image - TEM MNPs: Transmission Electron Microscopy Image of magnetic nanoparticles synthesized for the project.

It is not that we don’t have these regenerative pathways, it’s more like they are “asleep”. We want to be able to activate these pathways when and where we want, so we can get this spatio-temporal control that is difficult to achieve in vivo with other techniques. turned into biochemical signals, using in vitro models of the skin. It’s important to tightly control this process and avoid excessive cell division and protect other areas of the body. “We aim to strike the right balance. We need to activate this pathway, but only when we want and where we want,” stresses Dr Moros. Researchers are investigating how to specifically activate this pathway using magnetic nanoparticles, which Dr Moros says represents a highly novel approach. “We are using magnetic nanoparticles, which can be

activated by stimulating them. So even if the nanoparticles go to other parts of the body, the effect will be localised,” she outlines. “We will be able to activate these pathways when and where we want, so we can get this spatiotemporal control that is difficult to achieve with other techniques.” The magnetic nanoparticles are modified with fragments of cadherins, proteins found on the surface of cells which are responsible for attachment to other cells. The nature of the cadherins depends on the type of cell. “For

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SIROCCO Remote control of cellular signalling triggered by magnetic switching Project Objectives

SIROCCO will use magnetic switchers to provide a powerful magnetomechanical transduction tool for studying mechanotransduction. To this aim, magnetic nanoparticles with high magnetic moments will be functionalized with engineered fragments of cadherins. SIROCCO aims to control, with high precision and spatio temporal control, different pathways related with mechanotransduction in order to enhance wound healing and to modulate stem cell fate.

SIROCCO Overview

instance E-cadherins will be located mainly on epithelial cells. We have chosen this target to functionalise our nanoparticles to obtain a more specific binding,” explains Dr Moros. A nanoparticle functionalised using engineered fragments of cadherins will then attach to a cell through the cadherins on its surface, after which Dr Moros and her colleagues will apply a magnet. “The nanoparticle will be pulled or stimulated by the magnet. With this force, the cell will think that there is a certain level of pressure, and then it will activate this signalling pathway, leading to cellular proliferation,” she says. “This will occur only in cells and in the area where we have stimulated these nanoparticles with the magnet, avoiding adverse effects.” These nanoparticles need to be extremely small to specifically target the cadherins, but they must also have sufficient magnetization to be attracted to a magnet, which represents a significant challenge in research. Instead of just iron oxide, Dr Moros is looking at using other materials such as ferrites doped with manganese that are known to have high magnetic potential. “We are doing a lot of work on designing the nanoparticles and the magnets to stimulate them,” she says. A lot of attention is currently focused on making sure that the cadherins on the nanoparticle are oriented correctly, as otherwise they would not be able to interact with the cellular cadherins. The project is primarily a proof-of-concept, with researchers aiming to demonstrate that these technologies can be applied not only to wound healing, but also to directing stem cell fate. “We want to develop this technology, which is comprised of the magnetic nanoparticles attached to the cadherins, and also the magnets,” continues Dr Moros. “The technology is part of a new area of research, called magnetogenetics. We want to be confident that this technology can be used in a reproducible way, to activate these regeneration pathways.”

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Wound healing Research is still at a relatively early stage, with Dr Moros currently working to produce the engineered cadherin fragments to place on top of the nanoparticles, conduct the functionalisation process, and bring together several other strands of research. There are many different parts of the puzzle, but the results so far are positive. “We have had good results with the magnetic nanoparticles and we have the protein fragments,” says Dr Moros. The technology could be extremely useful for studying mechanotransduction processes, about which much remains to be learnt, with Dr Moros saying it holds some significant advantages over the available alternatives. “This technology could be applied in vivo and in deep tissues, and we’re looking to achieve precise spatial and temporal control,” she outlines. “A second area of application is in wound healing – in the long-term, it could be used in Crohn’s disease for example.” This is not an immediate prospect however, and at the moment research is more fundamental in nature. At the moment Dr Moros is investigating cadherins typical of epithelial cells, using in vitro models of the skin. “We are now seeing that we have achieved a degree of specificity. These magnetic nanoparticles mainly attach in cells that have this cadherin presence.” But in future she could broaden out her research to look at other types of cadherins. “There are also other cadherins that are present on other types of cells. Later on we could start changing the cadherins on the nanoparticles to study other cell types or pathways,” she says. The project is set to run until the Spring of 2025, with Dr Moros and her colleagues working to improve and refine the technology in what is a relatively new area of research. Confirmation that these regeneration pathways can indeed be activated with this technology would represent good progress, says Dr Moros, and provide solid foundations for further development. “Once we can activate these pathways, we can then look at accelerating the regeneration of tissue,” she says.

Project Funding

The SIROCCO project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 853468).

Contact Details

Project Coordinator, Dr María Moros Instituto de Nanociencia y Materiales de Aragón(INMA) Edificio Circe C/Mariano Esquillor 15 50018 Zaragoza (España) T: +34 876555647 E: mamoros@unizar.es W: http://morosmaria.com

Dr María Moros

My research focuses on the synthesis and smart functionalization of magnetic nanoparticles (MNPs) for biomedical applications. To test the toxicicty and the activity of these materials I pioneered in Spain the use of an invertebrate model organism (Hydra vulgaris), which provides valuable data before reaching vertebrate animals. Inspired by this animal that can fully regenerate, I introduced a new research line that focuses on the remote and temporal activation of intracellular signals using MNPs (magnetogenetics) for regenerative purposes. This line has been awarded with a ERC Starting Grant.

How does the immune system respond to bacterial infections? The surface of virtually all bacteria are coated with sugar polymers, called glycans. We spoke to Professor Emma Slack, Dr Milad Radiom, Dr Yagmur George Turgay and Suwannee Ganguillet about the SNUGly project’s work in investigating how the immune system recognises these glycans, which could inform the development of vaccines against certain pathogens. The salmonella enterica pathogen is a common cause of food poisoning, usually after being transferred from farm animals or rodents via contaminated food. This particular pathogen is widely used in laboratories as an animal infection model, as researchers have a lot of very good handles on how to work with it. “With this bacterium, we understand what quite a lot of its genome does, we understand the structures on its surface, and we understand how it invades,” explains Professor Emma Slack. As Group Leader in the Laboratory for Food Immunology at ETH Zurich, Professor Slack is the Principal Investigator of the SNUGly project, in which researchers are looking at how the immune system responds to bacterial infections like salmonella enterica. “We’re looking at how the glycans that coat the surface of basically all bacteria are recognised by the immune system,” she says. “We’re investigating the constraints on how you produce an effective immune response that targets these sugars, and the effect of that on the bacteria.”

Immune response This research is focused primarily on salmonella enterica and e.coli at this stage, with Professor Slack and her colleagues mainly using mice in their work, but it could hold wider relevance to other pathogens and hosts. Most of what is currently understood about the immune response against pathogens, particularly protective antibody responses, comes from viruses. “A lot of work has been done on the affinity of antibodies binding to proteins or small molecules,” outlines Professor Slack. Previous work using immunological tools called haptens has shown how to select for higher affinity B-cells – which play an important role in the immune system – while further important insights have also been gained. “It’s been shown how high-affinity antibodies against nitrophenol can be made. This hapten has also been used to show how B-cells get selected to get into immune responses in the first place, while very interesting work has been done looking at how B-cells bind to antigens, and how B-cells selectively take up antigen from different types of membranes among cells,” continues Professor Slack.

Figure. 1. Atomic force microscopy (AFM) is used to probe antibody-bacterial glycan interactions. (A) An AFM image of S. Tm SB300. The surface is fully exposed with O-antigen molecules. (b) Schematic of AFM molecular level measurement of interaction forces between antibody and O-antigen. (c) A series of interaction forces between STA121 Fab and O5:O12 O-antigen giving an unbinding force 70–110 pN. The unbinding force is measured on retraction cycle (red).

These earlier findings are based on having a very small, well-behaved, rigid antigen however, which is not the case with the glycans associated with salmonella, called O-antigens. This particular antigen has a highly flexible structure that is radically different to nitrophenol. “You can think of nitrophenol as being a bit like a door handle on a solid door which you can grab onto, whereas the O-antigen is like a big bucket of slime,” says Professor Slack. Researchers in the project are investigating how these O-antigens bind to antibodies; Dr Milad Radiom, a Senior Assistant at the Laboratory, is using atomic force microscopy (AFM) to look at antibody-bacterial glycan interactions on the single molecule level. “The surface of the bacteria is effectively a carpet of these glycans. With AFM we can look at the carpet, and at individual molecules within the carpet,” he explains. “We can look at different effects, like O-antigen-antibody binding, opening O-antigen coil and pulling it out of the membrane, with great precision, examining forces in the range of tens to hundreds of piconewtons (10 -12 of a newton).”

This enables researchers to probe and understand the underpinnings of binding affinity, which may then affect the immunogenicity of an antigen, essentially its ability to stimulate an immune response. As Senior Scientist at the Laboratory, Dr Yagmur George Turgay is investigating the relationship between the strength of binding and immunogenicity. “We’ve gathered the tools that we need to perform certain experiments, including the glycans, the pathogen and the antibodies. We have antigens which are completely different in terms of binding affinity,” he outlines. In vitro antigen sampling assays will then be conducted using knock-in mice which express these different antibodies as B-cell receptors, from which Dr Turgay hopes to gain deeper insights. “We will check whether the stronger-binding molecule would sample more antigen, compared to the weaker binding antibody or B-cell receptor. We’ll also look at whether this would then lead to a stronger immune response,” he continues. “In order to get a good immune response you not only need to pull at the glycan, but also to drag along certain proteins.”

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These proteins are taken up in the B-cell, then digested and presented to a T-cell, a process which is not fully understood. The nature of the pull on the glycan, and the proteins that are then taken along, depends on many physico-chemical parameters. “It depends on the stiffness of the presenting membrane for example. It makes a difference whether the thing that the glycan is attached to is stiff or soft,” points out Dr Turgay. The fact that the mice have a B-cell receptor specific for a glycan also enables researchers to track how B-cells behave in a whole animal when exposed to antigens that bind with different affinities, a topic PhD student Suwannee Ganguillet is investigating. “We’re using lipid bilayers, in which we integrate lipidlinked O-glycans. We’re trying to simplify what happens in vivo into an in vitro model, that we can analyse under a microscope,” she explains. “This is dynamic, live microscopy. We can look at B-cells specific to that glycan, and see how the cell responds. We can see how much antigen is taken up, how that antigen is processed and can look at the T-cells and measure the activation strength.”

Vaccine effectiveness The wider aim here is to understand the fundamental biology that affects the effectiveness of a vaccine. All of the reagents and genetically modified animals are in place, and a lot of in vitro work has been done looking at the biophysics of antibody-glycan interactions. “We’ve been

using AFM, as well as other techniques like surface plasmon resonance, so we know the overall affinities of the antibodies we’re looking at,” says Professor Slack. The next major step will be to get in vivo animal experiments up and running, and to look at transgenic B-cell responses to different types of vaccine. “We can do almost infinite permutations of these experiments, so we’re going to have to be quite selective,” continues Professor Slack. “We’re also interested in extending this and starting the process of generating reagents for other bacterial glycans. So we want to extend the scope of this research beyond salmonella and have a tool-set that we can compare for different glycans and different pathogens.” One possibility is extending this research into capsular polysaccharides, sugar polymers which have a very different structure to glycans. These polysaccharides are often charged, whereas O-antigens are typically neutral. “The capsules we’re interested in are mainly anionic, containing things like sialic acids,” says Professor Slack. This is a technically challenging area, and so Professor Slack and her colleagues are very busy as they seek to build a fuller picture. “The problem with many of the capsular polysaccharides is getting an antibody response in order to make monoclonal antibodies and generate reagents in the first place, because these are often very non-immunogenic structures. This requires quite a lot of synthetic biology or carbohydrate chemistry, which is also very challenging,” she outlines.

SNUGly Systems-level novel understanding of anti-glycan immunity Project Objectives

Protective immunity against bacterial infections relies heavily on antibody responses that target bacterial surface glycans. However, the molecular constraints on induction of high-affinity glycan-targeting antibody responses remain poorly understood. We aim to better understand the influence of glycan structure on each stage of B cell activation, with a particular focus on intestinal immunity.

Project Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme, Starting Grant.

Project Partners

• Professor Raffaele Mezzenga, D-HEST, ETH Zürich, Switzerland (Expertise on soft materials and atomic force microscopy) • Professor Beth Stadtmueller, University of Illinois, USA (Expertise in recombinant antibody production and structural analysis)

Contact Details

Milad Radiom Senior Assistant Institute for Food, Nutrition and Health Vladimir-Prelog-Weg 1-5, 8093 Zürich E: milad.radiom@hest.ethz.ch W: https://slacklab.ethz.ch/ Yagmur Turgay E: yagmur.turgay@hest.ethz.ch Emma Slack E: emma.slack@hest.ethz.ch Suwannee Ganguillet E: suwannee.ganguillet@hest.ethz.ch The SNUGly project team

Emma Slack is a British/Swiss scientist who trained in Cambridge, London, Hamilton (Ontario) and Bern before joining the ETH Zürich as an Ambizione fellow. Milad Radiom studied mechanical and chemical engineering in AmirKabir University of Technology, Nanyang Technological University, and Virginia Tech. He is fascinated by mechanobiology across the length scales. Yagmur Turgay studied biochemistry in Frankfurt, Germany, before completing his PhD at ETH Zürich. He is interested in modalities of antibody-glycan interactions for the development of oral vaccines. Suwannee Ganguillet completed her Bachelors Degree in Biology at the University of Lausanne before moving to Zürich for her Master’s in Microbiology and Immunology at ETHZ, where she carried out her thesis in Professor Slack’s lab.

Figure. 2. STA121 and STA5 IgG binding kinetics for S.Tm O-antigens. Binding of the indicated S. Tm O-antigen derivatives to immobilised STA121 and STA5 recombinant IgG was analysed by Biacore T200 SPR measurements. Sensograms from real time single-cycle kinetic measurements (black curves) were fitted using heterogeneous ligand kinetic model (red curve). KD1 and KD2 are shown on top of each sensogram.

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How do cells communicate? Cells use different languages to communicate with each other, while they can also vary the volume or duration of these signals to send information, which ultimately affects the fate and behaviour of cells. We spoke to Dr Katharina Sonnen and Sonja Weterings about their work in using new technologies to investigate how cells talk to each other, which could open up new therapeutics avenues in future. The fields of developmental biology and

Cell signalling

adult tissue homeostasis have traditionally been viewed as separate, with scientists tending to communicate primarily with peers in their own area of research. However, similar cell signalling processes are involved in development and tissue maintenance. “There are certain principles in an adult organism that control whether a cell duplicates, or whether it becomes a muscle cell or a skin cell for example. These principles also apply in development, which starts with a single cell, which then makes the whole organism,” explains Dr Katharina Sonnen, Group Leader in the Sonnen Lab at the Hubrecht Institute in Utrecht. The focus in Dr Sonnen’s lab is on investigating the underlying basis of cell signalling, using new technologies to build a fuller picture. “Improved microscopes allow us to visualise cell-cell communications within tissue, in a dish. There are also technologies now to change or modify cell signals, which allow us to decode cell-cell communication,” she outlines.

As the head of the laboratory, Dr Sonnen is now working to gain deeper insights into cell signalling pathways and the transmission of biological information, using two model systems. The first of these model systems is somitogenesis, a phase of embryonic development. “In this phase the vertebrae are formed in a step-wise way, while several different organs form at the same

simplified model of the small intestine,” outlines Sonja Weterings, a PhD student in the lab. “We dissect the small intestine of a mouse and then grow these cells as mini-guts in a dish, which we then use in our research into cell signalling.” A variety of different techniques are being used in this research to visualize and investigate the mode-of-action of cell-cell communication, one of which is fluorescence real-time

We’ve seen that cell communication in the embryo is dynamic, and we want to understand how it works. What is really going

on? How does it control cell proliferation? And is the mechanism similar in adult tissues? time,” says Dr Sonnen. A second model system that Dr Sonnen and her colleagues in the group are using is a novel model of the small intestine, an organ in which there is a regular turnover of different types of cells throughout adult-life. “In the lab, we can make little organs in a dish called organoids. We make use of what is essentially a

imaging. Cells are fluorescently labelled, then researchers can follow these coloured cells using a microscope which can effectively zoom in to look at single cells. “This also allows us to record the communication between cells. We can get cells to produce a colour when another cell talks to it. So a cell receives a signal – from

Figure 1: Study of signalling dynamics in embryonic development and tissue homeostasis.

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a neighbouring cell or one further away – then it will start to produce a colour,” explains Dr Sonnen. The nature of that signal can then be related to the subsequent behaviour of the cell. “We can look at the signal the cell receives, and then at what happens next. Does it proliferate, or die, or do something else entirely?” continues Dr Sonnen. “Then we change the signal and see what happens then. The main aim for us is to understand the communication system, to understand how cells talk to each other.” This might be between neighbouring cells or over larger distances, with cells effectively using different languages to communicate with each other at different ranges. Cells can also vary a single sound to transmit information, in what has been described as the Morse code of biology. “With Morse code, varying a single sound – making it long or short, or combining long or short – allows you to transmit information,” says Dr Sonnen. Through the use of a technique called microfluidics, Dr Sonnen is able to change the nature of cell communication, then she can assess the effects. “We don’t just look at what’s going on, but can now also change the signal and then see what’s going on. We basically combine fluorescence realtime imaging with microfluidics,” she explains. “We can inactivate communication for some time then activate it, and in this way we can externally control the periodic activation.”

Translational impact A deeper understanding of cell signalling could also help researchers develop treatments for conditions associated with certain aberrations in cell function. Researchers in Dr Sonnen’s group are investigating how cell-cell communication is changed in the context of cancer. “In this context there is too much cellular proliferation and too little cell specification or cell death, so the control mechanisms don’t work properly any more. How is that changed in a tumour? Can we maybe change it back to induce differentiation for instance, so that

the cell doesn’t proliferate?” she outlines. Certain chemotherapeutics are available that block this cell communication, yet internal mechanisms may keep a system running, while these treatments also typically cause adverse side-effects; now Dr Sonnen is investigating the possibility of a more targeted approach. “If we target the signalling dynamics more specifically it may be that we have a better outcome and less severe side-effects for the patient as well,” she says. This research provides a solid foundation for potential translational work in future, yet this rests first on a thorough understanding of cell signalling under healthy conditions. While very much aware of the long-term therapeutic possibilities which could arise from her research, Dr Sonnen says the priority in the lab at this stage is to dig deeper into cell signalling mechanisms, both in somitogenesis and the small intestine. “We’ve seen that cell communication in the embryo is dynamic, and we want to understand how it works. What is really going on? How does it control cell proliferation? And is the mechanism similar in adult tissues?” she says. Similar cell signalling dynamics have been observed in adult tissue, now researchers aim to heighten awareness of these similarities. “We go to conferences on development, as well as those that are more related to organoids or adult tissues,” continues Dr Sonnen. “We’re trying to basically build a bridge between research into development and homeostasis.” The project is currently at around the midway point of its funding term, and various different tools have been set up which will help researchers gain deeper insights. These signals have been shown to play a significant role in the development of cancer, underlining the wider importance of the project’s work. “More research is required before we can move towards translational work. But in the longer term, understanding cell signalling could allow us to control differentiation,” says Dr Sonnen.

Figure 2: The “morse code of biology”

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SignalingDynamics Signaling dynamics in the control of cell proliferation and differentiation during development and homeostasis Project Objectives

The objectives of SignalingDynamics are to understand how signalling dynamics control cell proliferation and cell differentiation in the context of embryonic development and adult tissue homeostasis. To this end, the segmenting vertebrate embryo is used as model system of embryonic development and the small intestine as model system of tissue homeostasis. By comparing these two systems, we aim to derive general principles of cell-cell communication in multicellular systems.

Project Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme, Starting Grant (StG), LS3, ERC-2019-STG. Grant agreement ID: 850554

Contact Details

Project Coordinator: Katharina Sonnen, PhD, Group Leader Hubrecht Institute Uppsalalaan 8 3584 CT Utrecht The Netherlands T: +31 (0) 30 212 18 00 E: k.sonnen@hubrecht.eu W: https://www.sonnenlab.org/ W: https://cordis.europa.eu/project/id/850554 Katharina Sonnen

Sonja Weterings

Katharina Sonnen: After a PhD in cell biology (University of Basel), Ina did a Postdoc at EMBL Heidelberg to study cell-cell communication in vertebrate embryos. In 2018, she established her own research group at the Hubrecht Institute to study how cells communicate with each other both during embryonic development and in adult tissues. For this work she received an ERC starting grant in 2019. Sonja Weterings: Sonja is one of the PhD students working on the ERC-funded project SignalingDynamics. Her work focusses on signaling dynamics in adult tissues, mainly the small intestine. She studied Molecular Biology and Biomedical Sciences in Utrecht.

Waking up to a new era in antibiotics? Bacteria can effectively hibernate during antibiotic treatment through a mechanism called persistence, and when they ‘wake up’ they can be as infectious as they were beforehand. Researchers in the PP-MAGIC project are investigating how bacteria become persisters, which could lead to the development of more effective antibiotics, as Professor Henning Jessen explains. Many of the antibiotics currently in use

PP-MAGIC project

target an active metabolism in bacteria, such as protein or DNA synthesis. However dormant bacteria, which don’t have an active metabolism and are essentially asleep, are generally not targeted by antibiotics and so can represent an ongoing threat to health. “If these bacteria ‘wake up’ again they can be as infectious as they were before,” explains Professor Henning Jessen, Chair of Bioorganic Chemistry at the University of Freiburg. Bacteria can essentially hibernate through antibiotic treatment, then wake up in more or less the same form, a mechanism called persistence. “Basically all bacteria can do this, it’s just a ramping down of metabolism,” continues Professor Jessen. “One idea about how they become persister bacteria is through the stringent response. They encounter stress – such as heat, PH changes, or limited nutrition – then go into this metabolic shutdown and become persisters. It’s actually quite easy to generate persister bacteria, because it’s a very general evasion mechanism.”

As the Principal Investigator of the ERCfunded PP-MAGIC project, Professor Jessen is now investigating a number of questions around the stringent response, including how bacteria become persisters. Molecules called magic spot nucleotides (MSNs) are known to play an important role in this respect. “This is not the only molecule regulating the stringent response, but it’s certainly very important,” says Professor Jessen. Researchers in the project have generated derivatives of these MSNs, and Professor Jessen and his colleagues are investigating whether they can be used to modulate the stringent response. “Some analogues that we generate in the lab should be inactive in a so-called ‘caged’ form. Once they are irradiated, they would be transformed into the real MSNs, a process called ‘uncaging’; then we can study how

https://onlinelibrary.wiley.com/doi/10.1002/anie.202117675

they affect cell growth, antibiotic resistance, and so forth,” he outlines. “There is also the possibility of not only turning them on, but also potentially reversibly switching the structures, providing the ability to turn them ‘on’ and ‘off’ repeatedly.” These MSNs are fairly well conserved in bacteria and the system is not present in humans, so in principle they represent a promising target for drug development. However, different enzymes are used to make these MSNs in different bacteria, and Professor Jessen says generating derivatives of them is a complex task. “The issue is that currently there are not many crystal structures available of these enzymes, where you could really do structure-guided design of inhibitors,” he explains. Researchers do however have the crystal structure of Staphylococcus aureus, a clinically relevant bacterium resistant to many drugs. “We already have the compounds and the enzymes, and we’re now starting the in vitro tests. The hope is that it would work on several different pathogenic bacteria, but this

https://pubs.acs.org/pb-assets/images/_ journalCovers/joceah/joceah_v085i022-3. jpg?0.09706519983187822

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is not yet clear,” says Professor Jessen. “We’re making small libraries of hopefully active compounds, and if they show promise then we could approach industry in future.” The idea will be to activate or de-activate these molecules with light. This approach would essentially enable researchers to look into the structures of different types of MSN, a topic about which little is currently known. “The way these different MSNs operate is not well understood,” acknowledges Professor Jessen. There is also an applied dimension to the project, with Professor Jessen and his colleagues aiming to ultimately translate their findings into improved antibiotics. “The idea would be to develop entirely new compounds, which - for example - prohibit bacteria from entering the stringent response. The compound itself wouldn’t be an antibiotic, but it would suppress this evasion mechanism,” he outlines. “In principle, bacteria in the presence of such compounds would not shut down their metabolism and would not stop dividing. An aggressive bacterium that continues to divide might not sound desirable, yet these more visible bacteria would then make better targets for traditional antibiotics or the immune system.”

then they will grow again, but if it is present they will die,” explains Professor Jessen. “This is why antibiotics should be taken for an extended period of time, even if you don’t have any symptoms any more.” A lot of antibiotics still work effectively, and are commonly prescribed to treat different conditions. The question is for how long that will continue, and many companies have halted their development programmes. “Cheap antibiotics are still available so they cannot make a lot of money from this, and development is very expensive,” explains Professor Jessen. The project’s research holds wider relevance in this context, as a deeper understanding of the mechanisms behind the stringent response could aid the development of effective new antibiotics. However, at this stage Professor Jessen is focused more on synthesising the MSNs rather than moving towards pharmaceutical development. “We now have very good methods of making these molecules. We have also developed the analytical abilities to measure and quantify these molecules, for example by incorporation of stable heavy isotope labels such as 18O for quantitative mass spectrometry,” he says. Researchers in the project have started to make inhibitors and switchable molecules,

One idea about how bacteria become persisters is through the stringent response. They encounter stress – such as heat, pH changes, or limited nutrition – then go into metabolic shutdown and become persisters. Antibiotic resistance This research is being conducted against a backdrop of growing concern about antibiotic resistance and the prospect of a post antibiotic era, where treatments against common infections are no longer effective. This so-called ‘silent pandemic’ of increased antibiotic resistance is a major public health concern, and is a correspondingly urgent research priority. “Bacteria can acquire resistance through several mechanisms. In this project, we’re studying one of the mechanisms by which bacteria can evade antibiotic treatments,” says Professor Jessen. The presence of these persister bacteria is one of the reasons why some antibiotics are typically prescribed for quite long periods. “There will always be a sub-population of bacteria that is dormant and then wakes up. If there’s no antibiotic present at that point

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while issues around the delivery of them into bacteria are also being investigated, and the early data looks promising. The next step would be to analyse these molecules and assess their effect on bacteria. “How do bacteria behave in the presence of the molecules we have made? Can we track this and somehow connect it to the stringent response?” outlines Professor Jessen. The hope is to measure the effect of these molecules on the growth rate of bacteria. “Do we get increased or inhibited growth rates? We also plan to measure the activity of known antibiotics in the presence of the molecules that we have made - hopefully we will see an increase,” says Professor Jessen. “We’re in quite a good position at this stage of the project. The synthesis and the analytics are both in place, and we now start to look into how bacteria respond to our novel compounds.”

PP-MAGIC (Photo-)Control of Persisters: Targeting the Magic Spot Project Objectives

Resistance of bacteria to antibiotics is an emerging threat to our societies. New antibiotics are required that rely on unexplored mechanisms. The project PPMAGIC aims to understand the bacterial stringent response to stress mediated by so called magic spot nucleotides. Inhibiting this central stress adaptation mechanism appears as a promising strategy to develop new antibiotics.

Project Funding

This project has received funding from the European Research Council Consolidator Grant (CoG). The Jessen lab is funded by the European Research Council Consolidator Grant (CoG)., the Deutsche Forschungsgemeinschaft (DFG), the Volkswagen Foundation and the University of Freiburg.

Project Partners

• Urs Jenal, University of Basel

Contact Details

Project Coordinator, Prof. Dr. Henning Jacob Jessen Chair of Bioorganic Chemistry Institute of Organic Chemistry Albert-Ludwigs-University, Freiburg Albertstr. 21 79104 Freiburg i. B., Germany E: henning.jessen@oc.uni-freiburg.de W: http://www.jessen-lab.uni-freiburg.de

Professor Henning Jessen

Henning Jessen was born in Hamburg, Germany. He received his doctorate in Chemistry in 2008. He then moved for a postdoctoral stay to the Ecole Polytechnique Federale de Lausanne, Switzerland. In 2011 he moved to the University of Zuerich, Switzerland, to start his Habilitation. He was promoted to SNF assistant professor early 2015. Since October 2015 he holds a chair of Bioorganic Chemistry at the University of Freiburg.

Soft implants as medical devices Researchers in the BIOELECTRIC project are working to develop a biocompatible, soft bioelectric implant that can secrete ions and molecules. This work could open up new possibilities in the treatment of a variety of medical conditions, as Professor Hagan Bayley explains. A lot of

communication in the body occurs through small molecules, such as hormones and neurotransmitters, or ions, such as chloride, sodium and calcium ions, which influence physiological processes by binding to receptors or affecting electrical activity. As the Principal Investigator of the EU-backed BIOELECTRIC project, Professor Hagan Bayley is working to develop a soft, bioelectric implant capable of secreting these molecules and ions in the body. “We want to make a device that can secrete molecules or ions in a spatially controlled manner, and be able to turn secretion on-and-off at will,” he outlines. Such a device holds wide therapeutic potential, for example in delivering therapeutics to accelerate wound healing or regenerate the spinal cord, yet Professor Bayley says the aim of the project is to develop a general technology rather than focus on a specific application. “We’re trying to devise a platform device that can be used for many different applications,” he says.

Synthetic tissues as implants This research builds on earlier work on a class of membrane proteins called protein pores, which can be used as sensors. A spin-off company, Oxford Nanopore, was established by Professor Bayley in 2005 to bring a platform sensing technology based on protein pores to the market. The company developed the MinION nucleic acid sequencer, while Professor Bayley and his colleagues at the University of Oxford moved on to pursue other avenues of investigation. “We took our interest in membrane proteins to make synthetic tissues. The idea was to use a 3-D printer to pattern tiny aqueous droplets with a volume of around 50 picolitres [2013 Villar]. We can get these compartments to communicate with each other by using protein pores,” he explains. “Living tissues comprise communicating cells and hence the printed materials behave as synthetic tissues [2019 Bayley; 2021 Alcinesio], which can be used as implants.” These materials are made using naturallyoccurring lipids to ensure biocompatibility, and then encapsulated in polymers to

A 3D-printed structure formed of droplets. The blue droplets contain a small molecule, which can be secreted through protein pores in the pattern of a cross.

make the implants more robust. This is an important consideration when an implant is employed over a long period, although there are also possible applications where the implant might have a shorter lifespan. “For example, if we want to use one of these implants for wound healing then we would want it to be degraded by the body over a

The device works according to broadly the same basic principles in these two cases, but with refinements that are relevant to the specific application. It’s important to demonstrate that the technology can be used to solve specific problems if it is to be commercialised, but at this stage Professor Bayley and his colleagues are looking more

We want to make a biocompatible device that can secrete ions and molecules. Further, we’d like to control secretion, to turn it on and off when we want to. few days,” says Professor Bayley. The aim is to develop a flexible technology that can secrete different therapeutics and therefore be used in different applications. “If you want to treat a spinal cord injury, you might want a device that secretes peptide growth factors, while if you’re trying to accelerate wound healing, you might want to secrete a combination of antibiotics,” explains Professor Bayley.

generally to develop and improve the device, bringing together several strands of research. “We’re exploring several different ideas,” he says. One important issue in the project is to control the implants from outside the body, without the need for lots of wires or other paraphernalia. “If these devices are relatively near the surface of the body, then you will be able to control them with light. If they are implanted in an

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area that’s not accessible to light, you might use magnetism or orally administered small molecules to activate the devices,” says Professor Bayley. The researchers have found it is relatively easy to make implants that can be turned on, but turning them on-and-off in a controlled manner is proving more challenging. Further, while it is fairly simple to secrete ions from the implants, Professor Bayley’s group is also looking at whether they can carry other therapeutics. “We would like the implants to secrete specific small molecules, or even to make small molecules and then secrete them. We’re trying to implement all of these ideas,” he says. The focus is on investigating fundamental ideas with the potential to propel advances in tissue engineering. “As well as the implants, we continue to work on synthetic tissues and printed living cells [2020 Zhou] capable of communicating with each other, also for medical applications,” continues Professor Bayley. The ultimate goal in this research is to produce devices that can aid the treatment of different medical conditions. The treatment of spinal cord injury is typically broken down into two main categories. “In one category the spinal cord is completely severed, which is currently very difficult to fix. If we could get nerves to re-grow consistently across a break in the spinal cord then that would be a considerable advance,”

says Professor Bayley. Partial damage to the spinal cord is usually more treatable, but Professor Bayley says it’s important that it’s addressed before the situation deteriorates. “If you just let matters take their course, often it doesn’t work out well,” he stresses. “If we can intervene, with an implant that stimulates local cellular growth, that would be very beneficial.”

Affordability The cost of the device is also an important consideration in BIOELECTRIC, with a view towards the wider application of soft implants and the establishment of a spinoff company to build on the project’s work. Not only does Professor Bayley aim to produce devices that can benefit patients, he also wants to drive the price down so they’re affordable, which is not always the case with new medical technologies. “For example CAR (Chimeric Antigen Receptor) T-cell treatments are very expensive. They are extremely important therapies, and are a massive breakthrough in cancer treatment, but they are hugely expensive,” he says. This is a situation that Professor Bayley is keen to avoid. “We want to drive the cost of anything we develop down to a reasonable level. We don’t want these devices to cost millions,” he stresses. “We try to use relatively simple building blocks that will be affordable.”

BIOELECTRIC A Soft Bioelectric Implant from Droplet Networks Project Objectives

The aim of the BIOELECTRIC project is to develop soft bioelectric implants using biocompatible materials, overcoming some of the issues associated with using stiff or metallic materials. Much of the research is centered on trying to control these implants externally, so that they can release ions and small molecules at particular times and particular locations for therapeutic purposes. The implants might be used in regenerating the spinal cord for example, or in healing wounds, or even to replace the retina. Researchers aim to make these implants more robust for long-term applications by encapsulating them in various polymers, while in other applications it may be desirable for the implants to disintegrate after a short lifetime.

Project Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Grant Agreement No. 957516.

Contact Details

Project Coordinator, Professor Hagan Bayley FRS Professor of Chemical Biology University of Oxford 12 Mansfield Road, Oxford, OX1 3TA T: + 01865 285100 E: hagan.bayley@chem.ox.ac.uk W: https://www.bayleygroup.co.uk/ Villar, G., Graham, A.D. and Bayley, H. A tissue-like printed material. Science 340, 48-52 (2013). Zhou, L., Wolfes, A.C., Li, Y., Chen, D.C.W., Ko, H., Szele, F.G. and Bayley, H. Lipid bilayer supported 3D printing of human cerebral cortex cells reveals developmental interactions. Advanced Materials 32, e2002183 (2020). Alcinesio, A., Cazimoglu, I., Kimmerly, G.R., RestrepoSchild, V., Krishna Kumar, R. and Bayley. H. Modular synthetic tissues from 3D-printed building blocks. Adv. Functional Materials, 2107773 (1-11) (2021). Review: Bayley, H., Cazimoglu, I. and Hoskin, C. Synthetic tissues. Emerging Topics in Life Sciences 3, 615-622 (2019).

Professor Hagan Bayley

Hagan Bayley is the Professor of Chemical Biology at the University of Oxford. He was the 2009 Chemistry World Entrepreneur of the Year and was elected a fellow of the Royal Society in 2011. His lab has developed techniques for the fabrication of 3D tissues, both living and synthetic.

A simplified schematic of a 3D droplet printer. Pulses from piezo ejectors produce picoliter droplets, which can be printed in a patterned manner.

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Image by Verónica Pablo

Creating paths for clinician-scientists Clinician-scientists combine clinical expertise with a background in research, and so are ideally placed to both treat disease and understand the underlying mechanisms. With the numbers of clinician-scientists in decline, the BITRECS programme has been established to help train the next generation and foster the scientific leaders of the future, as Elías Campo explains. The priority for

clinicians is always to provide high-quality care, which rests on a deep understanding of the different options available to treat a specific condition. While clinicians focus on the needs of their patients, scientific researchers aim to uncover deeper insights into disease and develop improved treatments, now the BITRECS programme aims to bridge the gap between basic and clinical science. “The idea behind this European Union COFUND Fellowship Programme that is also supported by ‘La Caixa’ Foundation is to extend training opportunities to people who wear these two hats, as both a clinician and also as a researcher, what is called a clinician-scientist,” explains Elías Campo, Director at IDIBAPS, a Biomedical Research Institute in Barcelona devoted to excellent translational research. IDIBAPS is associated with the Hospital Clínic of Barcelona, a renowned tertiary public university hospital. “A clinician-scientist is an invaluable asset in both research and medical settings, and they have played an important role in strengthening the existing link between the Hospital Clínic of Barcelona and IDIBAPS,” says Campo. This hospital has shown a historical commitment to research, with a fixed percentage of physician’s salaries donated to programmes promoting this activity. In line with this agenda, IDIBAPS was created in 1996, and since 2011 it has run its own specific funding schemes to promote the clinician-scientist career path.

Clinician-scientist This is not however a common career path, and the number of clinician-scientists is decreasing both in Europe and beyond. It is becoming ever more difficult to recruit highly skilled graduates into a career as a clinician-scientist, and then to subsequently retain them, in part because of the attractiveness of the other options available, such as positions dedicated entirely to treating patients. This is an issue of which Campo is well aware. “Sometimes the contractual opportunities offered by the research system are not really attractive in

them will also spend part of their time abroad at a hosting partner institution. “The idea is that participating in BITRECS allows them to focus on developing their research skills, to become the scientific leaders of the future,” outlines Campo. This is the result of involving many IDIBAPS stakeholders that provide their expertise to the programme under the coordination of the IDIBAPS Institutional Actions Office, which is run by its Head, Gemma Pascual, and the BITRECS programme manager, Agustín Rodríguez. The fellows had complete freedom in choosing the subject they wanted to address, with projects

A clinician-scientist is an invaluable asset in both research and medical settings, and they have played an important role in strengthening the existing link between the Hospital Clínic of Barcelona and IDIBAPS. comparison to what they may be offered elsewhere, so more competitive opportunities should be provided,” he acknowledges. The BITRECS programme aims to address this issue by giving post-doctoral researchers excellent working conditions together with the opportunity to focus solely on research, while also supporting their career development and providing mentoring and advice. The fellows are conducting research projects over a three-year period, during which they will be working at IDIBAPS and some of

in BITRECS covering a wide variety of topics; the common denominator is the quality of the research. “IDIBAPS wanted excellent research projects that could have a positive health impact,” says Campo “Although each research project is unique, all of them are focused on specific diseases and trying to develop improved treatments or strategies to better manage those disorders.” A high degree of focus as well as technical knowledge is required for this kind of research, yet this does not mean that the fellows

All BITRECS fellows work to have a positive impact on the understanding and management of different diseases, with the ultimate aim of trying to benefit society: Marco Antonio Alba on granulomatosis with polyangiitis, Helena Ariño on autoimmune encephalitis, Lorna Leal on HIV and SARSCoV2 infections, Gianluigi Li Bassi on acute respiratory distress syndrome and infection of SARS-CoV2, Gerardo Rodríguez Lobato on multiple myeloma, Isabel Valli on schizophrenia and bipolar disorder and Norma Verdolini also on bipolar disorder but at the same time considering the COVID-19 pandemic’s negative effects on mental health.

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The seven clinician-scientists’ BITRECS fellows.

BITRECS Biomedicine international training research programme for excellent clinician-scientists (2017-2023) Project Objectives

BITRECS aims at recruiting promising postdoctoral clinician-scientists researchers with clinical background, to help them become clinicianscientists leaders in the future. The programme is a way of fighting against the decrease on the number of those professionals in Europe and beyond. To preserve them is important for both their understanding of health problems directly from their clinical practice and their availability to perform genuine translational research.

Project Funding

are completely isolated from their medical colleagues and peers. Alongside conducting their research, the fellows also are encouraged to attend seminars and consult with colleagues on any particularly interesting clinical cases. “The fellows should participate in these kinds of activities and maintain professional relationships while they are dedicated to research,” outlines Campo. To enlarge their network of collaborators or disseminate their work abroad the fellows were also encouraged to attend training or networking activities supported with funding provided by the programme. However, the main priority for BITRECS is research, and the vision is that the fellows will choose to pursue a career combining clinical work and research once they have left the programme. “At IDIBAPS we are putting a lot of thought into the future career opportunities open to the fellows,” he says.

Career options The researchers themselves were asked to design a career development plan at the beginning of their fellowship, as well as a plan for the dissemination and exploitation of their

results. The fellows have already published a relevant amount of peer-reviewed scientific articles. At the same time they also have access to specific support, if they want to protect or even exploit any results arising from their projects, prior to publication. The programme itself is set to conclude around the middle of 2023, but the Institute is looking into the possibility of extending it, reflecting on its impact and the wider importance of training the next generation of clinician-scientists. This is part of the wider aim of encouraging the development of clinician-scientists, enhancing their professional profile and promoting impactful translational research. Clinician-scientists have an important role to play in connecting basic and clinical science, contributing to the goal of creating a wide impact on science and ultimately bringing benefits to patients and our society. Campo aims to heighten awareness of career possibilities in this area. “What we know is that IDIBAPS wants to continue offering positions in future to clinician-scientists from all research career steps,” he says.

The project has received the funding of: European Union’s Horizon 2020 research and innovation program (grant agreement 754550) and “La Caixa” Foundation (agreement LCF/PR/ GN18/50310006).

Outgoing hosting institutions

• Centre for Immunology and Vaccinology at Imperial College London (UK) • Institute of Clinical Trials and Methodology at University College London (UK) • Institute of Psychiatry, Psychology & Neuroscience at King’s College London (UK) • The Prince Charles Hospital (Australia) • University of Würzburg (Germany).

Contact Details

Gemma Pascual Agustín Rodríguez IDIBAPS Institutional Actions Office T: +34 933129401 E: bitrecs@idibaps.org W: https://www.clinicbarcelona.org/en/idibaps W: https://bitrecs.idibaps.org

Professor Elías Campo

Photo of a clinician-scientist.

Elías Campo is the Director of IDIBAPS, excellent biomedical research institute linked to Hospital Clínic of Barcelona pursuing translational research. He is also an outstanding clinician-scientist leading research on the pathology of lymphoid neoplasms. He is at the forefront of BITRECS programme and other funding schemes to promote the career development of clinician-scientists.

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Meat vs Climate

Agriculture, particularly with livestock, is taking the blame for playing a significant part in driving climate change and biodiversity loss around the planet. Could our global consumption of meat be the catalyst for environmental catastrophe, even our extinction? How could this be happening and what can be done? We have a big, meaty problem. By Richard Forsyth

alf the world’s habitable land is used for agriculture. The concept of countryside for most of us, is not rich, thick ancient forests, it’s large expanses of connected level fields. Of this farmland, when talking about the planet, 77 percent is used for livestock, yet livestock only produces 18 percent of the world’s calories and 37 percent of all our protein. In short, compared to growing crops and vegetables, it dominates the allocated space to produce a lot less food. This uneven equation is not the only reason to worry about meat being a sustainable food source, with a growing population and the available land shrinking.

Planet killing cow burps Livestock creates 14.5 percent of greenhouse gas from human-related emissions, according to the UN’s Food and Agriculture Organisation. Cows are responsible for two-thirds of that statistic. In fact, eating a couple of hamburgers a week for a year creates the equivalent amount of greenhouse gases as heating a home in the UK for 95 days. It’s become common knowledge that whilst we are filling up fields with cows, the cows are filling up the air with unpleasant gases. Livestock farming produces methane and nitrous oxide. Methane comes from a process which sounds much nicer than it smells, enteric fermentation, and by methane we mean around 95 percent burps and five percent farts expelled from your cow-shaped meat. Microbes in a cow’s stomach break down cattle feed into energy and protein, whilst expelling methane to the tune of between 70 and

120 kg from its orifices per year, equivalent to around 2,300 kg of CO 2 a year – that’s about the weight of a car. Staying with a car analogy, this is the same as burning 1,000 litres of petrol. Times that by 1.5 billion cows and bulls and you’ve got a burpy, farty cloud of doom around the planet. It’s not just the cow’s wind, it’s also their eight gallons of gushing urine a day, which produces the nasty greenhouse gas nitrous oxide.

Changing ‘pee-haviour’ Researchers in New Zealand and Germany have tackled this problem by experimenting with potty training calves, and after just 45 minutes every other day for a few weeks, 11 out of 16 animals were trained to use a latrine they termed the MooLoo. The calves learned they would only receive a treat if they used the latrine whilst receiving a mild spray of water if they had mishaps. Cows have the intelligence of two-tofour-year-old children, perhaps for some, another strong incentive to eat more vegetables. Cows indoors create another problem. If your cows are in a barn, the urine and excrement mix up to create the air pollutant, ammonia. In a very literal way, but also for the environment, this can stink.

Seaweed to calm the tummy In context, the biggest climate-killing bodily release is by far, the cow burps, so short of stopping cow farming, what can be done to calm those grumbly bovine stomachs. One solution suggested is to add a sprinkle of asparagopsis taxiformis, a red seaweed to the cow’s nosh,

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“A big issue with cattle, that you don’t have with crops, is that you need to feed them and use crops purely for that purpose. Dairy cattle-feed pellets can be made up from maize, barley, oat, soy, flax, seeds from legumes – broad bean and protein pea and dried beet pulp. The point is, we have to feed the food, using more of the valuable land to do so.” which means cows burp 85 percent less methane, as well as needing less quantity of food. The only catch is a requirement to grow 200 million tonnes of this to feed all the cattle on the planet. There are efforts afoot to use a seed bank to alter the genetic makeup of this seaweed into a simpler form that’s quicker and easier to harvest. A big issue with cattle, that you don’t have with crops, is that you need to feed them and use crops purely for that purpose. Dairy cattlefeed pellets can be made up from maize, barley, oat, soy, flax, seeds from legumes – broad bean and protein pea and dried beet pulp. The point is, we have to feed the food, using more of the valuable land to do so. Of course, cows are very big animals and require wide expanses or space and a lot of resources to sustain them. Therefore, say some problem solvers, why not just eat small animals? Fish and chicken, for example, don’t need the kind of land and infrastructure you need for cattle, or sheep for that matter.

largest producer of farmed insects revealed cricket farms produce half the CO 2 of a chicken farm and uses 25 percent less water, whilst using far less land and generating less waste. Ground-up crickets make a cricket powder that is high in protein, around 58 to 65 percent protein per insect and is comparable to skinless chicken in this respect. Cricket burgers are said to be a bit nutty and smoky in flavour. Cricket farming is not greatly established but food for crickets is usually similar to chicken feed with grains and flours. Biowaste is also being tested as cricket food, which could prove useful. Crickets convert feed into meat product more effectively too, with greater kgs meat product for equivalent feed, when compared to chickens. However, the fact still remains, you’re feeding your food, so it might be better to cut out the middleman (or middle cricket), and just have a bean burger to save time and the trouble of filling up another field to feed some bugs.

Smoky bug burgers

Veg and two veg

Going even further with this idea, why not go really small and eat insects? If insects seem a disgusting option, you may be surprised to learn they may already be in your diet. The red dye used in ice cream, listed as cochineal dye is from female cochineal beetles which eat red berries and are seen as a source of natural red colouring. Then there is Shellac from the lac insect (a parasite of trees in Asia) used for shiny red coatings on sweets. What is being proposed by climate aware food producers, is that we farm and harvest insects for protein to replace our other meat products. If determined to eat meat in a more climate-friendly way or when other options are not available, it can make sense. Thailand, the

Governments around the world are not, yet at least, convinced that quotas on meat-eating should be set and the emphasis for any change is still on the consumer. Meat is a sizable one trillion dollar industry and significant economic driver, damaging it would be uncomfortable for many economies, especially the ones hacking down trees to accommodate new farmland. For a large number of people, not eating meat is also either unappealing or unthinkable, meat being perceived as a necessary and tasty component of the human diet. Interestingly, and controversially, meat is not an essential part of the human diet. A grim statistic for meat-eaters is that around 45,000 deaths a year from heart disease,

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The natural world is under huge pressure from the way we exploit land available to us and in a paradoxical way, the more we need land for food, the quicker we exterminate environments and eco-systems that can give us food. cancer and strokes are linked to meat consumption. We can, today live without meat completely and remain healthy, even healthier, obviously depending on the way we eat different vegetables in combination, than when including meat in the food we choose. There is an abundance of protein and iron in the vegetable world and many substitute vegetablebased food products that have similar tastes and flavours to meat products. Today in wealthier economies, meat is very much a personal choice, no longer a necessary staple.

Frankenstein fillets There is one other idea, one that is extraordinary but one that will inevitably be a menu and shopping list option soon and that is, clean meat. This is also known as cultured meat, it is meat that is grown in a lab, no hooves or horns necessary! It sounds bizarre and it is, but it means not raising and feeding an animal, cutting out cruelty and using less oil, water and land in the process. It is estimated that one-hundredth of the land is needed to make clean meat compared to farm animals.

The first clean meat burger was produced in 2013 and offered to foodie journalists in London. Gastronomic critics, Hanni Ruetzler and Josh Schonwald bit into the burger for a taste trial. Ruetzler described it as “close to meat, but not that juicy.” She added, “the consistency is perfect.” A lot has happened since then and a full range of meat products are being promised. Due to the level of control you can have in the creation, you can have less fat, and more omega-3 fatty acids. This could be the healthiest meat you could possibly eat. Author, Paul Shapiro, more recently reviewed the taste of clean foie gras in the Guardian newspaper, which was a meat made in a laboratory. He claimed it tasted “rich and buttery, savoury and decadent”. To be clear, this is still meat, just without animal suffering or draining on natural resources. Despite still being the beginning of the journey there are around 50 companies eager to make clean meat commercial any time now, in a sector that has so much potential, it will inevitably grow. The process involves extracting cells from an animal via a non-invasive biopsy and putting them in a cultivator, so the cells think they are inside

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an animal. With a cocktail of ingredients including sugars, enzymes, salts, amino acids, growth factor proteins and more, the mix grows into muscle tissue, good enough to eat.

Extinction fates As cattle proliferate around the globe, in contrast, natural wildlife is in sharp decline. The loss of species is currently estimated to between 1,000 and10,000 times higher than the natural extinction rate – a figure that has defined this era as the 6th mass extinction phase for Earth and unlike the other five, it’s clear our unstoppable expansion of agriculture, overexploitation of wildlife and destruction of natural habitats are what’s making it happen. The Natural History Museum in the UK developed a tool they called The Biodiversity Trends Explorer which measured species abundance, species diversity and ecosystem health for starters. It enabled users to track modelled biodiversity changes since 2000 toward 2050 on global, national and regional levels. It provided a way to compare ecosystem biodiversity in different countries around the world. In short, they concluded in a press release in October 2021 that biodiversity loss had, as they put it so bluntly, ‘crashed through the safe limit for humanity.’

The demise of pollinators As agricultural land is widely responsible for natural habitat destruction, this is a factor in killing off pollinating insects, along with pesticides and urban expansion. About a third of plants that flower rely on pollinators to seed and losing pollinating species would be devastating. That equates to tens of thousands of species. A 2021 study discovered that pollinating creatures like bees, butterflies and hummingbirds have been fast in decline during the previous six years around the world. Pollinator species which propagate over 75% of crops and plants are dying out, creating another threat to the world’s food security. To get a taste (or lose it) of what it would be like in a world without pollinators, here are some things we like on our weekly menu that need them to exist: apples, strawberries, blueberries, watermelon, almonds, avocados, coffee, sunflower oil, tomatoes, grapes, beets cauliflower, cabbage, broccoli, turnips, cherries, cucumbers, onions, grapefruit, pumpkins and Brussel’s sprout and there’s more. The natural world is under huge pressure from the way we exploit land available to us and in a paradoxical way, the more we need land for food, the quicker we exterminate environments and eco-systems that can give us food.

clear that extinction events take around 10 million years to reboot and replenish life through evolution – and that is without humans in every corner. A burgeoning population will face a desolate world, without the chance of recovery for disappeared wildlife and without sustainable food supplies. It’s hard to imagine humans outliving an extinction era like the Devonian extinction, which occurred 251 million years ago and where 96% of species died out. One 2020 study in Scientific Reports, stated that if deforestation and consumption of resources continue at current rates, there could be a catastrophic collapse in human civilization and population in the next 20 to 40 years and the chances, according to this research, of our collective survival is less than 10 percent.

End of graze The one paradox of the meat economy that stands out, for the future of food and its sustainable management, is the question of allocating diminishing resources. Around 77 billion land animals are slaughtered every year for food. What is hidden behind this figure is that it means 77 billion mouths to feed over each of their lifetimes, that aren’t ours. Just focusing on that number alone shows it is a huge number of processed creatures turned to products. For a disturbing context of scale, that is equivalent to roughly the same as every person on Earth, slaughtered every year, in an annual animal Armageddon. The issues of pollution and land use from farmed land animals is overwhelmingly contributing to climate change. World leaders decided at the climate conference in 2021, COP26, that methane was a target gas to minimise. As ridiculous as it sounds, a world of burping cows might just be the tipping point for the worst-case environmental disaster we all dread to contemplate. The meat issue is in part helping veganism become the fastest growing food trend. For dedicated meat-eaters, vegan meals or vegetarian meals two or three times per week can be a positive ritual. Livestock based agriculture will need to adapt to dwindling land availability, making clean meat and insect-based products a solution for our future dinner options. We are certainly running out of time to address changes to consumer habits and supply chains. For a sustainable future, meat consumption and farming in its current form need to be addressed with urgency, however unpalatable that is for many of us.

When it’s gone, we’re gone Of course, with no sustainable environments and ecosystems to sustain them, the majority of natural animal life is under threat. In The Living Planet Report 2018, 16,704 populations of 4,005 vertebrate species were tracked, finding that global populations of mammals, birds, fish, reptiles, and amphibians have declined by 60 percent between 1970 and 2014, the most recent year with available data. For context, palaeontologists are

“Governments around the world are not, yet at least, convinced that quotas on meat-eating should be set and the emphasis for any change is still on the consumer. Meat is a sizable one trillion dollar industry and significant economic driver, damaging it would be uncomfortable for many economies, especially the ones hacking down trees to accommodate new farmland.” www.euresearcher.com

The ticking of the biological clock Biological rhythms have evolved so that organisms can anticipate both daily and seasonal changes in their environment and then adapt their behaviour accordingly. Researchers in the CINCHRON project are investigating the clock in a range of different insects, work that has relevance for understanding daily rhythms in humans, as Professor Charalambos Kyriacou explains. CINCHRON’s aim is to study the circadian and seasonal rhythms using a variety of insect models:

A lot of research into the circadian clock has historically focused on Drosophila, the fruit fly. Indeed, a Nobel Prize in Medicine/ Physiology was awarded in 2017 to the three US geneticists who identified the major clock genes in the fly. However, less is known about clocks in other insects, an issue that researchers in the CINCHRON project are addressing. “The aim of CINCHRON is to expand our knowledge of the biological clock into other species beyond Drosophila,” outlines Professor Charalambos Kyriacou, the project’s coordinator. The idea of the project is to study clocks in insects such as the pea aphid, which has a significant impact on crop productivity, as well as species like bees and silkmoths which have clear economic value. This research is being conducted against a backdrop of wider concern about the impact of climate change. “With climate change, the range of tropical insects is expanding – we’re already seeing that around the Mediterranean,” explains Professor Kyriacou. “We’re getting these insects – disease vectors – expanding their ranges. We want to understand their basic biology, including their circadian clock, which controls the timing of everything they do.”

Circadian and seasonal clock The circadian clock in these insects is typically localised in a very limited set of ‘clock’ neurons in the brain and these cells regulate rhythmic behaviour over the course of a day. Fruit flies tend to be crepuscular, meaning that they are very lively in the morning and just before dusk, but much less active in the middle of the day. “An insect wakes and has its morning burst of activity, then a siesta, then its evening behaviour. There is evidence that these neurons are divided into a ‘morning’ and an ‘evening’ oscillator, and they talk to each other. It’s important to be rhythmic, it’s a fitness character. An insect needs to anticipate when light’s coming on or off so they can get their physiology ready to meet the demands of the day or night. These rhythms are adaptive, and they can be adjusted,” explains Professor Kyriacou.

Inner clock: the circadian rhythm changes according to the light-dark cycle. This is the clock that regulates behaviours and physiological processes that change with a period of 24 hrs. DNA (the hour hand of the clock) hosts the genes that control the circadian system and it is possible to study them using molecular biology techniques, symbolised by the pipette (the minute hand). Medial clock: the seasonal clock controls those behaviours and processes that cycle with a period of one year (migration, hibernation etc). The seasonal clock is controlled by the changes in temperature and length of daylight. Outer clock: the different insects that CINCHRON is exploiting as model organisms to study the clocks. There are 12 insects positioned along the circadian and seasonal clocks. If an insect is represented more than once, it means that more than one lab is working on it. The four fruit flies (at 1, 5, 7 and 11) are different from one another to show different mutations that are used in our studies. Figures created by Joanna Szramel, Terence Al Abaquita, and Giulia Manoli Early Stage Researchers of the CINCHRON project.

There are 15 different PhD projects within CINCHRON, focusing on both the circadian and seasonal clock in several insect species. The seasonal ‘clock’ is important for hibernation. “An insect’s hibernation is called diapause. In some insects it’s brought on by reduction in temperature, but in most it’s photoperiodic, so short days and long nights (there is evidence that the 24 hour timer can measure these day/night lengths in some insects) heralds the oncoming winter so that insects can hibernate till the longer days of spring arrive,” outlines Professor Kyriacou. The relationship between the circadian and seasonal clocks has long

been a subject of scientific debate; Professor Kyriacou says recent evidence suggests that they are closely related. “If you disrupt some of the clock genes that build the molecular oscillator, you get very strong changes in what we call the seasonal phenotype,” he says. “For example, our colleagues in Groningen are studying a parasitic wasp called Nasonia that can be used for the biological control of pests. With techniques like Crispr-cas9, you can now disrupt these 24 hour clock genes and examine the effects on seasonal hibernation.” This could open up new possibilities in the control of species like pea aphids or Drosophila

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CINCHRON Comparative INsect CHRONobiology Project Objectives

suzukii that in recent years has become a major world-wide fruit pest. The simplest solution to pest control is to spray insecticide in whatever quantities are required, and while this approach may kill the insect, Professor Kyriacou says it also often causes wider issues. “Indiscriminate spraying leads to serious pollution problems,” he points out. Disrupting the seasonal clock of these insects would represent a highly attractive alternative. “If we can disrupt the seasonal clock so that these insects don’t go into hibernation, then the winter climate will kill them. That’s the idea, but we’ve first got to understand hibernation in order to be able to manipulate it,” acknowledges Professor Kyriacou. “We’ve made considerable progress in terms of understanding how the circadian and seasonal clocks talk to each other. If we can somehow disrupt the seasonal clock with a biological compound that’s specific to a pest species, then that would have implications for their hibernation and be less polluting than chemical control.”

Shift work This research also holds wider relevance in terms of understanding circadian rhythms in humans and the impact of sleep disruption on personal health. About a quarter of the Western population work shifts, disrupting sleeping patterns, and evidence shows that these people are at higher risk of experiencing health problems. “People who work shifts tend to die earlier, have more cardiovascular and metabolic problems, and are also more likely to develop cancer. It’s a major problem, and it costs Western economies billions every year,” explains Professor Kyriacou. A deeper understanding of the circadian clock could help researchers devise methods to prevent chronodisruption, a topic which Professor Kyriacou says is the focus of a lot of attention. “Some of my colleagues in Europe and the US are making small molecules that can interact with some of the key clock proteins. The aim is to shift the phase of the clock and prevent the social jetlag that shift workers experience,” he outlines.

If we can disrupt

the seasonal clock so that these insects don’t go into hibernation, then winter will kill them. That’s the idea, but we’ve got to understand hibernation in order to be able to manipulate it. A further aspect of the project’s agenda centres around research into the immune system in insects, which is known to have a circadian cycle. One project in CINCHRON involves examining the circadian clock and the immune system in the silkmoth, a species vulnerable to severe bacterial infections which can wipe out entire colonies. “Our colleagues in Italy are studying when silkmoths are more susceptible to getting infection. They’ve made significant progress in understanding the chrono-cycle of the immune system in silkworms, and how we can adjust the way they are raised to try and prevent them getting these bacterial infections,” says Professor Kyriacou. A similar approach could potentially be applied to boost resistance to infection in all organisms, not just insects, says Professor Kyriacou. “All organisms are resistant to infection in a circadian cycle,” he stresses.

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The CINCHRON project itself is nearing the end of its funding term, but there are plans to continue the research and broaden out into further areas, including the possibility of studying insects like the soldier fly. Several companies in Europe and the US are farming soldier flies as animal feed, and while many people today may find the prospect of eating them unpalatable, Professor Kyriacou says the idea is attracting interest as a potential source of nutrition. “With food security becoming an ever more pressing issue, we’ve got to look at alternative sources of food,” he stresses. Knowledge of circadian rhythms could help companies farming these insects to maximise productivity, a topic Professor Kyriacou plans to explore. “A new project would investigate how to optimise the rearing of these insects that are becoming important sources for animal feed, and could feed humans in the future,” he says.

The CINCHRON project is comprised of four workpackages, with the shared goal of developing a deeper understanding of biological clocks in insects. The four workpackages are centered around circadian chronobiology, seasonal chronobiology, metabolic chronobiology and commercial chronobiology. There are 15 different PhD projects within CINCHRON, in which researchers are investigating different topics around insect chronobiology. The researchers collaborate extensively across the different workpackages, sharing knowledge as they seek to both gain deeper insights into the clock, and also apply them in the practical context.

Project Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 765937

Contact Details

Dr Valeria Zonato Research Centre Manager Genetics and Genome Biology Department University Road Leicester LE17RH T: + 0116 252 3249 E: vz12@le.ac.uk W: www.cinchron.org W: www.neurogeneticsleicester.com

Prof. Charalambos Kyriacou

Dr Valeria Zonato

Valeria Zonato is the manager of the CINCHRON network, which offers training and funding to several PhD students working in the field of insect chronobiology. She has a PhD in genetics and genome biology. Charalambos Kyriacou is a Professor in the Genetics department at the University of Leicester. He has published widely in biological rhythms and evolution and neurogenetics of fly behaviour.

Look North for a deeper picture of decomposition The soil in northern ecosystems may freeze in Winter, yet recent research shows that decompositional processes can still continue during the colder months. Researchers in the FluxWIN project are taking gas flux measurements throughout the year, aiming to gain deeper insights into the processes behind Winter emissions of greenhouse gases, as Dr Claire Treat explains. A lot of

studies on the carbon cycle and greenhouse gas emissions have been conducted during the growing season in Summer when plants are active, yet less attention has been paid to the Winter months. Extrapolations to the cold season have been based on our understanding of these growing season processes, yet earth system models of carbon emissions tend to break down over the Winter months, for reasons that are not fully understood. “We don’t really understand why the models don’t work, whether it’s something to do with the physical soil properties for example, or representations of the soil dynamics,” says Dr Claire Treat, a researcher at the Alfred Wegener Institute in Germany. As the head of the ERC-funded FluxWIN project, Dr Treat is looking at greenhouse gas emissions both in the growing season and also outside it, reflecting a recent shift in perspective. “Over the past 15 years or so it’s been found that soil microbes can be active at colder temperatures than modellers - who parameterise soil decomposition processes had previously realised,” explains Dr Treat.

Greenhouse gas budgets The nature of soil thermodynamics means that the surface of the soil can freeze before the layer underneath, so decompositional processes can in fact continue into the Winter. This may then affect the greenhouse gas budget, a topic that Dr Treat and her colleagues in the project are investigating. “One of the questions we’re looking at is whether the freezing of

unaffected by human activity. “They haven’t been used for agriculture, and they haven’t been logged recently,” continues Dr Treat. “We plan to conduct several campaigns over the Winter and Spring, and take measurements over some longer periods over the course of a year. We’re very interested in the transition between Spring and Summer when plants are starting to come out.”

This high-frequency greenhouse gas analyser lets us measure pretty small fluxes of both methane and nitrous oxide. Our focus really is on carbon dioxide and methane, and also on this nitrous oxide component. the soil surface is enough to impede oxygen diffusion into the soil and make it anaerobic, and then turn a site that wouldn’t normally produce methane into a site where oxygen is sufficiently depleted that it does,” she outlines. Researchers are taking measurements at several ecosystems on the Siikenava II site in Finland, a location which has been relatively

This research involves using automated chambers to take the measurements throughout a whole year, without the need for a researcher to be physically present. Measurements are collected throughout the day at 6 hour intervals, providing researchers with a wealth of data. “These chambers are essentially like a gas sampling mechanism. They are highly portable,

The FluxWIN project investigates how greenhouse gas emissions and soil processes change throughout the year. In summer, warm soil temperatures and plant activity stimulate the production of methane (CH4) and net uptake of carbon dioxide (CO2). In the fall and spring, larger than expected emissions of CO2 and CH4 have been observed despite cooler soil temperatures and lack of plant activity. These periods are a focus of the project.

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FluxWIN The role of non-growing season processes in the methane and nitrous oxide budgets in pristine northern ecosystems Project Objectives

The importance of non-growing season greenhouse gas fluxes to annual budgets in pristine northern terrestrial ecosystems is growing in awareness. Greenhouse gas (GHG) fluxes during the non-growing season and freeze-thaw dynamics are still underrepresented and may be a reason why current process-based models predict inadequate annual methane (CH4) and nitrous oxide (N2O) budgets. FluxWIN is therefore investigating ecological and biogeochemical processes in global carbon (C) and nitrogen (N) cycles during the non-growing and shoulder seasons by combining high-frequency greenhouse gas measurements, biogeochemical monitoring and process-based modeling.

Automated, robotic chambers capture greenhouse gas emissions throughout the year. Here they are measuring CO2, CH4, and N2O exchange from a dry bog site.

Project Funding and can be used to take measurements for quite a long time” says Dr Treat. The chambers are being used together with a high-frequency gas analyser which is far more sensitive than the traditional gas chromatograph, enabling Dr Treat and her colleagues to detect smaller fluxes than was previously possible. “This highfrequency greenhouse gas analyser lets us measure pretty small fluxes of both methane and nitrous oxide (N2O). Our focus really is on carbon dioxide (CO2) and methane, and also on this N2O component,” she continues. “We have some preliminary measurements which we’re currently analysing, and we’re also planning the second year of measurements.” The project also has an experimental component, with PhD students working on experiments both in the field and the laboratory. The aim here is to tease out the processes underlying methane emissions during the cold season, particularly relating to methane production and oxidation. “These are the two main processes that contribute to the methane flux. We’re planning to do a comparison next Summer with data from another site much further north, in Finnish Lapland, that has some permafrost,” explains Dr Treat. A model has been developed to explain these processes, which Dr Treat plans to test using data from several sites. “The idea is to make sure that this model will work at Siikenava II, then we intend to test it at some other sites and assess whether it includes the right mechanisms. We have data from some long-term monitoring sites, such as Svalberg, and the Samoylov island station in the Lena River Delta in Siberia,” she says. “The idea is to investigate whether these mechanisms are important for climate models and models of the carbon cycle.”

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Climate models This research holds wider relevance in terms of refining complex climate models and understanding how the climate is likely to evolve in future as more permafrost thaws at northerly latitudes. The project will make an important contribution in this respect, with the establishment of measurement infrastructure at Siikenava II set to provide more data. “This will allow us to test and develop new instrumentation to improve methane flux measurements in particular,” stresses Dr Treat. However, the more immediate goal in the project is to build a deeper understanding of what controls these Winter emissions. “Is it related to some of these physical processes happening in the soil? Is it to do with the freeze-thaw dynamics, like the formation of an ice layer, that maybe results in anaerobic soil? Or is it changes in soil moisture dynamics, or soil biogeochemistry?” says Dr Treat. “It would be very exciting to identify a new mechanism. We should be able to have a complete annual budget of greenhouse gas emissions for a range of boreal sites, which will be very valuable.” Researchers have a pretty good handle on the amount of greenhouse gases that are released during the Summer, but if emissions during Winter and the transition to the colder months turn out to be higher than previously thought then this would dramatically change the overall picture. “If emissions during Winter, Spring and the shoulder seasons contribute an additional 20 percent on top of the growing season budget, then the picture looks very different,” points out Dr Treat.

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Grant Agreement No. 851181

Project Partners

• University of Helsinki • University of Eastern Finland

Contact Details

Project Coordinator, Claire Treat Alfred Wegener Institute Helmholtz Center for Polar and Marine Research Telegrafenberg A45 14473 Potsdam T: +49(331)58174 5412 E: claire.treat@awi.de W: https://www.awi.de/en/about-us/ organisation/staff/single-view/claire-treat.html

Dr Claire Treat

Dr Claire Treat is Junior Research Group Leader for Permafrost Region Greenhouse Gas Fluxes at the Alfred Wegener Institute. Her research focuses on the response of greenhouse gas fluxes to environmental changes resulting from various factors, such as climate warming and permafrost thaw.

Strategies to Lower Emissions and Improve Liveability in Urban Areas We talked to Bonnie Fenton from the EU ReVeAL project (Regulating Vehicle Access for Improved Liveability) about using UVARs (Urban Vehicle Access Regulations) to improve accessibility, lower emissions, improve air quality and public safety, and increase the overall quality of life within cities. Urban areas,

such as city centres, can be saturated with motorized traffic and the noise, hazards and pollution that come with it. To improve air quality, liveability, safety, and attractivity in cities, as well as to achieve wider sustainability goals, the ReVeAL project set out a range of UVAR options to pick and choose from to support the reduction of vehicular access to urban areas. UVARs are rules, regulations, restrictions and bans in relation that regulate under what conditions certain vehicles are allow to enter certain parts of a city (e.g. Low Emissions Zone, Congestion Charges, etc.). This is not an easy task and requires robust strategies to be successful. As Fenton, Sustainable Mobility Consultant at Rupprecht Consult, puts it, “It requires both ‘carrot’ and ‘stick’ methods for a city to achieve its goals. UVARs are seen as ‘sticks’, as they reduce vehicle access to certain parts of the city. This can be as extreme as a complete car-free area – a pedestrian zone – but there are many other options to reduce vehicle access. “Some people may be upset at the idea of no longer being able to drive into the city centre. They have the feeling like something is being taken away. But you can achieve higher levels of acceptance if you’re addressing a known problem, such as safety or air quality. If people don’t see a problem, they won’t see the need for change. Part of a city’s communication work is to make sure people are aware of the problem that needs addressing”. There is a problem. In terms of air quality alone, according to The European

The ReVeAL’s Building Blocks are a fundamental concept of the project; ©ReVeAL.

Environment Agency (EEA): ‘Air pollution is the single largest environmental health risk in Europe, causing cardiovascular and respiratory diseases that lead to the loss of healthy years of life and, in the most serious cases, to premature deaths’. “It comes back to what kind of cities we want to live in,” said Fenton. “A city might decide to implement UVAR measures to reduce emissions, pollution, speed, improve safety or the quality of life. Depending on what your goals are, you will make different decisions about what kind of UVAR measures you want to put in place. “ReVeAL systematises the process to show what is available and can be done and

what changes might happen. The context or the goals may be different from place to place, you need to decide what it is you want to achieve, and we have been developing what we are calling a ‘decision support tool’ which will help cities decide what might be appropriate, via UVAR building blocks.”

The Measure Fields ReVeAL has organised the possible measures into what it calls Measure Fields. These include Spatial Interventions, Pricing Aspects and Regulatory Measures. Spatial measures focus on changes to physical spaces like road layouts which might block access to vehicles or be altered

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Pedestrian zone sign in the city of Padua, Italy; ©ReVeAL.

London’s Ultra-Low Emission Zone (ULEZ) helps cleaning up the city’s air and operates 24 hours a day, 7 days a week, every day of the year, except Christmas Day (25 December) in the zone within the North and South Circular Roads; ©Shutterstock

Field trip to the Guizza’s superblock during ReVeAL’s Consortium Meeting in the city of Padua; ©ReVeAL

to favour more sustainable transport (like bicycles) or it may involve the reallocation of parking spaces to other uses. Pricing Aspects centre around putting a cost to going into a city space with a vehicle or a vehicle that pollutes more, such as penalties and fees in the form of congestion, pollution, or parking charges. If there are charges involved, those funds can be used for sustainable mobility improvements. London did this with its congestion charge, as the money collected was ploughed back into improving public transport. Further to these central ideas are Complementary Measures, a list of ideas such as incentives for fleet renewal, user exemptions, grants for adaptations and so forth. A complementary measure is defined within the project as an additional measure that complements a given UVAR building block to enable access of people, goods and services into the UVAR area while maintaining the goals of the UVAR, easing compliance and facilitating the best adaptation to the new reality. It may also

act to minimise any equity issues that may result from the measure it complements. There is a lot to consider for any city wanting to reduce traffic and the right mix of measures will be focused on a specific outcome. Technology and data play a key part in UVARs. For instance, number plate reading technology and air quality measuring devices. There is also Radiofrequency Identification, known as RFID, which uses

better environment. The emphasis is on communicating why measures taken are necessary, and how they promote benefits such as improved standards for air quality, traffic congestion and safety. For each of the building blocks in a plan, ReVeAL detailed what was incorporated and why. For instance, a school street might require the removal of vehicle traffic from in front of the school for a given period of the day, when the children are going to school.

Depending on what your goals are you’ll make different decisions about what kind of Urban Vehicle Access Regulations (UVAR) measures you want to put in place. radiofrequency waves to transfer data. This could be used to identify vehicles permitted to access without having to preregister them. A badge on the car could communicate automatically that a car is exempt from a rule without the need for time-consuming checks. What’s important in this project is the idea of transformation toward a

ReVeAL outlines a description of how that can be implemented and what to consider for building blocks that might fit well to achieve the desired environment around this area. For example, it may be worth considering cycle-only streets in the neighbourhood around a school, so children have access to bicycles, without needing to contend with other vehicles when riding to their school.

Médico Tornay Street in the city of Vitoria-Gasteiz is a great example of successful pedestrianisation works; ©Isabel Garnika Ortiz

Vitoria-Gasteiz’ redesign of the casas de Echevarría is part of the UVAR action of the city; ©QUINTAS.

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ReVeAL Regulating Vehicle Access for Improved Liveability

Project Objectives

The EU-funded CIVITAS ReVeAL project aims to add Urban Vehicle Access Regulations (UVARs) and associated policies and technologies to the standard range of urban mobility transition approaches in cities across Europe. The overarching mission of the project is to enable cities to optimise urban space and transport network usage, not only to decrease emissions and noise pollution but also to improve accessibility, sustainability, and liveability for every member of society.

Project Partners

https://civitas-reveal.eu/about/partnership/

More information

Contact Project Coordinators Olaf Lewald (City of Bielefeld) E: olaf.lewald@bielefeld.de Bonnie Fenton (Rupprecht Consult) E: b.fenton@rupprecht-consult.eu Contact Dissemination Managers Juliette Thijs (POLIS Network) E: jthijs@polisnetwork.eu Alessia Giorgiutti (POLIS Network) E: agiorgiutti@polisnetwork.eu Follow ReVeAL on Twitter: CIVITAS_REVEAL : https://twitter.com/CIVITAS_ReVeAL Join the ReVeAL LinkedIn group: CIVITAS-REVEAL : https://www.linkedin.com/groups/13754156/ Bonnie Fenton

Bonnie Fenton has worked in sustainable mobility at both the local and the international levels with experience both in Canada and across Europe. She has a particular interest in walking, cycling and shared mobility as well as in making connections between theory and practice. Bonnie coordinates the EU ReVeAL project.

There are all sorts of possibilities depending on the area being considered for changes. ReVeAL developed and tested UVAR packages and approaches in six participating pilot cities, namely Helmond in the Netherlands, Jerusalem in Israel, the City of London in the UK, Padua in Italy, VitoriaGasteiz in Spain, and Bielefeld in Germany. “We are learning through their experiences what works and what is challenging. From that, we are creating guidance for other cities to take forward. When a city is considering regulating vehicle access, we can show the kinds of factors that need to be thought through,” said Fenton. “For example, a low-emission zone needs to be planned in phases, not all at once, and people need to be informed about what is coming up in subsequent phases. We also need people to feel that their city centre is accessible for all. The trick is to make sure everyone has access – but not necessarily by the mode they are used to taking, like private cars.”

Changing the Identity of Spaces The pilot cities involved in the EU-funded project were all invested in the idea of change. Whilst traffic reduction was an outcome, more startling transformations redefined the way locations were perceived and used. To give an example, Bielefeld saw something of a minor regeneration unfold. “Bielefeld is a medium-sized city in Germany, and they have been focussing on the old town in the city centre. They looked at individual streets to see what they could do and have done quite a bit just using automated bollards (which can be raised and lowered, allowing delivery vehicles to come in at different times). They took away parking spaces and used that extra space for other things such as restaurant seating.

The Jerusalem Light Rail (Harakevet Hakala) stretches from Pisgat Ze’ev in the North (Heil Ha’avir Station) to Mount Herzl in the West; ©Аlex Ugolkov/Pexels.

Activities were planned during the pilot phase in the wintertime to make it more attractive to be there outdoors. It showed that these UVAR measures can make cities more attractive.” In Bielefeld the authorities monitored how people reacted to the changes, which was important because the aim is not to simply to draft regulations but to attain acceptance for a vision of the city’s future. Testing is fundamental. What can happen is the redefining of a city centre’s identity, making it a place to relax, enjoy venues and congregate with other people without traffic, noise and pollution. Urban living has long been synonymous with polluted air, the cut-and-thrust of cars and trucks and an environment that can be unhealthy and hazardous. The catalogue of measures created by ReVeAL will help support decision-makers in cities and builtup areas with heavy traffic to reimagine and reinvent their spaces, so people can enjoy life in them to a far greater degree. City of Bielefeld’s Jahnplatz has been redesigned to favour a more sustainable urban mobility; ©DSK GmbH.

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 815008. The sole responsibility for the content of this document lies with the authors. It does not necessarily reflect the opinion of the European Union. Neither INEA nor the European Commission are responsible for any use that may be made of the information contained therein.

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An intelligent platform for effective policing

Evidence gathered from digital devices plays an important role in modern criminal investigations, yet it is not always easy to gather and analyse relevant data. Researchers in the INSPECTr project are developing intuitive, easy to use tools and an intelligent platform that will help law enforcement agencies combat crime more effectively, as Dr Ray Genoe explains. Evidence gathered from

digital devices like phones, computers and tablets often plays an important role in modern criminal investigations, both for cybercrimes and non-cybercrimes. The police commonly search through a suspect’s devices for information relevant to an investigation, yet this can require a lot of time and resources. “Many law enforcement practitioners use up to 50 different tools to investigate a cybercrime. One tool might be for a certain type of mobile device, another for computer forensics, and so on,” outlines Dr Ray Genoe, Director of the Centre for Cybersecurity and Cybercrime Investigation, part of University College Dublin. There are a number of problems associated with this approach, one of which is the cost of purchasing licenses for these tools and training staff in how to use them. “One of those tools could easily cost a single officer thousands of

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Euros a year, while the training costs could run to tens of thousands,” says Dr Genoe.

INSPECTr project As the Principal Investigator of the INSPECTr project, a research initiative funded under the Horizon 2020 programme that brings together 18 partners from across Europe, Dr Genoe is working to address this, and many more issues. The aim in the project is to develop intuitive, easy to use tools that will be made freely available to law enforcement agencies (LEAs) and integrated on an intelligent platform. “The only outlay would be on hardware,” explains Dr Genoe. One significant challenge for researchers is to develop a common data format. “None of the tools currently used speak the same language, in terms of the reports that they output. Some of them might create PDF reports, others could produce XML with customised namespaces. What LEAs need is a

common data format, to assist with processing the huge volumes of data coming to them from disparate sources,” says Dr Genoe. “Once you have good analytic tools available, you can do time-filter analysis and cross-device and crosscase correlations, due to the common data format and analytical processes.” A common data format will also make it easier to discover evidence that may be held in other jurisdictions, which is an important issue when dealing with cross-border crime. Dr Genoe and his colleagues are working with the CASE ontology, which enables more detailed analysis of the evidence gathered, including for example the provenance of that evidence. “That’s very appropriate for court presentations and for validating your findings and chain of evidence,” he outlines, “and it is supported in INSPECTr by an immutable blockchain ledger that records every interaction with the tools on the platform”

One area where national linguistic differences have to be considered is in how the evidence that’s presented is interpreted. “We are working on a number of tools for that. For example, we’re working with partners who are developing what we would call multi-lingual natural language processing (NLP),” continues Dr Genoe. “We use NLP for a number of things, such as parsing legal documents.” Anonymity plays a strong role in protecting criminals online. One of the topics Dr Genoe is looking at with the AI tools is how to determine authorship, and whether linguistic markers can be used to assess whether two seemingly different individuals are actually the same person. “By analysing linguistic markers and the interactions between various authors, we can determine whether a criminal network has reappeared on another forum,” he outlines.

Many LEAs also encounter huge volumes of data during the course of an investigation, yet it is not easy to manually process all of the documents, messages, pictures and videos, a context in which AI tools can play an important role. “NLP and media processing tools, will help LEAs to make sense of the available data,” says Dr Genoe. There is also a forecasting element to the project’s work, with AI tools being used for intelligence-led policing. Similarly to how a business might scan the market to identify trends, LEAs can use AI tools to process historical data and anticipate problems before they occur. “For example, robberies might be known to increase in a specific residential area at a particular time of year. This can help guide decisions on where to deploy police at a particular time, thereby increasing public security,” says Dr Genoe.

A key feature of the INSPECTr platform is the ability to discover and exchange data, which is crucial given the cross-border nature of much cybercrime. Rather than physically exchanging a hard drive with a counterpart from another jurisdiction, the platform will provide the ability to exchange data with their peers in other countries on a technical level, which Dr Genoe says represents an important advance.”Information needs to be discoverable in other jurisdictions,” he stresses. This however needs to be controlled, and data must be discovered and exchanged in a way that is compliant with the relevant legislation. “We’re putting controls in place to ensure data privacy is respected and that the tools are used in a way that complies with legislation controls, while still enhancing the capacity of LEAs to investigate

The College of Science at University College Dublin (UCD) makes a substantial contribution to cutting edge research and education based on latest insight and pedagogy. This allows UCD Science to offer an extensive portfolio ranging from discovery to application, contributing to the global scientific community, to society and the economy alike. UCD is in the top 1% worldwide for impact of research publications in numerous scientific fields, including the field of computer science.

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crime effectively,” continues Dr Genoe. “Data exchange should occur after existing protocols have been observed, such as Mutual Legal Assistance Treaty (MLAT) approval.”

Ethical protocols Researchers are looking into how to manage the ethical and legal considerations around these types of issues through data protection impact assessments and data-sharing agreements. Once it is clearer how exactly the platform can be used in different jurisdictions, Dr Genoe believes it will bring significant benefits to LEAs. “The first point is the reduced training requirements for investigators. They will only have to learn one tool, which is our platform, because the interface to all of the other tools will be the same. It’s a kind of one-stop shop for all your tools,” he explains. This would be much more efficient than using multiple different tools. “If you want to use a certain tool on a certain day, you simply click, and it goes off and automates the process. Then it presents you with results in a format that you’d expect,” continues Dr Genoe. “Then you can go over to your analytics and expect to access the data with an analytics system that is capable of filtering through all of the data in a familiar and intuitive manner.”

to LEAs, Dr Genoe says they should not be used to reduce data or make decisions independently.”An AI system should offer suggestions to a human, and make those suggestions explainable. The data should be presented to a human user,” he says. “This way the issue of bias can be reduced and the ethical use of AI tools can be enhanced, while also reducing the risk of over-reliance on AI.” The aim is to replace what were previously manual processes with an automated approach that leads to standardised outputs which are easier to analyse, allowing staff to focus their energies on other work.

Looking to the future The platform is also very extensible, so new features can be quickly deployed to reflect changing demands. “We’ve utilised technologies that are sufficiently flexible to enable the rapid deployment of new features. If there’s something more that law enforcement need, they could put in a request,”says Dr Genoe. The project partners include both research organisations and LEAs, who play an important role in guiding research and providing feedback. “We operate a living lab environment, which is a way of co-designing and co-creating with your end-users, which in

The first point is the reduced training requirements for investigators. They will only have to learn one tool, which is our platform, because the interface to all of the other tools will be the same. It’s a kind of one-stop shop for all your tools. There is however potential for these tools to be misused, an issue of which Dr Genoe is well aware. The regulations in this area may vary across different parts of Europe, an issue that has been taken into account in the project. “For example, one of our tools can be used for the preservation of online media content. It can be used in certain jurisdictions, but not in others,” he outlines. “An administrative officer has to make a decision as to whether this tool can be available to a police officer.” Similarly, regional differences may render the tools ineffective in certain jurisdictions. “We’re going to provide a machine-learning framework where we’ll provide default models, which can then be re-trained for different regions,” explains Dr Genoe. “Furthermore, the AI tools in INSPECTr will simply prioritise media, and a human is required to make final decisions.” These tools are designed to prioritise the data to be presented to a human user rather than to make automated decisions themselves. While AI tools can bring significant benefits

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our case is the LEAs,” explains Dr Genoe. “We have monthly meetings with LEAs, where we can show them specific features.” These LEAs have developed three highly realistic use cases, on which all aspects of the platform will be tested, including digital forensics, open-source intelligence gathering and evidence exchange. These use cases are highly realistic scenarios, some of which involve multiple different jurisdictions. “They’re based on what LEAs are seeing out in the field. They’re very relevant, and they’re constantly being tweaked to address any changes that LEAs are seeing,” says Dr Genoe. The aim in the project is to reach technology readiness level (TRL) 6, essentially demonstrating a proof-of-concept, with Dr Genoe keen to explore the possibility of continuing the research and ultimately bringing the platform to practical application. “We’d like to take the recommendations and findings from LEAs on this project, and move forwards with further funding to make this a fully operational tool, at TRL 9,” he concludes.

INSPECTr Intelligence Network and Secure Platform for Evidence Correlation and Transfer

Project Objectives

The principal objective of INSPECTr will be to develop a shared intelligent platform and a novel process for gathering, analysing, prioritising and presenting key data to help in the prediction, detection and management of crime in support of multiple agencies at local, national and international level.

Project Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Grant Agreement No 833276.

Project Partners

https://inspectr-project.eu/index.html#partners

Contact Details

Project Coordinator, Dr Ray Genoe, Director of the UCD Centre for Cybersecurity and Cybercrime Investigation UCD School of Computer Science and Informatics University College Dublin, Belfield, Dublin 4, D04 V1W8, Ireland. T: +353 1 716 2466 E: ray.genoe@ucd.ie W: www.ucd.ie/cci/ Dr Ray Genoe

Dr Ray Genoe is Director of the UCD Centre for Cybersecurity and Cybercrime Investigation, part of University College Dublin. His main expertise lies in digital forensics, network investigations, cybercrime and cybersecurity, and software validation.

Autonomous agents to accelerate extended reality testing Extended reality systems (XR) are used in a wide range of sectors, yet they need to be tested before they can reach the commercial market. We spoke to Rui Filipe Fernandes Prada about the work of the iv4XR project in developing autonomous testing agents that promise to bring significant benefits to developers. An extended reality (XR)

system typically involves a representation of a virtual world, and many users quickly find themselves fully absorbed in that scenario, whether they’re in a flight simulation or playing a computer game. These systems are used in a wide variety of settings, from museums to combat training, but they first need to be tested before they can be applied, which is currently done in quite a labour-intensive way. “Currently a lot of human labour is required to test these XR systems, in the sense that you need users to test them,” says Rui Prada, coordinator of the iv4XR project. These testers are asked to try to perform specific tasks integral to the functioning of the system. “For example, the users might try to navigate from point A to point B in the virtual world, to interact with all the objects within it, or to combine objects,” explains Prada. “They are also asked to explore the system without much guidance. They might perform more open tasks such as to simply see what you can do, to try to finish a certain level in the game, or to find all the hidden objects. So in this case users have a bit more freedom.”

iv4XR project The aim in the iv4XR project is to automate two kinds of tests, using techniques from artificial intelligence. In one type of test there is a specific task that can be scripted, so it might be expected that it should be relatively simple to automate; however, Prada says this is a technically challenging task. “In these XR applications you need intelligence to adapt as things change. You cannot have a simple script which performs

a user when they perform a task, will they be happy with the result?” This may depend to a degree on whether a user is using the system for their own personal enjoyment or for training to develop their professional skills, and also whether they feel they are progressing. As part of the project, Prada plans to model the knowledge and skills of users, and to investigate how the structure of a system affects their ability to learn. “If we configure the

We are testing

the technical specifications of the systems, while we are also looking at the users. Will a person with a specific profile enjoy the game? Will they be able to perform the task, given the skills and knowledge that they have? well in XR – you need an intelligent agent to adapt,” he explains. The idea in the project is to essentially build models of individual users – autonomous testing agents – which can then test the system. “We are testing the technical specifications of the systems, while we are also looking at the users. Will a person with a specific profile enjoy the game? Will they be able to perform the task, given the skills and knowledge that they have?” outlines Prada. “Will the user be able to perform the tasks that they want to perform on the system? How does it feel for

levels of a game in a certain way, do users progress more quickly?” he asks. A user who fails to master the system as quickly as they may have expected may become discouraged, while another might quickly understand how it works then move on; by using multiple testing agents on a single system, researchers aim to build a fuller picture. “We try different profiles and we see how they use the system. That’s part of user experience testing,” continues Prada. “These autonomous testing

Screenshot from the space engineers game, Keen software.

Screenshot from the space engineers game (the game is developed by Keen software house).

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agents have emotions, and their emotional state changes depending on how they interact with the system. This is designed to mimic the emotional process of an individual person.” The amount of information that an individual user is able to absorb is another important consideration in the project, with Prada and his colleagues working to develop a model of cognitive load. If the cognitive load is too high then it will be difficult for users to learn, yet it’s also important that it’s not too low. “If the cognitive load is too low it means that it’s not engaging, it’s not really pushing the users,” points out Prada. The ideal scenario is to strike the right balance between engaging users without overloading them, which will enhance their enjoyment and help users develop their skills. In cases where an XR system is going to be used for training, the use of testing agents will also provide invaluable pointers. “You can explore what kind of actions or tasks the agent will perform more easily. You can then see if the tasks that these agents are performing are aligned with the training goals,” explains Prada. A testing agent may also use the system in ways that were not necessarily anticipated in development, exploring possibilities that may not have occurred to the average user. In a situation where a testing agent is being used to perform an open task, they may find interesting avenues of investigation. “The goal may be to explore a 3-D environment – an agent may try to go into places in many different ways, they can do things that are not expected. They can also do very repetitive things that people are not willing to do,” says Prada. These agents can be used at all stages of a project, but Prada believes they are particularly useful during development, giving companies an insight into user experience at an earlier point, while the agent is also designed to

adapt to changes in the system. “Our goal is that if you setup the agent and then change things, you can still use the same agent,” he continues. “This is because the agent is able to deal with the changes that have been made in the XR system.”

Commercial benefits The ability to use these autonomous testing agents could help speed up development, potentially leading to significant commercial benefits for companies keen to improve efficiency. Autonomous agents can generate results quickly without the hassle of setting up a user study, and they are always ready to work unsociable hours. “You can set up the agents to run through the night for example and get the results the next day, instead of waiting for a week,” points out Prada. These agents are not intended as a complete replacement for human testing, but Prada believes there are circumstances in which they can perform better than a human, and he is looking into the wider commercial potential of this research. “We are investigating market opportunities for these autonomous testing agents and trying to assess their potential in different areas, like game development and simulations for protecting critical infrastructures, such as nuclear power plants,” he continues. “We want to show that these technologies can be useful in automating testing.” A number of partners in the iv4XR consortium are using the testing agents, and the hope is to validate the project’s approach. This would then represent a strong basis to continue the development of the technology once the project reaches the end of its funding term. “We’re looking to gather more concrete data and are planning to publish a report on the benefits that this technology can bring to new markets,” says Prada.

iv4XR Intelligent Verification/Validation for Extended Reality Based Systems Project Objectives

Extended reality systems are used in a variety of sectors, from cultural heritage to flight training, for both entertainment and education purposes. These systems need to be tested before they can be applied, which currently is done by human testers in quite a labour-intensive way. The aim in the iv4XR project is to develop autonomous testing agents, essentially models of individual users, to explore virtual worlds. This could help companies develop more engaging systems and also speed up development.

Project Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 856716.

Project Partners

https://iv4xr-project.eu/consortium-2/

Contact Details

Project Coordinator, Rui Filipe Fernandes Prada INESC-ID | Instituto Superior Técnico, Universidade de Lisboa Senior Researcher | Associate Professor Edifício IST-Taguspark - Av. Prof. Aníbal Cavaco Silva, 2744-016, Porto Salvo, Portugal T: +351 21 423 3292 E: rui.prada@tecnico.ulisboa.pt E: rui.prada@gaips.inesc-id.pt W: https://iv4xr-project.eu

Rui Prada

Rui Prada is Researcher at INESC-ID in the AI for People and Society research group. He conducts research on social intelligent agents, affective computing, human-agent interaction, computer games, applied gaming, and game AI.

Above: Screenshot from MAEVE, the Thales use case (nuclear power plant simulator)

Screenshot from the space engineers game, Keen software.

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Science: A Casualty of War When Russia invaded Ukraine on 24 February 2022, it was a decision that would alter the world, not just in terms of loss, bloodshed and borders, but also in the dissolving of long-standing collaborations between the Western nations and Russia. For science, the conflict would bring about its own shockwave. Here we examine what has happened to the scientific community and some of the implications. By Richard Forsyth

s Russian tanks rolled into Ukrainian villages, scientists and research funding organisations from around the world withdrew from collaborations and partnerships with Russia on major science projects. International scientists did not for the first time in 22 years make their annual trip to the Northwest Science Station in Siberia to study ongoing climate change in the Arctic environment. Funding was withdrawn by the Max Planck Institute in Germany to those manning the station to check how quickly climate change was thawing the permafrost and how much methane was being released into the atmosphere. With Russian relations in tatters, access to the Arctic will be more challenging altogether for international teams, as Russia claims more than half of the land and sea of the Arctic coastline. This will mean in turn, a loss of understanding of a key aspect of how climate change is unravelling.

KYIV, UKRAINE - Feb. 26, 2022: War of Russia against Ukraine. Fighters of the battalion of territorial defense of the city of Kyiv — Photo by palinchak

Reuters also reported a halt to funding for high tech research facilities in Russia such as an ion collider and a neutron reactor as Europe was set to invest some 25 million euros. Germany in particular, has engaged in a great deal of scientific research in partnership with Russia. For instance, the research organisation, the Helmholtz Association (HGF), hosted 362 Russian guest researchers in 2019 alone. Freezing out Russia in collaboration, funding and exchange will leave a gaping hole in a vast array of research projects. It was Germany however, that was clear it would sever all links with the Russian scientific community from the beginning of the conflict, whilst not every country wanted to follow suit so quickly. Just after the invasion began, the Belgian Reactor’s Conference appealed that academic cooperation should continue as much as possible during the conflict.

KYIV, UKRAINE - Feb. 25, 2022: War of Russia against Ukraine. View of a civilian building damaged following a Russian rocket attack the city of Kyiv, Ukraine — Photo by palinchak

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Complete breakdown of collaboration There is a fear that science itself and indeed Russian scientists, not complicit in the war, will suffer from the consequences of this conflict. For that reason, many collaborators from Europe and Russia who have been working together on projects are less eager to break off relationships with their counterparts over what’s seen as a situation purely driven by the Russian state and beyond their control. A climate of fear imposed on free speech by Moscow has also meant it’s harder for Russian scientists to protest, despite early efforts. A letter was signed by 2,500 staff and students in the Moscow Institute of Physics and Technology stating they ‘could not support this senseless and outrageous war’ but it was deleted quickly when a new law meant that a prison term of 15 years could be handed out to people discrediting the Russian military. As it’s well known now, Russia refuses to call the situation a ‘war’, instead, it labels it a ‘special military operation’ and those who use the term ‘invasion’ or ‘war’ can be jailed, for sentences that would be more suited to serious violent crimes. It appears that any kind of backlash against the government line is punished. The clampdown on dissent by Russia’s ministry of justice has blocked the website for the Russian science newspaper Troitsky Variant

after a letter was published by the publication with 8,000 signatures from scientists and science journalists opposing the invasion of Ukraine. In the UK, The Guardian newspaper reported that many Russian scientists are trying to leave Russia, as it is widely perceived there is no future for science in Russia. The paper quoted Moscow physicist Dr Alexander Nozik, who said poignantly, “I believe and most of my colleagues believe that it just isn’t possible to do isolated science. In physics, the science journal system in Russia is mostly dead.” To exasperate the climate of research in Russia, university salaries have been reported to be slashed in the deepening economic crisis in the country. At the famous particle physics laboratory, CERN, Russia was suspended from official ‘observer’ status but the organisation did stand by Russian scientists working there. Indeed, it’s the big international projects where science gets the roughest ride from the implications of this conflict. ITER, the French fusion reactor project, to create the sun’s energy on Earth, is another example, as it is part-funded by Russia. ITER has been slow to respond because of this, and there is a lot at stake for the future of the world’s sustainable energy needs. They are trying to work out how to manage the situation without jeopardising so much progress on an energy project that could be essential to Mankind’s future needs.

“Principles, projects and allegiances in science around the world are being tested by Russia’s brutal invasion of Ukraine, and the ripples of the barbaric act will travel deep into our future.”

Kyiv ,Ukraine: 24th February, 2022 - people hiding in metro station — Photo by Fotoreserg

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KYIV, UKRAINE - Feb. 25, 2022: War of Russia against Ukraine. Rescue service works near a house destroyed by russian rocket in Kyiv — Photo by palinchak

Irpin, Bucha, Dmitrivka. Atrocities of the Russian army in the suburbs of Kyiv. Irpin. Houses of civilians destroyed by russian tanks. Russia’s war against Ukraine. KYIV REGION, UKRAINE.

Values mean more than research It’s worth realising that Ukraine’s scientists are also largely out of action, not because of isolation or lack of funds but because many researchers are either fleeing or fighting. Men of fighting age and many women too, have ditched research and university pursuits to defend their country. It’s been reported that at least one scientist, physicist Vasyl Kladko, has been shot dead by Russian soldiers. The science institutions are not spared the Russian bombardments, for instance, the Kharkiv Institute of Physics and Technology has been badly damaged in attacks. Another example of impossible conditions was when the science team working at Enamine Ltd, a key player in global drug research, had to abandon their work on a project around a pill for Covid treatment, as their lab was near the frontlines. The blunt hammer of war destroys so many futures in so many different ways, both directly and indirectly, and the simple truth is it is impossible to do science under fire and with the constant threat of death. Principles, projects and allegiances in science around the world are being tested by Russia’s brutal invasion of Ukraine, and the ripples of the barbaric act will travel deep into our future. Widely speaking, the West’s mood music is playing the same tune. In a display of solidarity

with Ukraine, the EU Commission suspended all cooperation with Russian research entities, which included stopping new contracts in their tracks and suspending payments on existing contracts. It is a comprehensive, unified stance with a sweeping impact. Margrethe Vestager, Executive Vice-President for a Europe fit for the Digital Age, summed it up succinctly by saying: “EU research cooperation is based on the respect for the freedoms and rights that underpin excellence and innovation. Russia’s heinous military aggression against Ukraine is an attack against those same values. It is, therefore, time to put an end to our research cooperation with Russia”.

No space for aggressors The conflict is not just affecting Earthly scientific pursuits. Space science has always been one of the greatest endeavours embracing strong collaborations of resources and teams between Russia, the USA and Europe especially. The invasion of Ukraine has dropped all this work into freefall. The European Space Agency (ESA) stopped its work with Russia on the ExoMars mission which meant postponing the launch of the rover which was supposed to take place in September. On 13 April ESA announced it

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Drone photograph.

“Ukraine’s scientists are also largely out of action, not because of isolation or lack of funds but because many researchers are either fleeing or fighting.”

was also cutting ties with Roscosmos on planned lunar missions such as the Luna-25 and Luna-27 lander and the Luna-26 orbiter. An ESA statement confirmed: “…the Russian aggression against Ukraine and the resulting sanctions put in place represent a fundamental change of circumstances and make it impossible for ESA to implement the planned lunar cooperation.” The International Space Station is affected, and Russia has announced it will pull out of the ISS in relation to the tensions and more precisely the sanctions imposed on Russia relating to the Ukraine conflict. NASA’s reliance on Russian Soyuz spacecraft for transporting astronauts will come to an end as private space companies like SpaceX will be expected to facilitate this need, and this is an interesting development because, like so many of the big collaborations, it has far-reaching implications for a changed world scape, a new socio-economic shift for the globe. Russia may well become to the West a place akin to North Korea, an untouchable land, isolated, unfriendly and with no ties or cooperative relationships. Unlike North Korea, Russia is the biggest country on Earth and one Europe and the US are used to dealing with and relying on, despite differences. Russia has not been completely scientifically isolated by the world and still has links to China, India and South Africa, despite appeals from

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these countries to resolve the war but the severed links and support from the West are having and will continue to have a long-term damaging effect for science in Russia and in general, as we draw a new red line between countries and their institutions. What we are seeing in science is what we are seeing in sectors like energy, with gas and oil to Europe being sourced elsewhere than Russia, in addition to the ratcheting up of reliance on forward-thinking solutions, like increasing renewables. In the same way, there is an urgent need to bolster and increase alliances and shared resources with countries onside or at very least, neutral, to this conflict. We will see an uncomfortable shuffling around of resources, supply chains, scientists and also exciting new partnerships endeavouring to replace Russian based research and Russian relationships. Inevitably, in a vast array of research, science will stall, but for many of these key projects, there will simply be adaption. The strength of European relationships is noticeably more connected and robust since the war began, and the redoubled relationships around Europe and other countries around the world could potentially, at least, promote a new era of cooperation for these researchers, as we move into a very different, if more challenging, geopolitical age.

Supporting open science The ability to share information is crucial to scientific progress, yet it is not easy to manage and share the vast amounts of data generated at Photon and Neutron Research Infrastructures (PaN RIs). We spoke to Professor Dr Patrick Fuhrmann and Dr Sophie Servan about the work of the ExPaNDS project in creating a framework for effective data management and supporting open science. The PaN RIs found across Europe play an important role in scientific research, helping scientists from a wide variety of different disciplines gain deeper insights into major questions in their fields. Facilities like DESY, HZDR and HZB in Germany, ALBA in Spain, MAX IV in Sweden, PSI in Switzerland, Elettra in Italy, SOLEIL in France, and Diamond Light Source, UKRI / STFC in the UK are home to sophisticated equipment which are used to generate photon and neutron beams. “What we do at DESY is accelerate electrons. We have mechanisms to produce electrons from high-energy, intense rays of very brilliant photon beams which are extremely short,” explains Professor Patrick Fuhrmann, Group Leader of ‘Research and Innovation’ at DESY, an accelerator centre based in Hamburg. The wider societal benefit of these facilities lies in what is done using these bright beams; Professor Fuhrmann says experiments are conducted at the very end of research in what is called a beamline. “The beamlines can be used for experiments on batteries, quantum technology and medical applications for instance. Essentially, they are relevant for any topic where you need to look at processes which are occurring on very small scales,” he outlines.

ExPaNDS project These types of experiments often generate enormous amounts of data, mainly in the form of images, which can become progressively more difficult to manage and share with other researchers as the volume increases. This issue lies at the heart of the ExPaNDS project, a European Union’s Horizon 2020 research and innovation programme grant which brings together 10 European PaN RIs, as well as the European Grid Infrastructure (EGI) federation. “Our goals in the project are two-fold. First of all, we want to create a policy framework for the facilities, so that they have a certain way of processing the data on the policy level. This is about agreements between a facility

The ExPaNDS project kick-off meeting, 9th November 2019.

and their customers - the scientists who produce the data,” says Professor Fuhrmann. A second major goal in the project relates more to the technical level. “We discuss possible formats for the data with the different facilities, and we encourage them to use the same formats. This relates also

wider goal of ensuring that data is shared according to the FAIR (Findable, Accessible, Interoperable, Reusable) principles. “Metadata fields have been defined and agreed, and this enables interoperability,” says Dr Sophie Servan, leader of the Management and Sustainability work package within ExPaNDS.

Do scientists really have to come to the facility to conduct their research? Up to now the answer was yes, but the real answer is actually no, only the samples have to come to the facility. Everything else can be done in an automated way. to the meta-data of the data, such as the frequency, the energy level and the time,” continues Professor Fuhrmann. “We want to encourage the facilities and the beamlines to record this data in a similar fashion, so that it can be more easily understood later on.” The data and meta-data captured from samples at these Photon and Neutron (PaN) facilities are mainly recorded in a standardised format called Nexus. This is part of the

On the technical level, the standardised file format ensures that different applications can open files, while Professor Fuhrmann says it’s also important that there is a common vocabulary used in association with the data. “We are trying to convince everyone to use the same key words, which is important to help Artificial Intelligence (AI) applications scan the data effectively,” he stresses. “The data relevant to a researcher is stored

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somewhere, but it may be difficult to find it. The meta-data catalogue holds only the most important key words of data. This catalogue holds all the key words of all the data generated by these PaN experiments in Europe, and researchers can search it.” A researcher may be interested in the lung tissue of a rat for example. They are able to search the catalogue for relevant experiments, using clear search terms, and they then receive a list of data, as well as details about where the experiment was conducted. “A researcher can download the image in that Nexus format, so they are better able to understand what it represents,” explains Professor Fuhrmann. There is also the possibility to add data from experiments conducted in the past, although Professor Fuhrmann says the best solution may be to simply do the experiment again, with the new generation of synchrotrons set to give researchers even deeper insights into the nature of matter. “The brilliance of the beams at the current facilities is increasing so fast that in most cases it is cheaper to simply repeat the experiment rather than convert the old data,” he stresses. “In many areas of science an experiment can be conducted again and again, and with improved facilities, it can be done better.”

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Accelerating scientific progress The wider aim here is to help accelerate scientific progress by encouraging data sharing through the European Open Science Cloud (EOSC). Making data more widely available helps spur scientific progress, as has been shown by increasing levels of access to the internet. “The more you make research available to everyone, the faster science accelerates,” says Professor Fuhrmann. Nevertheless, it is not always easy to encourage scientists to share their findings and adopt a less proprietary attitude to their research; by putting the FAIR principles at the heart of policy frameworks, the project aims to make data-sharing the default. “The users of the synchrotrons may not even know what’s happening, but they can benefit from this commitment to the FAIR principles,” outlines Dr Servan. “We cannot always change the attitude of the scientists, but we can change a little bit the attitude of our management, and we can make the routine work of incorporating the data into the catalogue automatic. A scientist doesn’t have to think too much about how they can meet the FAIR principles, they can focus their energy on their research.” As soon as an experiment starts and a detector is generating data, the most

important meta-data is extracted and then automatically put into the catalogue. The general policy is that all of the data generated in experiments should be included in the catalogue, which can then help guide research in the future. “Some scientific researchers use published data to set the initial parameters of models, for example in spectrometry. The more access they can get to accurate, well-described data from past experiments, the better they can fine-tune their model,” says Dr Servan. PaN facilities are also an important research tool across a wide range of other areas, from climate change, to energy, to quantum computing. While DESY itself is not directly involved in the development of quantum computers, Professor Fuhrmann says research at the facility can help lay the foundations for further progress. “For example, we’re not involved in the creation of an aircraft, but we help to make sure that the material is flexible, sufficiently strong, and doesn’t age too fast,” he outlines. “We can investigate the properties of materials at DESY.” The situation with quantum computers is more complex, as researchers have to consider quantum effects and how far certain materials are able to reflect them. However, the aim is still to evaluate whether a given

ExPaNDS EOSC Photon and Neutron Data Services

Project Objectives

The ExPaNDS project brings together partners from across Europe with the aim of helping share scientific data in a more efficient way. Experiments at photon and neutron facilities generate huge volumes of data, and the goal is to find an effective way to share and manage that data. A policy framework will be created for photon and neutron facilities, so that they have a certain way of processing data. This will then make it easier to subsequently find and share research, helping prevent repetition of experiments and spurring scientific progress.

Project Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 857641. Coordinated by DEUTSCHES ELEKTRONEN-SYNCHROTRON (DESY) Notkestraße 85, 22607 Hamburg, Germany

ExPaNDS Partners

1. ALBA Synchrotron 2. Deutsches Elektronen-Synchrotron 3. Diamond Light Source 4. E lettra-Sincrotrone Triested S.C.p.A. di interesse nazionale 5. E uropean Grid Infrastructure Foundation 6. H elmholtz-Zentrum Berlin 7. Helmholtz-Zentrum DresdenRossendorf 8. MAX IV Laboratory 9. P aul Scherrer Institute 10. Science and Technology Facilities Council part of UKRI 11. Synchrotron SOLEIL https://expands.eu/partners/

Contact Details

Professor Dr Patrick Fuhrmann ExPaNDS Grant Coordinator E: info@expands.eu W: https://expands.eu

material can be used for that purpose. “We can then give those materials to the people who are developing quantum computers,” explains Professor Fuhrmann. The PaN RIs within the ExPaNDS project have also been an invaluable tool for researchers investigating COVID-19, with pharmaceutical companies making use of the facilities in the development of therapies, from drugs to vaccines. The nature of the pandemic has also led to a re-think about the way these facilities are operated and managed. “Do scientists

The beamlines can be used for experiments on batteries, quantum technology and medical applications for instance. Essentially, they are relevant for any topic where you need to look at processes which are occurring on very small scales. really have to come to the facility to conduct their research? Up to now the answer was yes, but the real answer is actually no, only the samples have to come to the facility. Everything else can be done in an automated way,” stresses Professor Fuhrmann. “We are putting a lot of effort into making facilities autonomous and remotely accessible, with remote access to a probe from home.” This transformation has been stimulated to a degree by the pandemic, but also an awareness of the increasingly important role of robots in changing the samples as

beamlines grow ever more sophisticated. Remotely accessible beamlines is one issue being addressed in the League of European Accelerator-based Photon Sources (LEAPS) consortium, a project related to ExPaNDS. “The LEAPS consortium is also dealing with other issues, like distributed data management and portable analysis frameworks,” says Professor Fuhrmann. ExPaNDS itself is set to conclude within the next year or so, yet the work of enabling effective data sharing and fostering open

science will continue, with Professor Fuhrmann looking to build on the progress made in the project. “We have applied to become part of another EU project on FAIR data and analysis, called EOSC Future. This is a huge project on all kinds of science, not just Photons and Neutrons,” he outlines. “We are also in contact with PaN science organisations and are pushing for new projects. We are working with European infrastructures, for example the European Grid Infrastructure (EGI), to promote photon and neutron research.”

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Fabrics for the circular economy It is difficult to remove the chemicals and finishing substances commonly used to enhance sun protection in awnings and outdoor furnishings, which represents a major hurdle in terms of recycling acrylic waste from these products. Researchers in the REACT project are developing a chemical treatment process to enable the re-use of acrylic textile waste, as Daniele Piga explains. A lot of

attention in research is focused on developing methods to recover and reuse resources, as European industry seeks to move towards a more sustainable model. With awnings and outdoor furnishings, one major challenge is in removing the chemicals and finishing substances from acrylic textiles that were previously added. “A coating may have been added within the fabric to improve its weather resistance performance. This kind of impurity can be difficult to remove,” explains Daniele Piga, a researcher at Centrocot in Italy, a partner in the REACT project. A consortium bringing together seven partners from five countries, the project aims to develop a system of chemical treatments that will enable the re-use of these resources. “The project is focused on a call for the recovery and reuse of secondary raw materials. We are developing a system to remove these finishing substances in order to remove the impurity and get at the secondary raw material,” outlines Piga.

Chemical treatment The project’s agenda encompasses research into various different stages of the recycling process, from the classification of waste textiles through to the production of textiles and their eventual use in new products. Based himself at Centrocot, a textile research and testing centre, Piga’s focus is on helping to develop the chemical treatment

project nears its conclusion. “The Technology Readiness Level (TRL) of the project’s work is already very high,” says Piga. The treatment process could also potentially be applied on a wider range of fibres, a possibility that Piga and his colleagues in the project are keen to explore. The idea would be to use the same treatment on other fabrics, widening the impact of the project’s research. “It’s possible to apply this treatment more widely For example, we are looking into using the treatment process on polyester, which is a different kind of fibre,” explains Piga. With less than 1 percent of all textile waste currently recycled, this research could have a significant impact in terms of reducing waste, which is a major motivating factor behind the project’s work. “We have developed different prototypes of fabric for different applications,” says Piga.

REACT REACT prototype

removal rate is very high. The fibre is relatively undamaged and the recycled fibre is still very strong,” continues Piga. An entirely recycled fibre does not yet have the mechanical performance characteristics required for fabrics used in awnings and outdoor furnishings, so researchers have reduced the quantity of recycled material and added virgin

The project is focused on a call for secondary raw materials. We are developing a system to remove this finishing substance in order to remove the impurity and get at the secondary raw material. system. “We are investigating a different kind of process, involving two consecutive stages of treatment in water. The first stage involves a wetting agent and a sequestering agent, and in the second detergent is used,” he says. The aim is to remove 90 percent of chemicals added in the finishing process through this system, opening up the possibility of re-using these resources in textile production. “There is a lot of potential in this respect, because the

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acrylic. This still represents a significant step towards a circular economy however, where resources are not simply disposed of but rather applied again in production, so reducing waste. “The aim is to re-spin these waste materials and use them to produce new fabric,” outlines Piga. A significant degree of progress has been made in this respect, with researchers having already made a chair out of recycled fabric, and a lot of work is going into prototyping as the

MANAGING THE WASTE ACRYLIC TEXTILES @ 2019-2022 REACT Centro Tessile Cotoniero e Abbigliamento S.p.A. Piazza S.Anna, 2 · 21052 Busto Arsizio (VA) E: roberto.vannucci@centrocot.it E: margherita.trestini@martel-innovate.com E: donatella.macchia@centrocot.it E: galileo.disperati@martel-innovate.com W: www.centrocot.it : https://twitter.com/project_react

Daniele Piga is a researcher in the multisectoral R&I department at Centrocot.He holds aPhD in Chemical, Geological and Environmental Sciences, and has extensive experience in the plastics sector. Roberto Vannucci is REACT’s Project Coordinator and Projects Department Manager at Centrocot. He is responsible for R & D projects and providing services for the development and support of companies.

Motor winding work.

Winding cooling liquid galvanically separated manifolds.

Accelerating the development of high-speed machines High-speed machines are used in a growing range of applications, including in compressors and turbines. We spoke to Professor Lassi Aarniovuori, Professor Juha Pyrhönen and M.Sc. Juuso Narsakka about the work of the MUSK 2 project in developing a megawatt class universal high-speed machine, which they ultimately aim to bring to the commercial market. There is an extensive industrial market for induction motors, which are used in a wide variety of high-speed applications, including compressors, turbines and large heat pumps. Currently a tailor-made machine is required for each application, then different parts are coupled together in a highly iterative approach. “It takes huge amounts of engineering work to design a whole system,” outlines Lassi Aarniovuori, Associate Professor at LUT University in Finland. As the Principal Investigator of the MUSK 2 project, Professor Aarniovuori is now working to develop a megawatt class universal high-speed machine and to bring it to the commercial market. “In the project we’re working to develop essentially standalone machines, that can be used in various different applications,” he says.

MUSK2 project This research centres around the development of a high-speed, modular system which promises to bring significant benefits to the industrial sector, where efficiency and cost-effectiveness are prime

considerations. In this system, three active magnetic bearings (AMBs) are used instead of the traditional set of two bearings, helping to greatly reduce maintenance costs. “The AMB active materials are like in small electric motors. We use magnetic force to levitate the machine and adjust the position of the shaft relative to the bearings, so there is no contact between

overall, for example by mixing with the gas. By contrast, the high-speed machine that is being developed in the project does not have any roller bearings, while Professor Aarniovuori says it also has some other notable attributes. “The machine is a low-voltage one. We are using a lowvoltage converter, which is significantly lower in cost than its medium-voltage

In the project we’re working to develop essentially a stand-alone

megawatt class universal high-speed machine, that can be used in various different applications. the bearing and the shaft,” explains Professor Aarniovuori. The position of this rotor is measured and controlled on a continuous basis, so there is no need for oil, which Professor Aarniovuori says represents a significant benefit. “Typically, in compressor applications, you would like to have an oil-free system,” he says. The presence of lubricating oil is liable to have a negative impact on the system

competitors,” he outlines. It is much easier to create the insulating layer in the electrical machine, which means that other, more effective materials can be used elsewhere, improving efficiency, while there is no risk of partial discharges of electricity, which can have a detrimental impact on the system. “In low-voltage machines we do not have partial discharges,” stresses Professor Aarniovuori.

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MUSK2 Commercialization of a megawatt-class universal high-speed machine Project Objectives

Revolutionize the availability and applicability of megawatt-size high-speed electric motors. Create an electrically robust and highly efficient machine with a wide operation range. Opportunity for customers to purchase a high-speed electric machine without a long product development process. To develop a coupling mechanism that allows the machine to be operated with very small changes in different operating environments and with various applications. Even more environmentally friendly use of high-speed applications.

Project Funding

The MUSK 2 project is funded by Business Finland Research.

Contact Details

Motor directly water cooled end winding makes a neat package.

A further novel aspect of the machine is the direct liquid cooling system, which is a unique way of cooling down an electrical machine. Most heat is typically lost in the windings; in particular the end windings are a problem in high-speed machines. “This is because the wire must go from one side of the machine to the other, in which case it is difficult to cool an electric machine effectively,” says Professor Pyrhönen. Locating the cooling system inside the windings is a highly efficient approach, helping to extend the lifetime of the system and boost performance, while the design of the rotor means it can be used even in demanding conditions. “We have developed a solid rotor which is really durable and is suitable for harsh environments,” outlines Professor Pyrhönen. “For example, it could be used for compressing biogas or even hydrogen.” By utilising those technical advantages, the aim is to commercialise high-speed electric machine in the megawatt power range. Researchers have developed a proof-of-concept (PoC) machine in the lab, which is currently being tested, although Professor Aarniovuori says time is short. “At the same time as we were working on the construction of the machine, we have also had to build testing facilities. This has taken longer than expected,” he explains. The first phase of PoC testing is expected to be complete by the summer. The research

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will be continued at the university as its own projects, but the main focus next will be on commercialization actions.

Project Coordinator, Professor Juha J. Pyrhönen LUT University FI-53851 Lappeenranta Finland T: +358 40 5711 645 E: juha.pyrhonen@lut.fi W: www.lut.fi W: https://research.lut.fi/converis/portal/ detail/Person/176833?page=pers_has_ publ:6&auxfun=&lang=en_GB

Commercialisation There is already a lot of interest in this technology. Yet the ultimate commercial question is how customers feel about the introduction of new technology in part of their system? There is always a hesitancy around adopting new technologies, with companies comparing the benefits of the familiar, the tried and trusted, against the promise and potential of the new. “A company may ask ‘is it worth the risk to buy this new system’? Can we risk our name promoting this?” outlines Narsakka. “However, benefits of the high-speed technology are proven and well-known among customers so, with our new way to offer it for them may change the mindset rapidly”, states Narsakka. Customers need to see how technology works in an industrial environment. A real customer and practical application needs to be found in the first place to enable market penetration. One interesting area in terms of the application of this system is in the heat pump business. Over 30,000 fossil fuel power plants need to be replaced across Europe, representing potentially vast a market. “We have a chance to bring significant benefits in this respect,” says Narsakka.

Lassi Aarniovuori

Juha J. Pyrhönen

Lassi Aarniovuori is an Associate Professor at the Lappeenranta University of Technology (LUT) School of Energy Systems. Juha J. Pyrhönen is Professor of Electrical Machines and Drives at Lappeenranta University of Technology (LUT) in Finland, a position he has held since 1997.

Last mile parcel reshuffling model for collaborative logistics (VLTN).

Physical internet points the way to a smarter future The physical internet is a novel approach designed to help transport and logistics companies utilise more efficient transport modes and use the available container space more efficiently, alongside a variety of other benefits. We spoke to Dr Konstantinos Zavitsas about the work of the PLANET project in helping transport and logistics companies work in a smarter and greener way. A huge volume of goods and products are transported across the world on a daily basis, and managing these flows is a complex logistical challenge. Cargo may be initially transported by ship before then being loaded on to a train or truck, and it is not easy to ensure that the available space is used effectively and efficiently. “Empty space is a big problem in today’s transport and logistics industry. For example, a truck may be half full or carry a container that is only half full,” acknowledges Dr Konstantinos Zavitsas, head of analytics at VTN, a Green supply chain and logistics company based in Antwerp. One route to addressing this issue is by increasing the container sizes offering/availability and identifying what containers are appropriate for transporting a specific shipment. “Whenever some sort of cargo is being distributed it can be broken down into containers, following the digital internet paradigm,” says Dr Zavitsas. “It’s not just the standard container sizes that need to be considered. One idea is to develop more sizes of containers, so that there is less empty space inside a truck, and use algorithms/ mathematical models to optimally fit cargo into containers and containers into transport vehicles.”

Physical internet This is an important element of the physical internet, a new logistics system which is designed to promote smart decision making throughout supply chains and so improve transport efficiency. As part of the PLANET project, Dr Zavitsas is investigating trade

patterns at several ‘living labs’, with the longterm goal of developing an ICT system to help foster collaboration among transport and logistics stakeholders and ensure that transport infrastructure is used more efficiently. “We mainly consider the interface between global trade routes and the EU transport network, through sea-ports and rail routes to inland terminals such as the one belt, one road connection (OBOR) from China to Europe. We aim to cover a variety of modes for moving goods in and out of Europe,” he outlines. This research holds wider commercial relevance to the project consortium, which includes shipping companies keen to harness the power of data as a route to improving efficiency. “Let’s imagine that a company has a vessel in the Mediterranean and is looking to unload 1,000 containers at a Spanish port for onward transport to different parts of the Iberian peninsula,” says Dr Zavitsas. The port of Valencia would be one possible destination, while there are also alternatives such as Barcelona and others further afield. The intention may have initially been for the vessel to follow a specific route calling at several ports to unload cargo, but if circumstances change then it could be beneficial to change the route. “Maybe one of the ports has some sort of delay. A shipping company may not want their vessel to go to five ports and find big delays at all of them before they can enter,” points out Dr Zavitsas. One option could be to unload all the cargo at a single port, and then let hinterland transport such as road and rail take over; Dr Zavitsas

and his colleagues in the project are helping companies assess their options in this kind of scenario. “Would it be beneficial for a shipping company to unload everything at a single port? If a company decides to call at say three ports instead of five, then which ports should they be?” he outlines. “These are the kinds of questions we are addressing, which also helps us form a sort of unified database on the ports.” This would also provide deeper insights into the functionalities at specific ports, such as the infrastructure and facilities available. One aim in the project is to create data models which provide relevant information on ports to shipping operators, which can then inform their decisions. “It may be that there is a strike at a port, or there are hundreds of ships waiting to unload - we are offering this sort of integrated information. Alongside that, we also offer decision support systems that can make the decision for the operator, while also allowing the integrated management of clusters of ports, that will enable a more robust and efficient functionality,” explains Dr Zavitsas. The project’s agenda includes research into the whole supply chain, not just shipping, but also onward transport right to the final destination. “We are actually looking right down to the last mile, and we are trying to offer collaborative solutions, which includes looking at integrating traditional van deliveries with more efficient and green urban transport modes through parcel reshuffling and an integrated sharing platform,” says Dr Zavitsas.

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A wealth of data is available on last-mile logistics, where goods and products are delivered to customers, but much of it sits in entrepreneurial silos rather than being shared more widely. Researchers have found that they can develop dynamic solutions that track the progress of delivery runs during the day, which could help companies avoid wasted journeys and use their resources more efficiently. “We’ve shown that a solution like that is possible, and it can add value to the supply chain,” says Dr Zavitsas. The aim in the project is to try and solve these kinds of real-world problems using the physical internet, which Dr Zavitsas hopes will encourage enterprises to embrace this technology. “With last-mile logistics the question is whether a company is willing to open up its data to someone else who can help and prevent them from having to make a dedicated trip just to deliver a small number of parcels,” he outlines. “That solution will be beneficial in financial terms, as well as in reducing carbon emissions.”

do we just need to figure out ways to convince people to share data and enable IoT tracking?” he outlines. The aim here is to create a roadmap for the development of the physical internet in Europe; several scenarios of future trading patterns are being considered. “We have tried to develop possible scenarios for 2030 and beyond. These scenarios centre around more trade routes being opened, such as the North Arctic corridor,” continues Dr Zavitsas. “Other scenarios put more emphasis on environmental concerns and prioritise more efficient transport or the regionalisation of production.” The idea is to run the same strategic modelling on each of these scenarios, and from there assess which possible solutions are the most robust. This is a very important consideration in terms of dealing with strategic decisions, believes Dr Zavitsas. “This is why we are considering various different options for the future, such as investing in specific technologies, developing new infrastructure, or providing more sensing capability,” he explains.

We mainly consider the interface between global trade routes and the EU transport network, through sea-ports and rail routes to inland terminals such as the one belt, one road

connection (OBOR) from China to Europe. Transport infrastructure A further aspect of the project’s research involves using models to answer questions about the future of the physical internet. On one side of the project researchers are trying to deal with operational problems through collaboration and data-sharing, while on the other Dr Zavitsas and his colleagues are also looking at the likely impact of these developments and what they will mean for transport infrastructure. “What do we actually need to do? Do we need to invest in building a new railway line or highway? Or

The environmental impact of these solutions is also being taken into account in the project. “For example, a lot of companies are moving towards using greener electric vehicles or bikes in last-mile logistics,” says Dr Zavitsas. “In the first stage, the goal in the project is to monitor what is happening and assess the impact of every decision. We keep track of emissions, and we try – both at an operational level and also with respect to strategic projections – to assess the impact of each strategic level decision in terms of emissions.”

PLANET Progress towards Federated Logistics through the Integration of TEN-T into A Global Trade Network Project Objectives

The PLANET project addresses the challenges of assessing the impact of emerging global trade corridors on the Trans-European Transport Network (TEN-T) network and ensuring effective integration of the European network with the Global Network. This research is focused on two key R&D pillars: • A Geo-economics approach, modelling and specifying the dynamics of new trade routes and their impacts on logistics infrastructure & operations, with specific reference to TEN-T; • An EU-Global network enablement through disruptive concepts and technologies (IoT, Blockchain and PI, 5G, 3D printing, autonomous vehicles / automation, hyperloop) which can shape its future and address its shortcomings, aligned to the DTLF concept of a federated network of T&L platforms

Project Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Grant Agreement No. 860274.

Project Partners

• Inlecom (Coordinator) • CERTH • CATS • COS • COSTech • CPSI • Konnecta • DHL Supply Chain Spain DHL • EBOS • EGTC • Erasmus University Rotterdam EUR • ESC • CityLogin • FV • ZLC • GS1 China • GS1 Poland • HARDT HYPERLOOP • IBM Ireland • International Union for Road-Rail Combined Transport • Instituto Tecnológico de Aragon • ILIM • Jing Dong Logistics • New Generation Sensors • NEWOPERA AISBL • SIRMA AI • PANTEIA • PNO Innovation • Blockchain Fieldlab • Polish National Post • RÖHLIG SUUS LOGISTICS S. A • VLTN • Wuppertal Institute

Contact Details

Kostas Zavitsas, Head of Transport & Logistics Analytics | Vltn bv | Headquarters T: +44 758353 9654 E: k.zavitsas@vltn.be W: www.planetproject.eu : @PlanetH2020 : https://www.linkedin.com/company/ planeth2020 : https://www.youtube.com/channel/ UC5uIbN3KYkK_yx_tcnz8-wg Kostas Zavitsas

Dynamic simulation model of multimodal transport network (ITAINNOVA, 2022)

Kostas Zavitsas is Head of Analytics at VLTN, a Green supply chain and logistics company, and Senior Teaching Fellow at Imperial College Business School. He is an expert on machine learning and artificial intelligence, and investigates their applications in improving the efficiency and robustness of supply chains.

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Bringing noise into economic models Stochastic choice can be thought of as the idea that we don’t always make the same decisions even when confronted with exactly the same choices, so the appropriate model of human behaviour is one which incorporates this randomness. Professor Carlos Alós-Ferrer is bringing together insights from several different fields to work more effectively with random utility models. The topic of individual preferences, or the way in which people rank different options, is of great interest to economists, psychologists, and neuroscientists. Traditional economics models are deterministic, in the sense that they are based on the assumption that if an individual prefers option A to B then they will always choose A, yet this is not backed up the available data, says Carlos Alós-Ferrer, Professor for Decision and Neuroeconomic Theory at the Zurich Centrer for Neuroeconomics (ZNE). “The data suggests that there is a lot of noise, and when confronted with exactly the same options, people do not always make the same choices,” he explains. As the head of a research project based at ZNE, Professor Alós-Ferrer is investigating questions around stochastic choice. “This is the idea that decision processes in the brain are inherently noisy, and hence our choices always have a random component,” he outlines. “This means that the appropriate model of human behaviour is not one which uses deterministic preferences, but rather one which uses randomness.”

Random utility models This involves incorporating ‘noise’ at the behavioural level, which can be broadly thought of as inaccurate data which makes it

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more difficult to identify underlying trends. Researchers are working with random utility models – the standard for estimating preferences in economics – and bringing together insights from several different disciplines. “We are incorporating insights from psychophysics, psychology and neuroscience, so we can work more effectively with these random utility models,” says Professor AlósFerrer. Two particularly important insights have been identified. “The first is that, for any kind of decision, if you are close to being indifferent then you are going to make more mistakes,” continues Professor Alós-Ferrer. “The second is that if you are close to being indifferent, then your decisions are going to take longer. Those two points are regularities which are very strong and have been known about for more than a century in psychology, for example for perceptual decisions where people have to decide which of two objects is larger – we call them psychometric and chronometric effects respectively. What we are finding is that these effects are also very clear for economic decisions, which are typically based on unobservable scales as individual preferences instead of, say, the size of an object.” Researchers have been investigating how to incorporate these insights in preference

estimation and economic models of stochastic choice, work which involves several different strands of research. Recently, Professor AlósFerrer published a paper that essentially solves a long-standing problem in economics. “The problem is that when we think about recovering preferences, it is apparent that even if someone chooses A over B more than 50 percent of the time, we cannot really conclude that they prefer A over B,” he outlines. The reason is that noise can do strange things – it could have a bias, it could be asymmetric – and is by nature very difficult to observe. Now researchers are using insights from other disciplines to modify economic models. “We take inputs from psychology, which tells us that if you are closer to indifference, your decision is going to take longer. Thanks to computers, response times are easily observable today, so we have a lot of data on this,” says Professor Alós-Ferrer. “In that paper we built the response times into the models.” This enabled researchers to prove a formal result which identifies the conditions under which a distribution of response times shows that an individual indeed prefers option A over B, for example red wine over white wine, or a certain policy over an alternative. Personal choices are the result of underlying preferences

and behavioural noise, and in a sense Professor Alós-Ferrer has used response times to disentangle noise and preferences. “We can use response times to filter out the behavioral noise,” he explains. In the recent paper, researchers also explored how preferences for unobserved choices can be addressed with data about response times, building on insights from a previous experiment comparing various types of chocolate and snacks to a reference category, say, M&Ms. “People were asked a few questions - do you prefer M&Ms or Mars? M&Ms or Hersheys? M&Ms or some other snack?” outlines Professor Alós-Ferrer. “If somebody says that they prefer Hersheys to M&Ms, and also that they prefer Mars to M&Ms, it is still not clear which option they prefer out of Hersheys and Mars.” The time that an individual takes to make a decision involving comparisons to M&Ms are however predictive of whether they prefer Hersheys or Mars, or some other option. If they rapidly decide that one option is superior then that means the utilities

are very far apart, while if they take longer then that means the difference in utilities is relatively small, from which researchers can draw wider insights. “We can predict your preference from those observations, without having seen your decisions between Hersheys and Mars,” explains Professor Alós-Ferrer. Researchers have built on the data gathered in this experiment. “We applied our techniques to the first part of the data. We predicted the decisions that we were going to see later in the experiment, using our techniques, and then we compared those predictions to what actually happened,” continues Professor Alós-Ferrer. “Around 80 percent of our predictions were correct, which is pretty positive. We are now working on other applications of that, in areas like stochastic choice.”

Preference reversal phenomenon A further dimension of Professor AlósFerrer’s research centres on what is called the preference reversal phenomenon, which is related to perceptions of risk. When asked to

choose between gaining a relatively small sum with a high probability and gaining a larger sum with a lower probability, many people tend to choose the safer option. “Not many people take the long shot,” says Professor Alós-Ferrer. The problem is that those who prefer the safer bet to the long shot should logically value it more highly in monetary terms, yet Professor Alós-Ferrer says there is abundant data to show that this is in fact not the case. “People for example may say; ‘I prefer an 80 percent probability of gaining £20 to a 20 percent probability of getting £100’. That is perfectly fine, as it just means that people are typically risk averse. The problem is that when you ask the same people to give a monetary value to those options, many of them will give a larger value to the option they did not prefer. So in effect they are saying that they prefer less money to more,” he outlines. “This is one of the most robust phenomena in economics, there’s 50 years worth of research on this. This represents a significant behavioural anomaly, and it has been studied by researchers in

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psychology, economics and neuroscience.” Researchers have ben able to essentially uncover the roots of this anomaly by using a model of stochastic choice. Analysis of previous data shows that many people miscalculate the value of the long shot, and as money is easier to comprehend than probabilities, they often end up with an incorrect number. There is a clear shift in attention toward outcomes (relative to probabilities) when evaluations are monetary, and this attentional shift drives the reversals. “We have essentially been able to show that this is what is happening, using both choice and eye-tracking data,” explains Professor Alós-Ferrer. These behavioural anomalies are also an important consideration in terms of evaluating public opinion on spending priorities. “In evaluating what kinds of public works people are interested in, two different methods are often used to get at our preferences. On the one people are asked; ‘do you prefer this or that?’ That’s a direct method, an ordinal one. On the other hand, they’re also asked; ‘how much money is this worth to you?’” continues Professor Alós-Ferrer. This is a cardinal method which focuses you on monetary amounts. “There is an inconsistency there, and so it’s not

has nothing to do with a bias. This is important because it is very typical, whenever you see an apparent anomaly, to try to explain it with a bias in the human brain, but this is the wrong way of analysing the data,” he outlines. The two methods should be equivalent, yet when we examine reversals, we are looking at evaluations conditional on a choice, say, an observed preference for the long shot. If most people are risk-averse but choice is stochastic, then a lot of those choices are actually mistakes, in the sense that people have made choices that contradict their own preferences. Now suppose you condition on those choices. The evaluations going the other way simply reflects the fact that you were conditioning on a lot of mistakes. “If eight people out of ten say that the long shot is worth less than the safe bet, even though they have chosen the long shot, then you may conclude that there is an anomaly, there must be a bias,” says Professor Alós-Ferrer. The reason that conclusion would be wrong is that when you are conditioning on the alternatives, on people’s choice of the long shot, and most of those are in fact mistakes. “This is just because people are risk-averse,” explains Professor Alós-Ferrer. “If most of those are

Stochastic choice is the idea that even when we are confronted with exactly the same decision situation, we don’t always make the same choices. This means that the appropriate model of human behaviour is not one which uses deterministic preferences, but rather one which uses randomness. clear which method should be used in order to accurately gauge public opinion.” A further experiment was also conducted in which participants were asked to choose between taking part in lotteries with a high chance of winning a small amount or in others with small chances of winning a large amount. However, instead of being asked to provide monetary values, they were also asked to rank the lotteries in the experiment from least- to most-preferred. Now, both the choices and the rankings are ordinal methods, yet they also produce inconsistent results, and the inconsistency goes in exactly the opposite way to the other experiment on lotteries described earlier. “Amongst the people who chose the long shot, a lot of them valued the long shot lower than the safe bet,” says Professor Alós-Ferrer. While on the surface this result seems very difficult to understand given the similarity of the methods, Professor Alós-Ferrer has discovered that it is in fact exactly what should be expected once the regularities of stochastic choice are taken into account. “It’s perfectly normal, and

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mistakes then when you look at evaluations, and take into account that choice is stochastic and the probabilities of mistakes in different methods are independent, most of the time the evaluations you are seeing reflect the actual preferences and are not reversals..” The wider problem here is that applying incompatible methods to assess public opinion can produce contradictory results, making it difficult to reliably gauge public views on spending priorities or other issues. As a decision scientist, Professor Alós-Ferrer holds a deep interest in uncovering personal rankings, or preferences, a topic which will remain high on his research agenda. “This is fundamental because only by uncovering personal preferences can we make predictions about future behaviour,” he says. “The other fundamental problem in economics is to evaluate welfare. If I implement a policy at aggregate level, what effect is this going to have on individual welfare? I can only evaluate that if I know what you prefer. So we’re always interested in uncovering preferences.”

THE NEUROECONOMICS OF CONFLICT The Neuroeconomics of Conflict and Preference Strength in Decision Making

Project Objectives

Homo Oeconomicus does not play dice, but Homo Sapiens might. The human brain makes decisions in a gradual, stochastic way. When people are closer to indifference, they make more mistakes and take longer to decide. These robust effects can be used to understand decision anomalies and to estimate preferences better.

Project Funding

The Neuroeconomics of Conflict and Preference Strength in Decision Making is funded by the Swiss National Science Foundation (SNF)

Contact Details

Project Coordinator, Carlos Alos-Ferrer Co-Editor in Chief, Journal of Economic Psychology NOMIS Professor for Decision and Neuroeconomic Theory Zurich Center for Neuroeconomics (ZNE), University of Zurich T: +41 79 866 71 60 E: carlos.alos-ferrer@econ.uzh.ch W: https://alosferrer.github.io/ “Stochastic Choice and Preference Reversals,” Carlos Alós-Ferrer, Johannes Buckenmaier, and Michele Garagnani (2022), Discussion Paper. “The Gradual Nature of Economic Errors,” Carlos Alós-Ferrer and Michele Garagnani (2022), Journal of Economic Behavior and Organization, 200, 55-66. “Strength of Preference and Decisions Under Risk,” Carlos Alós-Ferrer and Michele Garagnani (2022), Journal of Risk and Uncertainty, forthcoming. “Attention and Salience in Preference Reversals,” Carlos Alós-Ferrer and Alexander Ritschel (2022), Experimental Economics, 25, 1024-1051. “Time Will Tell: Recovering Preferences when Choices Are Noisy,” Carlos Alós-Ferrer, Nick Netzer, and Ernst Fehr (2021), Journal of Political Economy, 129 (6), 1828-1877. “Attentional Shifts and Preference Reversals: An Eye-tracking Study,” Carlos Alós-Ferrer, Alexander Jaudas, and Alexander Ritschel (2021), Judgment and Decision Making, 16 (1), 57-93.

Carlos Alós-Ferrer

Carlos Alós-Ferrer graduated in Mathematics and received his Ph.D. in Economics from the University of Alicante. He became a professor of microeconomics in Konstanz and later in Cologne. In 2018, he joined the University of Zurich as Professor of Decision and Neuroeconomic Theory. He is the Editor in Chief of the Journal of Economic Psychology.

Was it all Greek in Southern Italy? Large numbers of Greek people migrated from the mainland during the first millennium BC and new colonies were established in different areas around the Mediterranean. This colonisation process has mainly been viewed from the Greek perspective, yet evidence shows that local people also had a major influence on cultural development, as Professor Martin Guggisberg explains. Many Greek people

migrated from the mainland to different areas around the Mediterranean during the first half of the first millennium BC, particularly to Italy. These migrants established colonies along the Southern Italian coast, including Paestum and Taranto, and brought with them many aspects of Greek culture. “People spoke Greek, buildings were inspired by Greek architecture and the Greek economic system was adopted. The region became essentially part of the Greek world until the Romans conquered the entire area around the 3rd-2nd century BC,” outlines Martin Guggisberg, Professor of Classical Archaeology at the University of Basle. This process of Greek colonisation has previously been investigated mainly from the Greek point of view, yet evidence shows that the local people weren’t simply absorbing Greek culture. “Evidence from the necropolis of Francavilla Marittima tells us more about the local people. They had their own civilisation – we can see how these two civilisations merge,” says Professor Guggisberg. Grave of an adult man in a crouched position, late 8th - early 7th century BC

Investigating colonial identity This topic is at the heart of Professor Guggisberg’s work as the Principal Investigator of a research project looking at questions around the impact of the Greek colonisation on cultural identity, on both the settlers and the local population. While the Greeks had a marked cultural influence, there is also evidence that many local customs and practices persisted, which Professor Guggisberg says is leading to a shift in perception. “This is changing our view of what happened; from an imperialist perspective, where the Greeks came and took over, to a model of co-existence with the local population,” he explains. There is evidence of cultural interaction from around 800 BC but it was not until later that permanent settlements were established, now Professor Guggisberg and his colleagues are looking to gain deeper insights into the interaction between Greeks and the local, indigenous populations. “We are excavating graves in the necropolis – the cemetery – of Francavilla Marittima, a native settlement situated next to the Greek colony Bronze armlet, pendant and other jewellery of a female burial, 8th century BC

of Sybaris founded at around 710 BC in northern Calabria,” he outlines. There are burials at this site dating back to the 8th century BC and thus to a period prior to the foundation of the Greek colony, with evidence showing that locals were laid to rest with different items, such as jewellery made of bronze and amber as well as iron weapons and tools. This cemetery was used until around the end of the 6th century BC. “We are studying these graves, because we want to better understand the cultural and ethnic identity of these people,” says Professor Guggisberg. Greek settlers and their descendants lived alongside local people in this area, now researchers are analysing archaeological remains to see whether this is reflected in physical evidence from these graves. “We’re analysing teeth, as they are quite well preserved and offer us the opportunity to do anthropological and scientific investigations, such as the determination of tooth abrasion or isotope analyses,” outlines Professor Guggisberg. “Strontium isotopes depend on the food that you ate during your lifetime - they are in the soil, as well as in rocks and water. If you live One-handled drinking cup, 8th century BC

Exploring Identity: Swiss students excavating ancient burials at Francavilla Marittima, Southern Italy.

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in a certain landscape and you feed from crops, cattle and local resources, then you will have in your teeth the same isotopes as those found in the local landscape.” Researchers are conducting isotope analysis to see where people originated from, whether they were local, indigenous people, or if they had migrated from elsewhere. Alongside isotope analysis, Professor Guggisberg and his colleagues are also looking at artefacts that were included as part of burial rites. “People were buried with dress ornaments, consisting of mainly local, bronze neckrings, armlets and pendants. They also had standardised sets of pottery and containers of liquids - possibly of wine - with a few cups or vessels for drinking. This was the local tradition,” he says. At a certain point however the local vessels were replaced by imported Greek vessels, showing that there was contact and cultural exchange between locals and the Greek settlers. “The Greek containers were probably the more highly esteemed, the more prestigious vessels,” continues Professor Guggisberg. “However, the Greek vessels had different functions to the local ones which they replaced in the graves. The appeareance of a big container, the so called Krater, for example attests to the adoption of the Greek custom of mixing wine with water.”

The aim in the project is to shed new light on these interactions over the first half of the first millennium BC. While researchers found many graves at Francavilla Marittima from the 8th and 6th centuries, it is only relatively recently that Professor Guggisberg and his colleagues have found burials from the period inbetween, the 7th century, which had previously been a gap in the record. “For the first time we have found burials from throughout the 7th century,” he says. Analysis of these graves shows a process of gradual transformation as Greek practices became more common. “In the Iron Age, in the 8th century BC, people were buried in a crouched position. In the 6th century, we find that corpses were buried in a supine position, lying on their back, which corresponds to the Greek tradition,” outlines Professor Guggisberg. “In the 7th century, we can see how corpses become ever more stretched, more supine. The legs are no longer flexed as densely as in the past.” A similar transformation has been observed with burial gifts. In the graves of the 7th century BC, new grave goods like perfume flasks were sometimes included, which is a product typical of the Greek world. “The presence of these perfume flasks underlines the fact that their owners were familiar with the Greek concept

People spoke Greek in Southern Italian colonies, buildings were inspired by Greek architecture and the Greek economic system was adopted. The region became essentially part of the Greek world until the Romans conquered the entire area around the 3rd –2nd century BC. Symposium The Krater was used during a Greek drinking ceremony called a symposium, at which colleagues, friends, political partners and others would drink together in a very specific ritual act. If this same vessel is found in a nonGreek context, this raises questions about whether the custom of holding a symposium had spread to the local population. “Did these non-Greek people have symposia too? If so, did the symposium still function in the same way?” says Professor Guggisberg. Drinking wine was also part of a religious belief system, and if local people adopted the same customs then Professor Guggisberg says this may point to wider changes. “If we now see that local people drank wine in the Greek way, using these mixing bowls, does that mean they also took on the Greek religion and way of life?” he asks. “There are lots of questions which are only now starting to emerge. The nature of the interactions between these two civilisations is much more complicated than it first appears.”

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of what a body is and how it has to be treated in death,” says Professor Guggisberg. This shows that the process of the local population becoming culturally Greek was accelerated at the time of the foundation of the nearby Greek colony of Sybaris at around 710 BC, and became ever more dynamic over time. With Southern Italy today once again seeing large numbers of migrants, Professor Guggisberg believes it’s important to investigate questions around cultural identity and interaction. “We want to connect our archaeological results with present day developments,” he says.

INVESTIGATING COLONIAL IDENTITY Investigating colonial identity: Greek and Native interaction in Northern Calabria (800 - 500 BC) Project Objectives

In the early 1st millennium BC the Mediterranean world is shaped by processes of human migration and mobility as reflected in the so called “Greek Colonisation”. By combining archaeological investigations and natural scientific analyses (stable isotope) on skeletal remains from various burial grounds in Southern Italy, the present project aims to establish a broad interdisciplinary basis for the discussion of the resulting social, cultural, and economic transformations.

Project Funding

This project is funded by the Swiss National Science Foundation (SNSF).

Project Partners

• Integrative Prehistory and Archaeological Science (IPAS), University of Basel • Museo Nazionale Archeologico della Sibaritide • Soprintendenza Archeologia Belle Arti e Paesaggio per la provincia di Cosenza

Contact Details

MA Marta Billo-Imbach Projektassistentin Francavilla Marittima Universität Basel Klassische Archäologie/ Departement Altertumswissenschaften | Petersgraben 51 | 4051 Basel | Schweiz T: +41 61 207 29 50 E: marta.imbach@unibas.ch W: https://klassarch.philhist.unibas.ch/de/home/ Professor Martin Guggisberg

Martin Guggisberg is Professor of Classical Archaeology at the University of Basle. He has a long-standing interest in questions around cultural interaction in the ancient Mediterranean, which led to the research at Francavilla Marittima. He is an active member of several scientific societies and has participated in many research projects.

Cluster of burials with excavated and reconstructed graves of the 8th and early 7th century BC

What are the fiscal effects of municipal mergers? Switzerland is a highly decentralised country, and municipal governments have a significant degree of autonomy at the local level over fiscal policy and expenditure. What is the fiscal effect of mergers between municipalities? What happens to tax rates and expenditures? These questions are at the heart of Professor Marko Köthenbürger’s research. A high degree of political authority is devolved to the local level in Switzerland, where municipal governments have extensive powers over fiscal policy and expenditure. While many people feel a strong sense of identity with the municipality in which they live and relish its autonomy, there are also arguments in favour of merging municipalities. “Through merging or cooperating, municipalities may be able to realise economies of scale and procure goods more efficiently,” points out Marko Köthenbürger, a Professor in the Department of Management, Technology and Economics at ETH Zurich. As the head of a research project based at ETH Zurich, Professor Köthenbürger is investigating the fiscal effects of mergers on municipalities,

in which their size is an important consideration. “A smaller municipality in Switzerland may have between 500-1,000 inhabitants while at the other end of the scale there are quite large municipalities, like the city of Zurich. Further towards the Alps, municipalities are generally quite small,” he says.

Local services A smaller municipality may have difficulty in recruiting qualified personnel to run local services, while they also have to meet certain standards in the provision of services, and it is these smaller, less well-connected municipalities that tend to seek to merge. The aim may be to help them work more efficiently, but a proposed

merger first requires the consent of the populations affected. “A merger process in Switzerland is subject to a referendum by all the participating municipalities,” explains Professor Köthenbürger. While many proposed mergers have been rejected in Switzerland over recent years, others have been approved, now Professor Köthenbürger and his colleague in the project, Christian Stettler, are analysing the data on tax rates and expenditures in these latter cases. “We’re investigating how these mergers affected the fiscal outcomes in terms of tax rates and expenditures,” he outlines. “We have data on the socio-economic characteristics of these municipalities, as well as on things like their size, population, age structure and taxable income.”

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The tax rate in these municipalities, at least the part that goes to the municipality itself, is determined at the local level. Evidence shows that on average the tax rate goes down after a merger, particularly in smaller municipalities that may have had a relatively high tax rate beforehand, an area of great interest to Professor Köthenbürger and his colleague in the project. “Why are the tax rates in smaller municipalities that participate in mergers so high?” he asks. This is partly a reflection of their fiscal needs and the challenges they encountered in providing services, which is one reason why they may seek to merge with larger municipalities with lower rates, while Professor Köthenbürger says the prospect of reduced taxes is also attractive to the population affected. “There is a need to effectively compensate the population in the smaller unit that is giving up a degree of identity, of political autonomy. One way to compensate is by reducing taxes,” he explains. This would be more difficult in a case where a municipality participating in a merger had a low tax rate already, where any further reductions would have a significant impact on revenues. The data shows that smaller municipalities tend to have a higher tax rate than the merging partner, leaving room to compensate the local population via reductions. “The relative difference in tax rates gives us an indication of how much scope there is to compensate the

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smaller municipality for the loss of autonomy,” outlines Professor Köthenbürger. There are also other ways to compensate the smaller municipality, for example by committing to keeping schools open so that students don’t have to travel too far, but Professor Köthenbürger says tax reductions tend to hold particular weight. “It’s possible to make promises like improving road connections between two municipalities, but then the question is; how credible are these promises? One way to really demonstrate commitment is by lowering taxes,” he says.

achieve comparable living standards across Swiss municipalities. “These equalisation systems may be interpreted as reducing the tax autonomy of municipalities, because they have to give up some tax revenues,” continues Professor Köthenbürger. The use of tax rate reductions to compensate for the loss of identity and political autonomy might be influenced by the equalisation system, which differs across cantons. To account for it, “We are conducting our research within cantons, as then we can compare municipalities that are subject to the same equalisation system,” as emphasized by Professor Köthenbürger.

The effect of mergers on municipalities is a topic of interest not only in Switzerland, but also in other countries where mergers take place at the local level. A promise to improve transport connections may take several years to fulfil, in which time there may be another election and priorities may change, whereas the tax rate can be reduced much quicker. Once taxes have been reduced, it then becomes more difficult to increase them in future, so it may be viewed as a more concrete shift. “In that sense reducing taxes is a commitment device, not only to do it now, but also to keep them low in the future,” says Professor Köthenbürger. Municipalities are embedded in a fiscal equalisation system, reflecting a desire to

Expenditures The municipalities also have a high degree of autonomy on tax expenditure, yet evidence suggests that mergers don’t have a significant impact in this respect. While there is often an increase prior to the implementation of the merger, this may be due to the preparatory work involved, and expenditures typically go back to their previous level within a few years. “If you look at data from five years after a merger, expenditures are at more or less the same level as before the preparations for the merger started,” says Professor

FISCAL EFFECTS Fiscal effects of inter-municipal cooperation and mergers

Project Objectives

Switzerland is a highly decentralised country, and municipal governments have a significant degree of autonomy at the local level over fiscal policy and expenditure. What is the fiscal effect of mergers between municipalities? What happens to tax rates and expenditures? These questions are at the heart of the research project.

Project Funding

This project is funded by the Swiss National Science Foundation (SNSF).

Contact Details

Project Coordinator, Marko Köthenbürger ETH Zürich Dep. of Management, Technology, and Ec. Prof. Dr. Marko Köthenbürger Professur f. Öffentliche Finanzen LEE G 110 Leonhardstrasse 21 8092 Zürich Switzerland T: +41 44 6325446 E: koethenbuerger@ethz.ch W: https://pec.ethz.ch/ W: https://mtec.ethz.ch/people/ person-detail.MTkzNDQw. TGlzdC8yODk2LC0yMDgyMjgwMDQ4.html

Marko Köthenbürger

Marko Köthenbürger is a Professor in the Department of Management, Technology and Economics at ETH Zurich. His main research interests are public economics and political economy, and he has published extensively in economics journals.

Köthenbürger. While this may on the surface seem to suggest that mergers don’t help municipalities achieve economies of scale, Professor Köthenbürger says analysis of subcategories shows a more complex picture, where certain savings can be achieved. “If we have a detailed look we find certain indications that there are economies of scale,” he outlines. “For example after a merger public administrations don’t have to replicate certain functions, and this is reflected in administrative expenditures.”

the national border. “The effect of mergers on municipalities is a topic of interest not only in Switzerland, but also in other countries where mergers take place at the local level.” Many municipalities in countries across Northern Europe have merged over recent years, as decision-makers strive to strike the right balance between local autonomy and efficiency. While Swiss municipalities have a high degree of autonomy over both tax policy and expenditure, in many other countries local governments have less control over tax

We’re investigating how mergers of municipalities affected the fiscal outcomes in terms of tax rates and expenditures. The Swiss setting is interesting to study since, relative to other countries, municipal tax and expenditure autonomy is significant. The finding that expenditure savings relate to administrative expenditures only may be related to the fact that municipalities cooperate with each other without losing political autonomy, another topic that Professor Köthenbürger is investigating in the project. Two municipalities may coordinate on specific issues like rubbish collection for example, and this improves efficiency already. The main goal in the project is to assess whether there are any systematic patterns in the fiscal outcomes of mergers, and while the empirical data relates to Swiss municipalities, Professor Köthenbürger says this research holds wider relevance beyond

policy, so may take a different approach when it comes to compensating local residents affected by a merger. “They cannot always redistribute savings via tax rate reductions, so they may increase other expenditures in order to benefit local residents,” explains Professor Köthenbürger. In the Swiss case, mergers tend to lead to tax rates going down, which might lead to more intense competition between municipalities, says Professor Köthenbürger. “To what extent can mergers be seen as a way to reduce taxes?” he asks. “ The merger process typically isn’t initiated to increase competition, but it can have that unintended effect and provoke reactions in other municipalities.”

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EU Research Summer 2022

Articles inside

INVESTIGATING COLONIAL IDENTITY

THE NEURO-ECONOMICS OF CONFLICT

Fiscal effects of inter municipal cooperation and mergers

PLANET

MUSK2

REACT

CINCHRON

ExPaNDS

ReVeAL

iv4XR

INSPECTr

Science a Casualty of War

Meat vs Climate

FluxWIN

BITRECS

BIOELECTRIC

SNUGly

OBSERVE

PP-MAGIC

MATURE-NK

SignalingDynamics

SIROCCO