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The Committee to Protect Journalists named winner of the Chatham House Prize 2018 News Release sysadmin 5 October 2018

The Committee to Protect Journalists (CPJ) has been voted the winner of this year’s Chatham House Prize.

Creon Butler appointed to lead Global Economy and Finance Programme News Release sysadmin 22 October 2019

Creon Butler has been appointed to lead the Global Economy and Finance programme at Chatham House, joining the institute at the beginning of December. He will also form part of the institute’s senior leadership team.

Sir David Attenborough and the BBC Studios Natural History Unit awarded Chatham House Prize 2019 for ocean advocacy News Release sysadmin 18 November 2019

The 2019 Chatham House Prize is awarded to Sir David Attenborough and Julian Hector, head of BBC Studios Natural History Unit, for the galvanizing impact of the Blue Planet II series on tackling ocean plastic pollution.

Chatham House Prize: Malawi Judges Win for Election Work News Release NCapeling 23 October 2020

Malawi’s constitutional court judges have won the 2020 Chatham House Prize in recognition of their 'courage and independence in the defence of democracy'.

Supporting Civic Space: The Role and Impact of the Private Sector 23 September 2020 — 2:00PM TO 4:15PM Anonymous (not verified) 23 December 2020 Online

The meeting provides an opportunity to explore the drivers of – and barriers to – corporate activism.

A healthy civic space is vital for an enabling business environment. In recognition of this, a growing number of private sector actors are challenging, publicly or otherwise, the deteriorating environment for civic freedoms.

However, this corporate activism is often limited and largely ad hoc. It remains confined to a small cluster of multinationals leaving potential routes for effective coordination and collaboration with other actors underexplored.

This roundtable brings together a diverse and international group of business actors, civil society actors and foreign policy experts to exchange perspectives and experiences on how the private sector can be involved in issues around civic space.

The meeting provides an opportunity to explore the drivers of – and barriers to – corporate activism, develop a better understanding of existing initiatives, identify good practice and discuss practical strategies for the business community.

This meeting is the first of a series of roundtables at Chatham House in support of initiatives to build broad alliances for the protection of civic space. 

The regional and international implications of restrictions to online freedom of expression in Asia 25 March 2021 — 12:30PM TO 1:30PM Anonymous (not verified) 12 March 2021 Online

Panellists discuss the latest developments affecting online freedom of expression in the Asia region.

Please note this is an online event. Please register using the link below to finalize your registration.

In recent years, state-led clampdowns on online freedom of expression have become widespread in several countries across Asia, further intensified by the COVID-19 crisis.

The reasons for this are complex and diverse – drawing upon history, culture and politics, in addition to external influences. Across the region, governments have been accused of silencing online criticism and failing to uphold rights to free speech.

Individuals have been arrested, fined or attacked for the alleged spread of ‘fake news’, raising concern among human rights organizations. In some countries, this has culminated in the imposition of new social media rules, which could require social media companies to censor posts and share decrypted messages.

In China, the government’s restrictive online regime has relied on a combination of legal, technical and manipulation tactics to manage control of the internet, and now includes attempts at censorship beyond its borders.

Panellists will discuss the latest regional developments affecting online freedom of expression in the Asia region, and will consider the broader regional and international implications for technology governance.

This webinar launches the publication Restrictions on online freedom of expression in China: The domestic, regional and international implications of China’s policies and practices.

Monitoring of trade deals needs a risk-based approach Expert comment NCapeling 24 May 2021

On human rights issues, trading partners must do more than trust to luck.

The recent row within the UK government about the treatment of agricultural products in a proposed new trade deal with Australia provides a reminder that changes to trading arrangements can have social and environmental costs, as well as benefits.

Although the UK government clearly feels political pressure to demonstrate its ‘Global Britain’ credentials with some speedily concluded new deals, rushing ahead without a full understanding of the social, environmental, and human rights implications risks storing up problems for later. In the meantime, calls for better evaluation and monitoring of trade agreements against sustainability-related commitments and goals – ideally with statutory backing – will only get stronger.

EU experiences with these kinds of processes are instructive. For more than 20 years the Directorate General for Trade of the European Commission (DG Trade) has been commissioning sustainability impact assessments (SIAs) from independent consultants in support of trade negotiations, and since 2012 these assessments have explicitly encompassed human rights impacts as a core part of the analysis.

These processes have since been augmented with a programme of periodic ‘ex post’ evaluations of trade agreements to ‘analyse the observed economic, social, human rights, and environmental impacts’ of live trade deals and to make recommendations about any mitigation action which may be needed.

For credibility and objectivity, the Commission outsources much of its sustainability assessment and ex post evaluation activities to independent consultants, who are encouraged to innovate and tailor their approaches subject to broad methodological parameters laid down by the Commission. Over time, experiences with specific assessment and monitoring assignments have enabled external SIA practitioners – and the Commission itself – to progressively strengthen these processes and underlying methodologies.

Yet despite the improvements there remains legitimate questions about whether the human rights aspects of these SIA processes – and subsequent evaluations – are having real policy impact. The difficulty of predicting human rights impacts of trade agreements in advance – as the COVID-19 crisis amply demonstrates – suggests a need for realism about the extent to which a ‘one off’ process, often carried out at a time when there is only ‘agreement in principle’ as to future trading terms, can produce a robust roadmap for heading off future human rights-related risks.

Human rights impact assessments have a potentially valuable role to play in laying down the substantive and structural foundations for future human rights monitoring as part of a broader, iterative, human rights risk management strategy. But the fragmented manner in which many trade agreements approach human rights issues, and the fact that outcomes are the product of negotiation rather than necessarily design, make it difficult to turn this vision into reality.

Controversies surrounding the SIA process for the EU-Mercosur agreement illustrate why striving for more coherence in the identification and subsequent management of human rights-related risks is important. In June 2019, the Commission decided to wrap up negotiations with the South America Mercosur bloc, even though the SIA process for the proposed agreement was still incomplete and the interim and final SIA reports yet to be delivered. Frustrated NGOs made their feelings clear in the form of a formal complaint – and a slap on the wrist from the EU Ombudsman duly followed.

However, when it eventually appeared in December 2020, the final SIA report for the EU-Mercosur deal did include a number of interesting recommendations for responding to specific areas of human rights-related risk identified through the pre-signing assessment process – such as flanking measures designed to address issues pertaining to health, equality, and protection of indigenous peoples, and stressing the need for ‘continuous monitoring’.

Hopefully these recommendations will be proactively followed up, but there are reasons not to be overly optimistic about that. To the extent that these recommendations might have required, or benefitted from, some tweaks to the terms of the trade agreement itself, it was clearly too late. And while there may be opportunities for EU institutions to follow up the recommendations through unilateral ex post evaluation processes, current legal, policy, and institutional arrangements provide few guarantees this will take place.

The credibility of the EU SIA programme has clearly taken a knock because of the problems with the EU-Mercosur process, and stakeholders could be forgiven for questioning whether expending time and effort on engaging in these processes is actually worthwhile. As a first step towards rectifying this, the Commission should be transparent about how it plans to respond to the EU-Mercosur SIA recommendations regarding flanking measures and follow up – ideally consulting with stakeholders about the various human rights monitoring options available.

Looking further ahead, the Commission should be urging SIA practitioners to deal more expansively with the options for follow up human rights monitoring in future SIA reports, setting out recommendations not just on the need for ongoing monitoring of human rights-related issues but on the detail of how this might be done, and how progress towards human rights-related goals could be tracked. And creativity should be encouraged because, as detailed in a newly-published Chatham House research paper, there may be more opportunities for human rights monitoring than first appear.

The SIA process could also provide a forum for exploring complementary measures needed to make future monitoring efforts as effective as possible – jointly and unilaterally; politically, structurally, and resources-wise; both within the framework of the trading relationship and extraneously. The credibility of the process – and hence stakeholder trust – would be further enhanced by commitments from the Commission to be more transparent in future about how different human rights monitoring recommendations laid out in SIAs have been taken into account in subsequent negotiations, in the supervisory arrangements developed for specific trading relationships, and in the implementation of EU trade policy more generally.

Why the next generation is key to protecting human rights Expert comment LToremark 23 June 2021

Strengthening youth participation in public affairs is essential to building inclusive and democratic societies that respect human rights.

Young people have always been drivers of social and economic reform, and today’s global youth population is more numerous and interconnected than ever before. While they have been at the forefront of civic rights movements in recent years, young people are largely excluded from discussions around human rights norms and how to monitor their protection and defence.

Young people are consistently underrepresented in intergovernmental mechanisms and national dialogues, which not only squanders their potential to contribute to effective solutions but also risks disengagement and disillusionment with multilateralism more broadly, at a time when many are already warning of the fraying of the international liberal order. Although there are actors and initiatives working to lift barriers to youth participation in governance – such as the UN Secretary-General’s Envoy on Youth, Jayathma Wickramanayake, or the UN 2016 Not Too Young To Run campaign – these efforts tend to fall short in effecting real change and rarely translate into institutionalized procedures.

While ‘the youth’ is a heterogenous group, comprising different ages, ethnicities, national identities and interests, their participation in realizing human rights is essential to addressing the current challenges and possibilities of human rights for future generations. This will help foster more effective solutions to rights-related challenges, re-build trust in the international human rights framework among younger demographics and broaden and deepen commitments to human rights across generations.

Human rights policies and the online environment

Young people tend to be more technologically literate than their predecessors and also represent the majority of internet users and social media consumers in many countries. They can therefore play a key role in innovating and imagining rights-based solutions to emerging problems for the human rights framework, such as illegitimate collection of data by governments and companies, microtargeting by online platforms, and the sharing of harmful content online. In many cases, international human rights practices have failed to keep pace with these changes and the challenges they bring.

Younger demographics may also approach these novel human rights issues from different starting points. For example, a UK study found that 30 per cent of 18-24 year-olds were ‘unconcerned’ about data privacy compared with only 12 per cent of those aged 55-64, and it has been shown that younger people tend to be more discerning of fake news compared to older generations. There may be a need for human rights institutions and practitioners to acknowledge and bridge these gaps in perspective and understanding to ensure long-term support for proposed solutions.

International cooperation for human rights protection

It has been suggested that young people have reaped the benefits of previous human rights-based policy reforms and have a strong sense of what rights they are entitled to and why these need to be protected through an international framework. Young people are also generally more supportive of multilateralism compared to their older counterparts, as demonstrated by a 2020 survey by Pew Research Center on global attitudes, which showed that 72 per cent of respondents aged 18-29 stated they have a favourable view of the UN, compared with 58 per cent of respondents aged 50 and older.

At a recent Chatham House workshop, young participants from countries as diverse as Lebanon, Kenya and the United States expressed concern that growing hostility towards globalization threatens to undo progress in human rights standards and multilateralism more broadly, progress that they have seen and benefitted from. The rise of nationalist and populist parties has also seen countries shift their attention inwards, as evidenced by former president Trump’s decision to withdraw the US from the Paris Agreement on climate change, and threats by Brazil’s president, Jair Bolsonaro, to follow suit.

Engaging more actively with younger individuals on global human rights reform will help ensure the long-term relevance of multilateral cooperation as well as domestic buy-in of human rights commitments.

Awareness of the interconnectivity of global problems

Young people’s proficiency on online platforms has enabled greater coordination and knowledge sharing without geographical constraints, allowing young activists – like Greta Thunberg – to inspire global movements and foster online discussions about intersectional solutions to modern-day challenges.

This intersectional and transnational lens will be a vital component of building solutions to politically or historically complex issues and can be leveraged to foster better understanding of competing human rights claims relating to issues such as land re-distribution in South Africa or limitations on freedom of movement during the COVID-19 pandemic. These democratic forums and platforms will ultimately help build a global community committed to and engaged with human rights.

Capturing the next generation’s potential

With these concerns and areas of potential in mind, how can human rights institutions and mechanisms create more meaningful avenues for youth input? 

Recent Chatham House research has suggested that multilateral institutions’ efforts to engage youth has often taken the form of ‘superficial listening’, for example inviting a high-profile youth actor to a one-off event or appointing youth delegates who are not able to participate in formal discussions or mainstream governance forums. While encouraging youth participation in meetings focused on human rights can lead to positive change, tokenism can discourage future engagement and dilute the effectiveness of the forums in question.

Capitalizing on the potential of the next generation can be achieved through integrating youth councils and advisers into national and international human rights policy processes, as well as human rights institutions. A few replicable models are already operational, such as the Y7 and the Y20 delegations – the official youth engagement groups for the G7 and G20 – that advance evidence-based proposals to world leaders ahead of the G7 and G20 summits.

At the domestic level, grassroots youth-led movements can help bridge the gap between local constituencies and international policymakers, with youth activists on the ground helping to implement human rights standards and fighting against the spread of misinformation. Strong local networks and civic spaces are essential for pushing back against human rights abuses, and youth activists should be mobilized to connect the efforts of domestic and international bodies to the real issues on the ground; for example, canvassing grassroots youth networks on domestic and traditional customs before implementing development agendas around women’s rights.

As well as providing insertion points for youth policy actors, human rights institutions must communicate their goals more effectively to younger generations and promote intergenerational and inclusive dialogue, for example by holding virtual consultations that  give access to individuals from different backgrounds. Similarly, they should ask young people about their priorities for human rights reform using regular and accessible surveys or by sharing information on online platforms regularly used by this demographic. This will ensure lasting buy-in from the next generation, essential for the relevance and sustainability of the human rights framework in the years to come.

This piece draws upon insights gathered at a workshop hosted by Chatham House in March 2021, which brought together the Institute’s networks of next generation groups including representatives of the QEII Academy Ambassadors, the Panel of Young Advisers, and the Common Futures Conversations community, as well as young members from the South African Institute of International Affairs.

Learnings must become practice as the Taliban return Expert comment NCapeling 7 September 2021

There is greater awareness of the adverse impact of counterterrorism measures and sanctions on humanitarian action. It is time to apply lessons learned.

The 9/11 attacks prompted the international community to adopt a wide range of counterterrorism measures. Debate continues over their compliance with international humanitarian law (IHL) and human rights law, and their effectiveness.

What has become clear is that some of these measures have made it difficult for humanitarian assistance to be provided to the millions of people living in areas under the control of armed groups designated as terrorist, or where such groups have a significant presence.

These include Al-Qaeda in Yemen’s Arabian peninsula, ISIL affiliates in Syria, Al Shabaab in Somalia, Boko Haram in Nigeria, Hamas in Gaza, and various Al-Qaeda affiliates in the Sahel. The lessons painfully learned need to be applied to Afghanistan under Taliban rule.

Impeding humanitarian work

Traditionally, legal counterterrorism measures criminalized acts of violence but, in recent years, measures adopted by the UN Security Council, the European Union (EU), and some states unilaterally, have expanded to address broader forms of support for terrorist acts and to groups designated as terrorist.

When these measures apply in situations of armed conflict – and in the absence of adequate safeguards – they can impede humanitarian organizations from operating as foreseen by IHL and in accordance with humanitarian principles, which require life-saving assistance to be provided in an impartial manner. Restrictions in sanctions imposed for policy objectives other than counterterrorism create similar tensions.

Prohibitions on making funds or other assets available directly or indirectly to persons or groups designated as terrorist can capture incidental payments made during humanitarian operations and relief consignments which are diverted and end up in the hands of these designated groups.

The most extreme restrictions cover the provision of medical assistance, in violation of the foundational principle of IHL that everyone who is wounded and sick – civilian or fighter – is entitled to medical care without discrimination, and those who provide it must not be punished.

Humanitarian organizations have been highlighting these problems for more than a decade. Recent developments give cause for cautious optimism that a turning point has been reached, as the bodies imposing counterterrorism measures and sanctions internationally and domestically have begun to demand compliance with international law and IHL.

In 2019 the UN Security Council unanimously issued a binding demand to member states to ensure all counterterrorism measures they adopt comply with obligations under international law, including IHL.

Recent renewals of UN country-specific sanctions have included similar demands with regards to measures taken by member states to give effect to them. Although this still falls short of an express exception for humanitarian action, it is a significant development, and a strong encouragement to include appropriate safeguards when implementing UN measures domestically.

Similar encouraging practice is discernible at EU level, and new domestic counterterrorism laws adopted by several states include safeguards for humanitarian action.

Applying lessons learned to Afghanistan

It is too soon to know what policies the Taliban will adopt, and the measures that the international community will take to promote compliance with IHL, human rights, and counterterrorism objectives. Nonetheless, policymakers implementing sanctions – and considering their expansion – cannot ignore their potential adverse impact on humanitarian action. They must bear in mind five key lessons.

First, there must be clarity on current legal restrictions, starting from who is designated under sanctions and counterterrorism measures. The UN Security Council has never designated the Taliban per se. Instead, it has listed ‘individuals, groups, undertakings and entities associated with the Taliban’. At present this list includes 135 individuals and five entities, four of which are ‘hawalas’ – money changers – the other being the Haqqani Network, a Sunni Islamist group.

UN financial sanctions require states to freeze the assets of designated persons and groups and ensure no funds, financial assets, or economic resources are made available to them, either directly or indirectly.

EU and UK sanctions simply replicate the restrictions and designations imposed by the UN, but the US has designated the Taliban as a ‘specially designated global terrorist’ which makes the Global Terrorism Sanctions Regulations applicable. These prohibit US nationals from making any contribution or provision of funds, goods, or services to, or for, the benefit of the Taliban.

Second, while listed individuals may play a role in the forthcoming Taliban administration, sanctions do not prohibit providing resources to a government department headed by a designated person.

There is a distinction between an individual and a department, and prohibitions in counterterrorism measures or sanctions on the provision of funds or other assets apply to the designated person, not to the department they may head.

Problems may arise if a designated person appropriates resources for personal benefit or to undermine policy objectives for which the sanctions were imposed. But this does not bring the department within the scope of the designation. Instead, the issue must be addressed from a prevention of diversion perspective.

Third, sanctions and counterterrorism measures must be designed so as to minimize their adverse impact on humanitarian action. One way of doing so is designating leadership figures rather than groups. The new US administration took this approach towards the Houthi in Yemen, with the designation of the group being revoked and new designations focusing on its leaders.

The chilling effect of sanctions is far broader than the actual restrictions they impose. Commercial actors in particular limit their activities in areas they perceive as high risk. In view of this, the effect of expanding existing designations to list the Taliban, now that it is in control of Afghanistan, would be to turn targeted sanctions into comprehensive ones.

In parallel, sanctions or counterterrorism measures should include express safeguards, which exclude funds, assets, and other support provided during humanitarian action from the restrictions – ideally in the form of exceptions or, if an option, general licences.

The adverse impact of the US Global Terrorism Sanctions has been limited until now, as only a small number of humanitarian actors subject to US measures operated in areas under Taliban control. This has now changed, and it is imperative the US issue a broad general licence to exclude assistance provided during humanitarian action from the sanctions.

Fourth, restrictions in funding agreements must not be more onerous than the underlying measures they aim to promote compliance with – in particular, they must not require screening or exclusion of final beneficiaries from the assistance they have been determined as requiring.

Finally, engagement with non-state armed groups for humanitarian purposes is essential for conducting operations effectively and safely, both for humanitarian organizations and the people they are trying to assist. Counterterrorism measures and sanctions do not prohibit such contact even when such groups or their members have been designated.

The past two decades have given states ample time to learn to avoid the adverse impact of sanctions and counterterrorism measures on humanitarian action. The people of Afghanistan deserve that these lessons now be applied.

Our research paper IHL and the humanitarian impact of counterterrorism measures and sanctions identifies the principal points of friction between these bodies of law, clarifies outstanding issues and misunderstandings, and offers practical recommendations for resolving tensions.

Protecting universal human rights: Imagine a better world Explainer Video NCapeling 19 November 2021

Short animation examining why protecting and defending human rights ensures an equitable response to humanitarian crises and addresses economic inequality.

Human rights are not policies that can be overturned, they are not granted by governments. They belong to everyone as human beings.

For the most part, states are meeting their commitments to defend and protect universal human rights. But increasingly some governments are beginning to shy away from their obligations, and some are even actively seeking to subvert human rights.

And the regional and international bodies created and charged with defending these rights are being challenged by the rise of new powers and political movements.

Chatham House is built on big ideas. Help us imagine a better world.

Our researchers develop positive solutions to global challenges, working with governments, charities, businesses and society to build a better future.

SNF CoLab is our project supported by the Stavros Niarchos Foundation (SNF) to share our ideas in experimental, collaborative ways – and to learn about designing a better future.

Why the private sector should protect civic society Explainer Video NCapeling 10 December 2021

A short animation explaining the crucial role that the private sector can play in protecting and defending civic space.

This video explainer introduces a synthesis paper which analyses how the private sector can support the protection of civic society space.

The private sector is in a unique position to work with civil society organizations to uphold and defend civic freedoms and support sustainable and profitable business environments. Companies have the capacity, resources and expertise to enhance the protection of civic space.

By doing so, this helps create a society in which fundamental rights and the rule of law are respected and exercised by governments, private citizens, and all organizations which, in turn, is critical to a sustainable and profitable business environment.  

For more information, download the report.

How are war crimes prosecuted? Explainer Video NCapeling 26 April 2022

Explaining what war crimes are and how, in the circumstances of Ukraine, could war crimes be prosecuted.

The Geneva Conventions and Protocol 1 describe what they call ‘grave breaches’ of international humanitarian law, and both Ukraine and Russia are parties to these treaties.

Grave breaches include directly attacking civilians and launching an indiscriminate attack affecting the civilian population or civilian property.

Many states and the International Criminal Court (ICC) also have the possibility to prosecute a wider set of war crimes although, in the past, states have not prosecuted many such crimes committed outside their own territory.

Neither Russia nor Ukraine is a party to the ICC Statute, but Ukraine did declared it accepted the Court’s jurisdiction for crimes on its territory, and and investigations have now started.

But there are several problems to be overcome to achieve successful prosecutions, such as the collection and preservation of evidence, proof of the intent of the suspects in the heat of war, how to be arrest suspects, and the issue of immunity.

Sanctions must not prevent humanitarian work in Ukraine Expert comment NCapeling 30 May 2022

Restrictions on supply of certain items and financial sanctions can impede vital relief unless adequate safeguards are put in place such as exceptions or general licences.

Sanctions play a major role in the response to Russia’s invasion of Ukraine. The United Nations (UN) has not imposed sanctions, but an important number of states have done so. They have imposed a wide array of restrictions and the number of targeted – or ‘designated’ – persons is unprecedented.

The public has been captivated by the freezing of oligarchs’ assets. There is ongoing discussion about seizing them to provide compensation for war damage. Debate continues about how far to ban oil and gas imports.

One aspect of the sanctions has received far less attention, even though it can exacerbate the effect of the conflict on civilians. Some of the trade restrictions and financial sanctions pose immediate and concrete challenges to the capacity of humanitarian organizations to work in Ukraine and in neighbouring states.

Trade sanctions imposed by the European Union (EU) and UK prohibit the export or supply of certain goods and technology in the transport, telecommunications, energy, and oil or mineral exploration sectors to non-government-controlled areas of the Donetsk or Luhansk oblasts, or for use there.

Restricted items include technical equipment which is necessary for humanitarian operations, such as water pumps and refrigerating equipment, but also far more mundane items such as vehicles for transport of persons and goods, and office equipment that are necessary for humanitarian organizations trying to work in the region.

Designations can reduce options for support

Financial sanctions also raise problems. Some are immediately apparent. Significantly for humanitarian operations, the two de facto republics of Donetsk and Luhansk are designated by the EU, the UK, and the US. Consequently, it is prohibited to make funds or assets available to them directly or indirectly.

This prohibition covers the payment of any taxes, licences, and other fees to these authorities, as well as the provision of assets to ministries under their control in the course of humanitarian operations, such as ministries of health and education.

Designations of other entities may also be relevant, such as Russian ‘state enterprises’ which operate in these areas and are the sole providers of commodities necessary for humanitarian response, such as heating fuel.

These are the designations which most obviously impact humanitarian response. However, more than 1,000 persons and entities have been designated and humanitarian organizations must avoid purchasing goods and services from them.

Risk-averse commercial partners

Commercial actors – such as banks, insurers, freight companies and commodity providers – whose services are required by humanitarian organizations must also comply with the sanctions. Experience shows that the due diligence measures adopted by humanitarian organizations do not always allay concerns of risk-averse sectors such as banks.

Fears of violating the sanctions, coupled with the fact humanitarian organizations are rarely profitable clients, have led them to severely restrict the services they provide.

This is not the first occasion the problem has arisen. What is different in relation to Ukraine is the number of designated persons and the ‘sanctions packages’ adopted in quick succession. As compliance officers struggle to keep abreast, their institutions become even more risk-averse.

For UK banks, the situation is exacerbated by the adoption of the Economic Crime (Transparency and Enforcement) Act 2022. This amends existing rules by removing the requirement for the UK Treasury to prove knowledge or reasonable cause to suspect that a transaction violated sanctions, imposing strict liability for sanctions violations.

Time for the UK to follow others

The EU, the US, Switzerland, and other states which have imposed sanctions have sought to mitigate their adverse effects by including safeguards for humanitarian action. Although the UK has largely replicated the measures adopted by the EU in terms of restrictions and designations, it lags behind in including such safeguards.

The UK trade restrictions and financial sanctions do not include exceptions for humanitarian action. While several general licences have been issued, none relate to humanitarian operations.

Instead, the UK measures foresee only the possibility of applying for specific licences – from the Treasury in the case of financial sanctions and the Department of International Trade for trade restrictions. But obtaining specific licences is a time-consuming process which is simply not appropriate for emergency response.

If the UK is to show it is serious about responding to the immense needs caused by the invasion it must introduce appropriate safeguards in its sanctions – either in the form of exceptions or general licences.

What matters is they cover all key humanitarian organizations responding to the Ukraine crisis that are subject to UK sanctions – either because they are UK persons or because their funding agreements with the UK government require them to comply with UK measures.

These include UN agencies, funds and programmes, components of the International Red Cross and Red Crescent Movement, and non-governmental organizations (NGOs) responding to the crisis in Ukraine and neighbouring states. The provision must also clearly extend to commercial entities which provide necessary services for humanitarian operations.

Given the UK recently adopted an exception along similar lines in relation to the Afghanistan sanctions, there is a valuable precedent for Ukraine.

What are the priorities for the new UK prime minister? Expert comment GBhardwaj 2 September 2022

Experts from across Chatham House examine the range of domestic and foreign policy issues facing Rishi Sunak as he prepares to lead the UK government.

Experts from across Chatham House’s research programmes give their insights on a range of issues facing Rishi Sunak as he becomes UK prime minister, covering energy prices, the climate change agenda, war in Ukraine, China and the Indo-Pacific, Africa, the US, global health, international law and security, science and technology, trade, and the global economic crisis.

Rising energy prices

Antony Froggatt, Senior Research Fellow and Deputy Director, Environment and Society Programme, Chatham House

The social and economic impact of high energy prices this winter may be greater than that of COVID-19. However, in contrast to the pandemic, there has been ample warning of the expected scale of this crisis.

The European Union (EU) gets much more of its energy from Russia than the UK does, but all are part of a largely informal European price zone which is why UK consumers are now facing, what would have been to many, unimaginable bills despite no longer importing energy from Russia.   

The cost of energy will continue to be a major concern for households and businesses and, given the cost of interventions, will significantly affect government finance.

The current policy of capping the unit price for six months increases affordability but will only offer some relief for this winter. The new government urgently needs to look at what happens to bills in the spring and next winter which, from a gas supply perspective, may be even worse than this one.

The EU has reacted with much greater purpose, proposing new legislative packages to diversify supply, accelerate the deployment of renewable energy, make adjustments to markets, and put in place energy saving measures. While these are unlikely to be enough they will make a difference and can become a benchmark for UK policy.

The role that government plays in assisting public and private sectors to save energy will be important. This is where past administrations have wasted the last eight months, where public information campaigns and small technology changes, such as refurbishing and resetting boilers and larger energy consuming products or insulating homes, would have made a difference.

Action needs to be taken across all levels, including co-ordination with the devolved administrations and local government.

Support for new supply needs to be immediately given to new low-carbon technologies which can deliver both cheaply and rapidly, primarily onshore wind and solar, which also help to decarbonize the sector.

The UK will need to maintain, and more likely increase, its relationship with the EU on energy as it continues to trade gas and electricity which is likely to require the resolution of tricky issues such as the Northern Ireland Protocol.

However, the discussions at the European Political Community in early October on greater co-operation on North Sea grids, creating an important opportunity for the accelerated deployment of offshore wind, needs to be taken forward.

Other supply options and market restructuring will be needed and they all must balance affordability, security of supply, and environmental considerations.

The agenda on climate change

Professor Tim Benton, Director, Environment and Society Programme, Chatham House

The record temperatures this summer show how the changing climate is impacting the daily lives of UK citizens. Climate change remains the most important challenge of this century and one that the prime minister will rapidly need to get a grip of ahead of COP27.

Hosting COP26 in 2021, along with Italy, was seen as an important post-Brexit opportunity for the UK in the climate space and ensured the development of many new multilateral sectorial initiatives, such as on climate finance, the Global Methane Pledge and on electric vehicles, while further supporting other emerging initiatives, such as on loss and damage. It will be important for the new prime minister, and the UK’s credibility, to continue to deliver on these.

Concrete things that are needed are a fast roll-out of renewable energy rather than fast-tracking more fossil fuel production, driving ahead the net-zero agenda particularly around land use and food and considering how to restructure markets to better deliver the long-term goals.

Grasping the need to address the demand-side of consumption growth, and not just supply, is key. The UK has prided itself on being a global leader on the climate over the last 15 years but let’s hope that is now not in peril.

Russia and the war in Ukraine

James Nixey, Director, Russia and Eurasia Programme, Chatham House

Supporting Ukraine and confronting Russia are indisputable foreign policy priorities so it is highly likely the new prime minister will look to continue on this path and go with both popular and expert consensus in assisting Ukraine generously and standing up to Russia.

The other question, though, is to what extent the UK’s position can continue to make a difference to the outcome of the war.

Bringing the waverers of western Europe more firmly on board is surely beyond any UK prime minister’s ability considering the UK’s post-Brexit behaviour where the UK still has its own questions to answer including over the failure to tackle the problems of Russian influence at home.

That said, Brexit may not always be relevant to shared hard security challenges. Other countries do see the difference training, money and weapons are making and, if these continue to bring success, it is possible even the waverers can be guilted into providing more aid and economic support.

However, supporting Ukraine is one thing. Truly understanding Russia and devising a coherent Russia strategy is another. What needs to be learned is that Russia, in its present incarnation, cannot be reasoned with whatever the state of the war.

Therefore, given the threat Russia poses to the UK and other democracies, Britain now needs to consider how it can assist with engendering change in Russia. This should not be confused with engineering ‘regime change’ as the Kremlin accuses the UK of doing already.

But it does suggest a more proactive, less defensive Russia policy is required, rather than waiting for the Russian people to instigate change from within. That will take a degree of leadership and political will rarely seen in UK politics.

China and the Indo-Pacific tilt

Ben Bland, Director, Asia-Pacific Programme, Chatham House

Both candidates in the last Conservative leadership contest argued during their campaigns that China was the biggest long-term threat to the UK’s national security. They both promised to call out China’s violations of human rights and international law and extend curbs on China’s access to sensitive technology.

However, to successfully respond to the scale of the challenge, the next prime minister will need to do much more than say what they do not want from Beijing. There needs to be a convincing, positive vision for how the UK can navigate a world where the centre of global economic and geopolitical gravity is moving eastwards.

The Indo-Pacific ‘tilt’ which Liz Truss oversaw as UK foreign secretary was a good start. But tilting isn’t a strategy. So what comes next?

At a time when its in-tray is full of problems closer to home, the UK government needs to sustain enhanced levels of engagement in the Indo-Pacific, particularly in Southeast Asia, while investing at home in the UK’s Asia literacy.

That should include more support for research and education about China as well as the rest of this dynamic region. Labelling China a threat does not make it go away. The UK needs to learn how to live in a world where Chinese power and influence will continue to grow from Asia to Latin America and across the UN and other multilateral organizations.

Investing in the UK’s knowledge of, and relationships in, Asia will also support British businesses as they look for new opportunities in fast-growing but challenging emerging markets such as India, Indonesia, and Vietnam.

The UK’s Middle East policy

Dr Lina Khatib, Director, Middle East and North Africa Programme, Chatham House

The UK government must restore a distinct cabinet position for the Middle East and North Africa and reorient to give Iran’s regional role greater focus.

The Middle East portfolio remains hefty and complex and requires diplomatic engagement to match. No sooner had the UK merged the ministerial Middle East portfolio into the broader one of minister of state for Asia and the Middle East than the war on Ukraine began, directing Western attention to Gulf Arab countries as one potential energy source to offset the loss of Russian oil and gas. Yet Gulf Arab countries are hesitating to fully heed Western calls to increase energy production. 

One key cause is Gulf Arab perceptions that the UK and other Western countries have overlooked their concerns of the threats that Iran poses to their security and political clout.

Despite the UK’s characterization of Iraq as ‘post-conflict’, and of the situation in Syria as a ‘crisis’, recent clashes in Baghdad’s Green Zone and American and Israeli bombing of Iran-linked targets in Syria, as well as recurring attacks by Iran-backed groups on targets in Gulf Cooperation Council (GCC) countries, underline Iran’s role in ongoing instability in the Middle East, which threatens the interests of the UK and its allies in the region.

Although the UK’s Foreign, Commonwealth and Development Office resources have been recently redistributed to further support response to the Russian invasion of Ukraine, the UK can, and must, use existing resources earmarked for the Middle East to engage more effectively.

The two are not wholly distinct: Russia is using Iranian drones to attack Ukraine and Iranian military personnel are active on the ground in Ukraine in aid of the Russian military. Iran and Russia’s ongoing military intervention in Syria paved the way for their cooperation in the invasion of Ukraine.

The UK must restore diplomatic cabinet distribution to give the Middle East the attention it requires, but also revising its approach, putting Iran’s regional and international interventions high on the agenda and in parallel to efforts on the Iran nuclear deal.

The UK sees GCC countries as a potential alternative source of energy to Russian oil and gas specifically and as important trade partners more broadly. UK foreign policy must not compartmentalize its approach to the Middle East.

Diplomatic engagement on Iran’s regional role is a key factor in strengthening trust between the UK and its Middle Eastern allies, including in the GCC, which in turn supports the UK’s economic and security priorities. This means UK policy must approach Iran not just more comprehensively, and coherently, but also as a component of the broader strategy of dealing with the geopolitical and economic threats presented by Russia. 

Africa and the UK

Alex Vines, Director, Africa Programme, Chatham House

Senior UK politicians often claim that Africa is a priority but UK prime ministers and foreign secretaries rarely visit the continent. Boris Johnson attending the Commonwealth Heads of Government Summit in Kigali in August was his first as prime minister where he was accompanied by Liz Truss who was then his foreign secretary.

Despite saying she was an Africa enthusiast as secretary of state for international trade and president of the Board of Trade, Truss had never visited the continent. Her focus was consistently on other parts of the world except for defending the UK’s contested partnership with Rwanda to repatriate to Kigali informal migrants to the UK.

Viewing global politics through the lens of great power rivalry has cast African states as second tier players, disrespecting their agency and prided sovereignty and ignoring the preference of many states to remain non-aligned on issues pertaining to great power competition.

This is a mistake as 25 per cent of the UNGA is comprised of African member states and, of them, 21 are Commonwealth members with Gabon and Togo recently joining. The Russian invasion of Ukraine and intensifying competition with China is a reminder that in this era of sharper geopolitics, Africa increasingly matters for UK’s foreign policy objectives.

The new prime minister will need to review the 2021 Integrated Review, which downplayed much of Africa for UK strategy and advocated a pivot focus to East Africa. The war in Ukraine, coupled with democratic reversals in East Africa and worsening stability in West Africa requires a UK priority rethink. With limited resources to support an expanded UK footprint, sharper focus and defined ambition is important.

Continuity is important too. Since 1989, there have been 21 ministers for Africa, an average tenure of just over 18 months. This is not the time to change the UK’s minister responsible for Africa but it is the moment to make once again that post focused just on sub-Saharan Africa rather than also covering the Caribbean and Latin America too.

The UK-US relationship

Dr Leslie Vinjamuri, Director, US and Americas Programme, Chatham House

As the US approaches its midterm elections, the new prime minister should think carefully about the UK’s response to potential disruption or challenges to the legitimacy of electoral results.

The US faces a period of unpredictable politics with the possibility of significant disruption, upheaval, and the potential for violence. The UK should be careful to differentiate between being independent with respect to partisan politics, which is essential, from being neutral with respect to democracy and especially the integrity of elections.

It would be a mistake for the UK prime minister or the next foreign secretary to be neutral on the question of free and fair elections and the importance of democracy in the US. Boris Johnson’s administration, especially his foreign secretary, was poorly equipped to respond to questions about the outcome of the 2020 presidential elections and prevaricated more than once. 

On foreign policy, a shared interest in supporting Ukraine and strengthening NATO is the current anchor for this partnership, but its historical foundation is both deeper and wider.

The new UK prime minister should demonstrate to the US, and to the world, that Britain is serious about its existing international commitments, especially in the Euro-Atlantic and through NATO, but also with respect to Northern Ireland and Europe.

The UK should deepen its participation in the new European Political Community and seize any opportunity to strengthen mechanisms for security cooperation with Europe. It should aim to restore Britain’s reputation as a nation committed to international, regional and domestic multilateral and legal frameworks.

These measures strengthen Britain’s attractiveness to the US and so lend it greater influence in this essential partnership. Any move to undermine the Northern Ireland protocol should be carefully measured against its wider impacts, not only with Europe, but also with the US.

Continuing Boris Johnson’s policy of restraint, rather than demanding a US-UK trade deal, is wise given the persistence of anti-trade sentiment in the US Congress and the looming US midterm elections.

The prime minister should also do what they can to lend support and work effectively and pragmatically with this US administration. What comes next could be disruptive so now is the time to leverage US power and lock the US into durable commitments that enhance international stability and prosperity.

US president Joe Biden is determined and pragmatic. He will choose the partners that best enable him to deliver his foreign policy priorities. The UK will be both more attractive, and less supplicant, to the US if it has a strong relationship with Europe.

Global health priorities

Robert Yates, Director, Global Health Programme and Executive Director, Centre for Universal Health, Chatham House and Emma Ross, Senior Research Fellow, Global Health Programme. 

Global health has been one of the areas where the UK has historically been seen as punching above its weight due to the magnitude of its financing for global health programmes and its reputation as a leader in global health initiatives.

However, the UK’s standing has taken a significant hit since the start of the pandemic with it demonstrating a lack of solidarity in combatting COVID-19 when it hoarded vaccines and failed to lead the G7 in raising adequate funding for the COVAX facility and blocked attempts to share vaccine technologies with developing countries.

Slashing the international aid budget and deprioritizing global health within its aid strategy has further tarnished the UK’s reputation as a global health leader.

Rebuilding the UK’s hard-earned status as a leading force in global health by at least restoring the level of official development assistance (ODA) for health, if not enhancing it, should be one of the new prime minister’s top priorities.

This should include support for major initiatives such as the Financial Intermediary Fund for Pandemic Prevention, Preparedness and Response (FIF), the Hub for Pandemic and Epidemic Intelligence in Berlin and the vaccine technology transfer hub in Africa.

There is a risk that the ongoing pandemic treaty negotiations will result in a weak instrument of little value. The UK prime minister should prioritize the successful outcome of the negotiations by championing provisions that ensure the treaty makes a meaningful difference in enhancing global health security.

There is a need for workable mechanisms to ensure countries cooperate next time in preventing, preparing for and responding to a pandemic and supporting countries that need extra resources while, another related priority, should be to engage in efforts to reform the International Health Regulations in a way that strengthens global health security.

Championing international law

Rashmin Sagoo, Director, International Law Programme, Chatham House

Compliance with international law is in the best interests of the UK, and the new UK government needs to recognize this.  

The UK wants Russia to comply with the UN Charter and stop its aggressive war against Ukraine. It wants China to recognize the rights of its Uighur citizens, for women to be protected from violence in armed conflict, for compliance with nuclear non-proliferation treaties and  negotiate lucrative international trade agreements. 

These are all excellent aims and they should continue to be pursued. But exhortations to the rest of the world to support the international rules-based order ring hollow if they come from a government which itself does not itself adhere to those rules. 

How the UK conducts itself domestically is a mirror of how it conducts itself internationally. What elected UK officials say and do here matters elsewhere. How we treat the rule of law in this country impacts how others treat it – and us.  

The new prime minister has an opportunity to lead by example by ending the slow but dangerous habitualization of the British public becoming numb to government ‘intentions’ to break international law whether or not such threats are ultimately carried out.

There should also be a full public and parliamentary scrutiny of constitutionally significant proposals, such as the Northern Ireland Protocol bill and reform of the Human Rights Act, rather than fast-track them past a public distracted by the cost-of-living crisis. 

International law is founded upon principles of mutual trust, cooperation, good faith and reciprocity. To be a credible global leader, the UK must put the rule of law, including international law, at the heart of both its foreign and domestic policy. They cannot be disaggregated.   

Strengthening international security

Dr Patricia Lewis, Director, International Security Programme, Chatham House

Security and defence will be high on the agenda for the new UK prime minister. Russia’s war in Ukraine and the potential for sudden, wider escalation remains a serious concern.

Threats of nuclear weapons use, possible false flag ‘dirty bomb’ threats, the continuing attacks on the Zaporizhzhia nuclear power plant threats and veiled references to chemical or biological attacks has demonstrated the willingness of Russia to take enormous risks in regard to threatening Europe as a whole in order to achieve its aims.

If Ukraine’s counter-offensive continues to make gains, then NATO countries will likely be threatened again in this manner. These are not just threats to Ukraine but to NATO states. And, most likely, given the significant role it has played in supporting Ukraine militarily, aimed primarily at the UK.

In the longer term, the UK prime minister needs to review the 2021 Integrated Review of Security, Defence, Development and Foreign Policy. The review came following the decision to increase defence spending and the UK secretary of defence Ben Wallace – continuing in place –has been clear that he has no need to increase his budget further although that may change as the impact of inflation becomes clearer across the board.

The Integrated Review is all about serious investment in the science and technology needed for security and defence in the future. Without such investment the UK will not be able to contribute to international security even in the limited way it can now and certainly not in an ambitious way in decades hence.

There are many long-term security threats that the UK will need to grapple with in addition to Russia’s aggression in Europe, not least of which are China’s rising military capabilities and global ambitions.

In the Arctic and Antarctic, China along with several other major economies, has serious ambitions for exploiting natural resources in terms of minerals, energy, particularly as climate change drives fish stock to the polar seas.

The newly-established AUKUS arrangement which plans to produce a nuclear-powered submarine capability for Australia also provides a mechanism for joint investment by Australia, the UK and the US in science and technologies such as in artificial intelligence (AI) and quantum technology. There are discussions about extending this arrangement to other countries such as Japan and could also include the space sector.    

Meanwhile, at home, in the short-term, there will be increasing calls to end Russia’s war in Ukraine. The prime minister will need to be ahead of that game so that Ukraine is supported and European security is enhanced rather than further stressed.

This will require a new approach to international security – a need that was further highlighted at the end of August in New York with yet another collapse of agreement in the Treaty on the Non-Proliferation of Nuclear Weapons as a result of Russia’s veto.

The UK has long played an important diplomatic role in finding creative solutions for international security and the new prime minister would be well advised to lever that reputation.

Supporting science and technology

Marjorie Buchser, Executive Director, Digital Society Initiative, Chatham House, David Lawrence, Research Fellow, UK in the World Initiative Chatham House and Alex Krasodomski, Head of Innovation Partnerships, Chatham House

In science and technology, the UK currently finds itself in a balancing act between the US and the EU: ideologically attached to the light-touch approach of the US while dependent on the EU as an export market and for supply chains.

While Brexit in theory gives Britain more regulatory freedom, UK companies have often ended up abiding by EU regulations they are unable to shape. The new prime minister should explore forms of regulatory cooperation with the EU that prioritize market access while offering incentives to attract scientists and boost technical innovation.

Beyond transatlantic and European partnerships, it is essential for the UK to foster coalitions with a broader group of like-minded democracies which will be crucial to addressing global technology concerns and countering China’s digital model expansion.

Entrenching the UK as a science and technology ‘superpower’ will require a collaborative approach and involve identifying critical areas where the UK can drive international efforts. For example, the UK should build on its recent successes in the sensitive issues of data flows and digital technical standards as well as encourage investment in open-source security and infrastructure.

Finally, it is essential to unblock the skills and talent pipeline. It is difficult and expensive for high-skilled workers to move to the UK and a key source of labour supply has been lost since leaving the EU. The UK should consider introducing a Commonwealth visa scheme and radically reduce the cost for science and technology companies to offer those visas.

Strengthening infrastructure and housing, particularly in areas that need levelling up, will allow talent to move to areas with the most productive opportunities. 

Trade, climate and green supply chains

Bernice Lee, Research Director, Futures; Hoffmann Distinguished Fellow for Sustainability; Chair, Sustainability Accelerator Advisory Board 

The new prime minister will soon find the answers to the UK’s supply security challenges and soaring energy and food prices as well as future growth lie not at home but are global problems.

At a time of crisis, solutions can only come from countries working together. The UK is a perfectly sized state with plenty of heft but it is not so large as to be able to afford to ignore the needs of others.

It should lead the convening of a growing ‘coalition of the willing’ on trade, climate and green supply chains which could include Australia and Canada as well as developing nations with large extractive sectors in Africa and Asia that are pro-trade, pro-climate, pro-development and pro-growth.

Even though working together on trade and green supply chains can reduce unwanted dependencies, support climate action and help businesses unlock the $26 trillion in market opportunities, many governments have yet to take bold steps due to a fear of disguised protectionism.

Meanwhile, the European Union (EU) carbon border adjustment mechanism (CBAM) is fuelling bitter divides on competitiveness and development concerns.

Trade retaliation is likely and most probably will happen in parallel with legal processes at the WTO. These dynamics mean trade will be underused as an instrument but will create challenging dynamics for COP27. 

Although the Agreement on Climate Change, Trade, and Sustainability (ACCTS) was launched in 2019, the UK could fill a leadership gap since no major economies have positioned themselves as leaders at the intersection of trade, climate, and green supply chains.

British International Investment, the UK’s development institution, should support the establishment and scaling of low-carbon, resource-efficient, sustainable and deforestation-free supply chains which could help fuel the next generation of growth in the UK and beyond.

Improve regulation, give priority to trade relations with the EU, and maintain transparency

Creon Butler, Research Director, Trade, Investment and New Governance Models, and Director, Global Economy and Finance Programme

The UK’s new prime minister comes into office with the country facing the most serious set of economic challenges since 2008-09.

But, in contrast to the global financial crisis, the causes of today’s crisis are more multifaceted and to a degree more UK-specific: the Brexit trade shock; increased public spending pressures linked to the backlog in the NHS and potentially serious long-term effects of ‘long COVID’ and disrupted schooling; the unprecedented shock to energy prices following Russia’s invasion of Ukraine linked in part to the UK’s lack of gas storage capacity; and the shock to market confidence in the UK’s economic management resulting from the 44-day Liz Truss administration.

While the new prime minister should not delay addressing the UK’s long-term challenges, there are three critical questions which will help determine the success or failure of the government’s approach.

First, should the priority be less regulation or, in the context of the tech revolution and the need to accelerate the transformation of the economy to net zero, smarter regulation?

Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer's diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of en-hancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatal mice resulted in higher mortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries.

CARM1 is a protein arginine methyltransferase (PRMT) that acts as a coactivator in a number of transcriptional programs. CARM1 orchestrates this coactivator activity in part by depositing the H3R17me2a histone mark in the vicinity of gene promoters that it regulates. However, the gross levels of H3R17me2a in CARM1 KO mice did not significantly decrease, indicating that other PRMT(s) may compensate for this loss. We thus performed a screen of type I PRMTs, which revealed that PRMT6 can also deposit the H3R17me2a mark in vitro. CARM1 knockout mice are perinatally lethal and display a reduced fetal size, whereas PRMT6 null mice are viable, which permits the generation of double knockouts. Embryos that are null for both CARM1 and PRMT6 are noticeably smaller than CARM1 null embryos, providing in vivo evidence of redundancy. Mouse embryonic fibroblasts (MEFs) from the double knockout embryos display an absence of the H3R17me2a mark during mitosis and increased signs of DNA damage. Moreover, using the combination of CARM1 and PRMT6 inhibitors suppresses the cell proliferation of WT MEFs, suggesting a synergistic effect between CARM1 and PRMT6 inhibitions. These studies provide direct evidence that PRMT6 also deposits the H3R17me2a mark and acts redundantly with CARM1.

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

Evolving evidence suggests that nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness. We explored the hypothesis that nicotine increases NGF by reducing lung fibroblast (LF) microRNA-98 (miR-98) and PPARγ levels, thus promoting airway remodeling. Levels of NGF, miR-98, PPARγ, fibronectin 1 (FN1), endothelin-1 (EDN1, herein referred to as ET-1), and collagen (COL1A1 and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary LFs exposed to nicotine (50 μg/ml), and in whole lung homogenates from mice chronically exposed to nicotine (100 μg/ml) in the drinking water. In selected studies, these pathways were manipulated in LFs with miR-98 inhibitor (anti-miR-98), miR-98 overexpression (miR-98 mimic), or the PPARγ agonist rosiglitazone. Compared with unexposed controls, nicotine increased NGF, FN1, ET-1, COL1A1, and COL3A1 expression in human and mouse LFs and mouse lung homogenates. In contrast, nicotine reduced miR-98 levels in LFs in vitro and in lung homogenates in vivo. Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, whereas treatment with a miR-98 mimic significantly suppressed luciferase expression in cells transfected with a luciferase reporter linked to the putative seed sequence in the NGF 3'UTR and also abrogated nicotine-induced increases in NGF, FN1, and ET-1 in LFs. Similarly, rosiglitazone increased miR-98 and reversed nicotine-induced increases in NGF, FN1, and ET-1. Taken together, these findings demonstrate that nicotine-induced increases in NGF and other markers of airway remodeling are negatively regulated by miR-98.

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

Expert

In animals, the response to chronic hypoxia is mediated by prolyl hydroxylases (PHDs) that regulate the levels of hypoxia-inducible transcription factor α (HIFα). PHD homologues exist in other types of eukaryotes and prokaryotes where they act on non HIF substrates. To gain insight into the factors underlying different PHD substrates and properties, we carried out biochemical and biophysical studies on PHD homologues from the cellular slime mold, Dictyostelium discoideum, and the protozoan parasite, Toxoplasma gondii, both lacking HIF. The respective prolyl-hydroxylases (DdPhyA and TgPhyA) catalyze prolyl-hydroxylation of S-phase kinase-associated protein 1 (Skp1), a reaction enabling adaptation to different dioxygen availability. Assays with full-length Skp1 substrates reveal substantial differences in the kinetic properties of DdPhyA and TgPhyA, both with respect to each other and compared with human PHD2; consistent with cellular studies, TgPhyA is more active at low dioxygen concentrations than DdPhyA. TgSkp1 is a DdPhyA substrate and DdSkp1 is a TgPhyA substrate. No cross-reactivity was detected between DdPhyA/TgPhyA substrates and human PHD2. The human Skp1 E147P variant is a DdPhyA and TgPhyA substrate, suggesting some retention of ancestral interactions. Crystallographic analysis of DdPhyA enables comparisons with homologues from humans, Trichoplax adhaerens, and prokaryotes, informing on differences in mobile elements involved in substrate binding and catalysis. In DdPhyA, two mobile loops that enclose substrates in the PHDs are conserved, but the C-terminal helix of the PHDs is strikingly absent. The combined results support the proposal that PHD homologues have evolved kinetic and structural features suited to their specific sensing roles.

Rhodopsin is a canonical class A photosensitive G protein–coupled receptor (GPCR), yet relatively few pharmaceutical agents targeting this visual receptor have been identified, in part due to the unique characteristics of its light-sensitive, covalently bound retinal ligands. Rhodopsin becomes activated when light isomerizes 11-cis-retinal into an agonist, all-trans-retinal (ATR), which enables the receptor to activate its G protein. We have previously demonstrated that, despite being covalently bound, ATR can display properties of equilibrium binding, yet how this is accomplished is unknown. Here, we describe a new approach for both identifying compounds that can activate and attenuate rhodopsin and testing the hypothesis that opsin binds retinal in equilibrium. Our method uses opsin-based fluorescent sensors, which directly report the formation of active receptor conformations by detecting the binding of G protein or arrestin fragments that have been fused onto the receptor's C terminus. We show that these biosensors can be used to monitor equilibrium binding of the agonist, ATR, as well as the noncovalent binding of β-ionone, an antagonist for G protein activation. Finally, we use these novel biosensors to observe ATR release from an activated, unlabeled receptor and its subsequent transfer to the sensor in real time. Taken together, these data support the retinal equilibrium binding hypothesis. The approach we describe should prove directly translatable to other GPCRs, providing a new tool for ligand discovery and mutant characterization.

Centrioles are key eukaryotic organelles that are responsible for the formation of cilia and flagella, and for organizing the microtubule network and the mitotic spindle in animals. Centriole assembly requires oligomerization of the essential protein spindle assembly abnormal 6 (SAS-6), which forms a structural scaffold templating the organization of further organelle components. A dimerization interaction between SAS-6 N-terminal “head” domains was previously shown to be essential for protein oligomerization in vitro and for function in centriole assembly. Here, we developed a pharmacophore model allowing us to assemble a library of low-molecular-weight ligands predicted to bind the SAS-6 head domain and inhibit protein oligomerization. We demonstrate using NMR spectroscopy that a ligand from this family binds at the head domain dimerization site of algae, nematode, and human SAS-6 variants, but also that another ligand specifically recognizes human SAS-6. Atomistic molecular dynamics simulations starting from SAS-6 head domain crystallographic structures, including that of the human head domain which we now resolve, suggest that ligand specificity derives from favorable Van der Waals interactions with a hydrophobic cavity at the dimerization site.

RNA-protein interfaces control key replication events during the HIV-1 life cycle. The viral trans-activator of transcription (Tat) protein uses an archetypal arginine-rich motif (ARM) to recruit the host positive transcription elongation factor b (pTEFb) complex onto the viral trans-activation response (TAR) RNA, leading to activation of HIV transcription. Efforts to block this interaction have stimulated production of biologics designed to disrupt this essential RNA-protein interface. Here, we present four co-crystal structures of lab-evolved TAR-binding proteins (TBPs) in complex with HIV-1 TAR. Our results reveal that high-affinity binding requires a distinct sequence and spacing of arginines within a specific β2-β3 hairpin loop that arose during selection. Although loops with as many as five arginines were analyzed, only three arginines could bind simultaneously with major-groove guanines. Amino acids that promote backbone interactions within the β2-β3 loop were also observed to be important for high-affinity interactions. Based on structural and affinity analyses, we designed two cyclic peptide mimics of the TAR-binding β2-β3 loop sequences present in two high-affinity TBPs (KD values of 4.2 ± 0.3 and 3.0 ± 0.3 nm). Our efforts yielded low-molecular weight compounds that bind TAR with low micromolar affinity (KD values ranging from 3.6 to 22 μm). Significantly, one cyclic compound within this series blocked binding of the Tat-ARM peptide to TAR in solution assays, whereas its linear counterpart did not. Overall, this work provides insight into protein-mediated TAR recognition and lays the ground for the development of cyclic peptide inhibitors of a vital HIV-1 RNA-protein interaction.

E. A. Rakhmanov and S. P. Suetin
Trans. Moscow Math. Soc. 83 (), 269-290.
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A. B. Bogatyrev
Trans. Moscow Math. Soc. 83 (), 217-225.
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A. V. Domrina
Trans. Moscow Math. Soc. 83 (), 201-215.
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A. V. Silantyev
Trans. Moscow Math. Soc. 83 (), 75-149.
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Z. A. Kasumov and N. R. Akhmedzade
Trans. Moscow Math. Soc. 83 (), 67-74.
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A. G. Sergeev, A. Kh. Khachatryan and Kh. A. Khachatryan
Trans. Moscow Math. Soc. 83 (), 55-65.
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A. P. Starovoitov and N. V. Ryabchenko
Trans. Moscow Math. Soc. 83 (), 15-31.
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