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Stavros Niarchos Foundation makes £3m grant for expansion at Chatham House

18 December 2015

The Royal Institute of International Affairs is pleased to announce a Cornerstone Contribution of £3m by the Stavros Niarchos Foundation (SNF) towards the Chatham House Second Century Initiative to support the expansion and renovation of the institute’s ground floor.

Following the institute’s purchase of the ground floor of the adjoining building (Ames House) in 2013, this generous grant from SNF will enable Chatham House to occupy this space and undertake a significant renovation project to create the ‘Stavros Niarchos Foundation Floor’ at Chatham House.

This will help the institute meet the growing demand for its research and analysis and take full advantage of its location in central London, given the city’s exceptional international connectivity and status as a global hub.

The SNF Floor will contain state-of-the-art meeting facilities for the institute’s research staff and fellows of the Queen Elizabeth II Academy for Leadership in International Affairs, and will significantly enhance the institute’s convening and communication capacities. To this end, the renovated space will include a ‘simulation room’, the Asfari Centre and a media room, as well as new breakout and meeting areas. The SNF Floor will be directly accessible from the ground floor of 10 St James’s Square, the institute’s main building.

The SNF grant is an important step forward for the institute’s Second Century Initiative which aims to ensure the institute’s long-term financial independence. The initiative has three principal targets:

● to endow a number of Research Fellowships and interdisciplinary Research Centres;

● to secure endowments to support the Queen Elizabeth II Academy for Leadership in International Affairs in order to nurture independent thinking on international policy among a new generation from around the world; and

● to secure the necessary physical space and infrastructure here in London to meet the growing demand for and scope of the institute’s work.

Dr Robin Niblett, director of Chatham House said: ‘We are enormously grateful to the Stavros Niarchos Foundation for this transformational grant which will significantly enhance Chatham House’s capacity to serve as a trusted and creative space for addressing the most important challenges in international affairs.’

Andreas Dracopoulos, co-president of SNF’s board of directors, said: ‘We are delighted to support the growth of Chatham House, one of Europe’s leading independent, non partisan policy institutes, at a time when the risks to global prosperity and stability are expanding. Chatham House’s reputation for providing world-leading analysis needs to remain as strong as ever and I am confident that this grant will help the institute take its research and convening activities in new interactive and interdisciplinary directions.

Editor's notes

Chatham House launched its Second Century Initiative in November 2014 as part of its preparations for its centenary in 2020. The Initiative aims to help secure the institute’s financial base and independence by strengthening its capacity to innovate in an increasingly competitive field of thought leadership and policy ideas. Renovation work on the ground floor of Ames House is expected to begin in the spring of 2016.

The Stavros Niarchos Foundation is one of the world’s leading international philanthropic organizations, making grants in the areas of arts and culture, education, health, medicine and sports, and social welfare. The Foundation funds organizations and projects that exhibit strong leadership and sound management and are expected to achieve a broad, lasting and positive impact for society at large. The Foundation also seeks actively to support projects that facilitate the formation of public-private partnerships as an effective means for serving public welfare.




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Oxford University Press to publish International Affairs

11 March 2016

Chatham House has signed an agreement with Oxford University Press (OUP) to publish International Affairs from 2017.

International Affairs, the institute’s peer-reviewed journal, has published high-quality, policy relevant articles for over 90 years and its global readership includes many of the world’s pre-eminent academic thinkers, policy-makers and practitioners. From January, when its current contract to publish with Wiley-Blackwell ends, OUP will assume responsibility to publish, distribute and market the journal to new and existing readers and audiences.

Vanessa Lacey, senior publisher for Oxford Journals, commented on the acquisition: 'We are thrilled to have been chosen by Chatham House to publish their prestigious journal International Affairs from 2017. International Affairs is a critically important, ‘must read’ journal of relevance to international relations academics and policy-makers alike. We look forward to partnering with Chatham House and International Affairs’ exceptional editorial team to reinforce its position as a global leader in its field.'

Robin Niblett, director of Chatham House, said: 'Chatham House is delighted to have teamed up with OUP, the world’s leading university press, to publish International Affairs. In terms of shared values, reputation and vision, OUP is an ideal partner for International Affairs and Chatham House. This is an exciting opportunity to develop further the journal’s digital outreach and its engagement with new audiences around the world.'

Andrew Dorman, commissioning editor of International Affairs also commented: 'The IA team is really pleased to be working in partnership with OUP to produce the journal. We share a common vision to publish cutting edge articles from across the discipline, which influence both the academic and practitioner communities in all parts of the world.'

OUP adds International Affairs, the foremost UK international relations journal and one of the top ten internationally, to a growing portfolio of respected international relations-related journals. 




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Exploring the Transatlantic Rift

27 August 2015

Xenia Wickett

Former Head, US and the Americas Programme; Former Dean, The Queen Elizabeth II Academy for Leadership in International Affairs
If the US and Europe drift apart, there will be grave consequences for Western global leadership.

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An American flag flies in front of the Brandenburg Gate, near the US embassy on 7 July 2014 in Berlin. Photo by Getty Images.

Is there a ‘crisis’ in the transatlantic relationship? Although the US and Europe are not irresistibly diverging, there are indications that governments and their populations on both sides of the Atlantic are becoming less aligned in their thinking and actions. And it is happening just when they need to become closer.

The ‘rise of the rest’, in which new emerging markets are coming to the fore, is creating a more competitive international environment. And the West is not putting on an adequate response. Unless the US and Europe want to relinquish leadership on building global norms and standards on key issues, their leaders once again need to work more collectively together.

Divides in the Atlantic community

The structures put together in the first half of the 20th century by the Atlantic community (such as NATO, the UN, the WTO/GATT, the IMF and the World Bank) provided the architecture and norms by which everyone functioned – and thereby primed the international context in their favour.

However, these institutions have become increasingly dysfunctional or unfit for purpose, and are increasingly ignored (like the UN) or replaced (as China’s new Asian Infrastructure Investment Bank [AIIB] is arguably attempting to do). That contextual advantage has gone. And there are many other good reasons to be concerned.

Shared values are a notable aspect of the strong and longstanding relationship between the US and Europe. But now, although the US does appear to be coming closer to Europe on some measures (Pew polling suggests America is becoming less religious and more liberal on gay rights and recreational drugs, for instance), there is clear evidence that differences of opinion are becoming more entrenched.

Policy divides between the US and Europe are commonplace, but recently the list of differences (and the degree of difference of opinion) appears to be growing. The split over joining the AIIB is the most recent of these, being a visible symptom of a larger fundamental difference of opinion on Asia. But other issues that divide include actions in Libya in 2011, Syria today, Russia, support for NATO, energy independence and what to do about climate change.

The study on elite perceptions conducted by Chatham House’s US Project in 2014 made clear how important Europeans perceived America’s traditional values to be, but also raised the concern that the US was losing sight of them (citing, for example, the lack of universal healthcare and attitudes towards the death penalty and gun laws). The visceral response of the German public to the Snowden revelations is a stark example of the divide in attitudes.

Special relationships

Anecdotally, the evidence is also not good. Over the past four years the general tone of conversations in Europe about the US has changed, due to huge uncertainty about whether the US is going to continue to play the same role it has in the past or whether it will leave Europe to face its challenges alone. Meanwhile, in the US the conversation around whether Europe will step up (particularly in security) has heightened tremendously. Four years ago, no one thought to question the transatlantic relationship. Today, on both sides, there is a lack of confidence.

The US-UK relationship has a special part in this – it has long been and still remains the centre-point of the transatlantic relationship. From a realpolitik perspective, the US sees the UK as valuable for three principal reasons: A) its role in the EU promoting common UK/US interests; B) the assets it brings to the table (particularly defence and intelligence); and C) its external perspective and its support internationally (ensuring the US is rarely alone). However, in the coming years A might go away and B is declining with falling defence spending, leaving only C. And a weak US-UK relationship could cause significant trouble for the wider US-Europe relationship.

It is all too easy to forget the importance of the transatlantic relationship. For many it is increasingly irrelevant – the emerging powers such as China and Brazil are far more interesting. And for others it is just an ever-present reality – the Atlantic allies have been so close and through so much that nothing can change it.

Neither of these is right. The transatlantic relationship is vital part of addressing global challenges and it is something that, if continued to be treated either with either contempt or ignorance, will be lost before we know it. For these reasons, the US Project is beginning new research that looks at the transatlantic relationship and asks whether there is a rift. If yes, we hope to explore what can be done to mitigate it – before it is too late.

To comment on this article, please contact Chatham House Feedback




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Brexit Would Be a Further Blow to the Special Relationship

20 April 2016

Xenia Wickett

Former Head, US and the Americas Programme; Former Dean, The Queen Elizabeth II Academy for Leadership in International Affairs
But increased British leadership, in Europe and beyond, could reverse the decline of US–UK ties.

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Barack Obama and David Cameron at the 2016 Nuclear Security Summit on 1 April 2016 in Washington. Photo by Getty Images.

The US−UK ‘Special Relationship’ is in decline, and a British decision to leave the EU would hasten its demise. As Great Britain increasingly becomes just one of America’s many strategic relationships, Brexit would speed the transfer of US attention and energy from the UK to the continent. This, however, does not need to be inevitable. The necessary ingredient to reverse this decline is stronger British leadership internationally.

The US government has made it abundantly clear that its preference is to see the UK remain in the European Union. In January 2013, when David Cameron had not yet committed to a referendum, Phil Gordon, the US assistant secretary of state for European affairs bluntly stated that it is in the American interest for the US ‘to see a strong British voice in that European Union.’ The fact that a senior US official would go so far – to be seen to intervene so early in a divisive domestic political issue – spoke volumes about how important this is to America. This week, President Obama will visit the UK to send an equally firm, if polite, message to the British public.

Why does the US want the UK to remain in Europe?

From the US perspective, there are three principal elements that the UK brings to the table in the bilateral relationship. The first stems from Britain’s capabilities, particularly in the military and intelligence arenas. US−UK intelligence sharing, the closest for both countries, has a long history dating back to the Second World War. For good or ill the UK has been among America’s leading allies in every major conflict the US has been involved in for the last quarter of a century – in the Gulf War, Bosnia and Kosovo, Afghanistan, the war in Iraq, the interventions in Libya as well as current operations against ISIS in Iraq and, belatedly, Syria.

The second relates to the political value of having a reliable partner in international engagements – and thereby avoiding the perception of acting unilaterally. Shared history and values, and thus often perspectives (as well as capabilities) have ensured that the UK has long been the first port of call for the US when seeking to solve international problems or build coalitions. At the same time, Britain’s historical global reach and diplomatic experience around the world (not least in areas of current concern such as Afghanistan, Pakistan, Israel and Palestine, and Iraq) have provided American policy-makers with valuable input on foreign policy issues that has contributed to their own internal decision making.

The third area of added value for the US is Britain’s place in the EU. While British and US policy preferences may at times diverge, as they have recently on the Israel−Palestine issue, for example, their common outlooks and interests mean that Britain is the closest thing that the United States has to having a voice in the EU. At the same time, the US also sees the UK as the country most likely to support an open trade and investment agenda and a more proactive approach to dealing with the challenges in Europe’s neighbourhood, policies that leaders in both countries agree are necessary to make the EU a more effective actor and better partner to the US on the international scene.

The transition from US−UK ties to US−European ties

In recent years, however, the US has begun to diversify its relationships within Europe, in part as the UK has become unable or unwilling to step up and fulfil these three elements of paramount importance to the US.

Defence and intelligence

With regards to defence capabilities, it is no longer the UK that the United States inevitably looks to first. In Libya, the operation that started with the defence of Benghazi from Gaddafi’s forces in March 2012 (that eventually came to remove Gaddafi himself) was jointly led by the French and the British, although then-French president Nicolas Sarkozy appeared to be the driving force. More recently, it was the French with whom the US partnered in responding to the terrorist activities in Mali and who were first to support the US in action in Syria (following a UK parliamentary vote to stay out in August 2013 and a belated vote to act in December 2015). But in recent years others have worked more closely with the United States militarily as well, including in particular Poland and Denmark (although with the new government in Poland, the relationship might wither again).

This trend towards more diversified military engagement with other European states looks set to continue in the near term. Despite taking a tough position in the 2014 NATO Summit to reinforce the NATO commitment of two per cent of GDP spending on defence, the Cameron government came very close to falling below this line in 2015 (after five years of real defence cuts). The eventual decision to commit to meet this target, along with the newly released Strategic Defence and Security Review (SDSR), have somewhat reassured American policy-makers of the UK’s continued ambition and capabilities. But there remains a lack of US confidence that this is only a temporary uptick in UK attention on defence. Meanwhile, America will continue to expand its horizons.

The story on intelligence sharing is slightly different, but here too obstacles have arisen in the close US-UK exchange of information. Since the end of the Second World War, the US and UK have been part of the ‘Five Eyes’ alliance – with Australia, New Zealand and Canada – that allows the close sharing of intelligence. And arguably, within the Five Eyes, the links between the US and UK are the closest of all. However, more recently, tensions have emerged. Over the past five or so years, the British judicial system in particular has pushed back on US confidentiality rules in ways that make the US intelligence services nervous of continuing to share information; given the current close relationship, this could be more of an obstacle than it is for other countries sharing intel with the US.

At the same time, with the ISIS-inspired resurgence in the terrorist threat in both Europe and the US, it is becoming increasingly clear that the close intelligence sharing between the US and UK must take place much more widely. The current systems – through NATO or INTERPOL – have proven too slow and ineffective, as the recent attacks in Paris and Brussels have made clear. Sharing among the US and UK, or even among the Five Eyes, is insufficient – increasingly the relationships will have to be broadened.

Partnership

The US is also looking elsewhere for partnership in its international engagements, including on some of the issues that are at the top of the inbox for the American president.

On responding to Russian actions in Ukraine, it is clear that German Chancellor Angela Merkel is in the lead, both in corralling Europeans to maintain the sanctions but also in negotiating with Russian President Vladimir Putin. This was highlighted in the creation of the Normandy format in the summer of 2014, a group encompassing Germany, France, Russia and Ukraine (but not the UK or the US), to resolve the situation in the east of Ukraine. On another issue of significant import to the United States, European economic prosperity and stability, Merkel is again the leading actor in Europe.

In the case of targeted bombing in Syria, it was not the British that were first to join the United States in the offensive against ISIS, but instead the French. President Francois Hollande also proved far more proactive after Syrian President Assad crossed the chemical weapons ‘redline’ in 2013, although in the end France was left hanging when President Obama decided to step back from military action after the failure of the British parliamentary vote to authorize UK involvement.

Finally, on at least one issue of great import to the US – China – the UK appears to be diverging meaningfully. The most recent case – the UK decision to join the Asian Infrastructure Investment Bank in March 2015 – is perhaps the starkest example of such differing policy positions that have caused significant frustration in the US.

Influence in the European Union

With regards to Europe, even before the referendum was formally announced, it was increasingly clear that the UK was less inclined to engage proactively in the EU. A number of factors have ensured that, particularly since 2010, the UK has become less influential there.

British influence has been diminished through actions by the Cameron government that have, perhaps unnecessarily, antagonized many across the Channel. Many European conservatives became frustrated early in Cameron’s tenure when he decided to take the Conservative Party out of the principal conservative group in the European parliament, the European People’s Party. This sentiment only worsened in recent years as, albeit for perhaps understandable domestic political reasons, Cameron conducted an adversarial negotiation with his European partners in an effort to secure reforms to the EU and changes in Britain’s terms of membership.

The UK also no longer sends its best and brightest to EU institutions. Many of the leading British officials who once occupied high offices there have left and been replaced by other continental Europeans. This deprives Britain of an important source of influence within the EU.

It is clear that if the US wants influence in the EU, it needs more partners there than just the UK. Britain is still important, and would be a strong driver to make the institution more efficient, but as its influence declines it is no longer sufficient. A Leave vote would immediately dispose of that influence entirely.

The UK is ‘one among many’ for the US

What is clear is that increasingly the UK is not ‘first among equals’ in Europe but ‘one among many’ for the United States. America is diversifying its relationships. More and more the US can find other allies and friends to fulfil the needs in which the UK no longer has interest.

If the UK leaves the European Union, the pace of this trend will only quicken. In addition to needing to find alternative partners to address these policy gaps, the UK will likely no longer have the time to devote to the United States that it does today. If Brexit takes place, Whitehall will find itself inundated with issues which had previously been managed by the EU, from trade deals with third parties to negotiating constant market access adjustments with the EU. Thus, very quickly, British resources are likely to be pulled from the US portfolio, and issues of common concern will get drowned out by other agendas. At least for a while, the US will likely get short shrift.

America’s response then can only be to hasten its search for other partners both in Europe and beyond. And there lies an inevitable negative spiral for the Special Relationship.

Can anything be done to save the Special Relationship?

There is no question that the US and UK will continue to have a strong and positive relationship, but it is clear that, without action, either in or out of Europe, its ‘specialness’ will decline. As the arguments above lay out, the only question is how fast this demise takes place. But there is something that could not only halt, but also reverse this trend.

As President Obama made starkly clear in his interviews with Jeffrey Goldberg in the Atlantic, what he wants most from partners and allies is for them to step up – to show more leadership (a sentiment that the Republican candidates for president would push even further). With the perceived failure of interventions over the last 15 years – from Afghanistan to Iraq to Libya –many politicians and publics have become wary of foreign military intervention. This is true in Europe and the US; but Americans have often felt that they have been left holding both the bag and the blame.  

It should be noted that more leadership does not necessarily mean more military engagement. Or even, necessarily, more spending on foreign policy tools (whether diplomatic, military or development). But it does mean a willingness to step up and take responsibility for trying to guide international events and for promoting common interests.

In the UK’s SDSR released towards the end of 2015, the government stated its intention to remain fully engaged globally; however, its actions belie this. Where Asia is concerned – an issue that is front and centre for the US – the UK joins other European powers in arguing that its lack of resources in the region makes it unable to contribute meaningfully to maintaining stability. Even closer to home, in the Middle East, the UK has been wary of leading.

It is understandable why the UK is hesitant to take such a leadership role, even as part of a coalition, in some of the larger strategic challenges the world faces. There are few benefits. Merely finding the human capital to coordinate an international response is difficult. The complexity of these problems ensures they rarely work out as hoped, and more often lead to international contempt rather than approbation. Thus it is no great surprise that the UK, along with much of the rest of the world, resists the temptation to be out in front. But there are opportunities – two issues that the US would likely welcome greater British leadership on would be building support in Europe for the Transatlantic Trade and Investment Partnership and taking a more active role in maintaining stability in Asia. Further, having a stronger European partner on issues in the Middle East (from Yemen to Syria) – Europe’s near abroad – is something that many American policy-makers have suggested. 

But the UK would not have to stand alone. With a little leadership from the UK, the US would provide support, as would many others currently loath to take the lead but with very strong interests in the outcomes. But someone has to start; as Obama made clear, there needs to be less ‘free riding’.

If the UK wants to reverse the decline of the Special Relationship, it will need to show more leadership internationally. This should not be as hard as it might seem. Not only does it conform to the government’s own strategy (as laid out in the SDSR) but public concern over further interventions is weaker than one might imagine. Such a leadership role would once again show to the United States the value of the Special Relationship.

This article has also been published by Real Clear World.

To comment on this article, please contact Chatham House Feedback




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Special relationships in flux: Brexit and the future of the US– EU and US–UK relationships

6 May 2016 , Volume 92, Number 3

A British exit from the EU would add to growing strains on the United States’relations with Britain and the rest of Europe, but by itself would not lead to a breakdown in transatlantic relations. It would, however, add to pressures on the US that could change the direction of the transatlantic relationship. From the perspective of Washington, Britain risks becoming an awkward inbetweener.

Tim Oliver and Michael John Williams

A British exit from the EU would add to growing strains on the United States’ relations with Britain and the rest of Europe, but by itself would not lead to a breakdown in transatlantic relations due to the scale of shared ideas and interests, institutional links, international pressures and commitments by individual leaders. It would, however, add to pressures on the US that could change the direction of the transatlantic relationship. From the perspective of Washington, Britain risks becoming an awkward inbetweener, beholden more than ever before to a wider transatlantic relationship where the US and EU are navigating the challenges of an emerging multipolar world. The article outlines developments in the UK, EU, Europe and the US in order to explain what Brexit could mean for the United States’ approaches to transatlantic relations. By doing so the article moves beyond a narrow view of Brexit and transatlantic relations that focuses on the future of UK–US relations. In the conclusion we map out several ways in which US views of the transatlantic relationship could be changed.




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Brexit Clouds TTIP Negotiations But May Not Scupper Deal

11 July 2016

Marianne Schneider-Petsinger

Senior Research Fellow, US and the Americas Programme
The British vote to leave the EU will slow progress on a transatlantic trade deal, but it also removes some UK sticking points from the process.

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A sign promoting the TTIP free trade agreement in Berlin. Photo by Getty Images.

With Britain’s decision to leave the EU, the clouds of uncertainty hanging over the proposed US-EU free trade deal (known as the Transatlantic Trade and Investment Partnership or TTIP) have become darker. The negotiations were formally launched three years ago and have stalled because of transatlantic differences (for instance over issues of investor protections and public procurement) as well as growing public opposition. For now, both the US and the EU negotiators are determined to weather the storm and continue talks when they meet in Brussels from 11-15 July.

The result of the UK’s EU referendum will blow a strong wind into the face of TTIP negotiators on three fronts. First, the Brexit vote will delay the TTIP talks as EU officials will focus their attention and political capital on the future UK-EU relationship. Once the UK government triggers Article 50 of the Lisbon Treaty, both sides have two years to sort out the separation proceedings. Only after it has become clear what Britain’s relationship with the EU will look like will the European side stop navel-gazing. The TTIP negotiations will likely continue in the meantime, but will be put on the back-burner.

Second, any progress on TTIP will require clarity on what both sides are bringing to the negotiating table. But until the final nature of the UK-EU relationship is known, it will be difficult for the American side to assess exactly how valuable the access to the remaining EU market is. This raises the question of whether American negotiators will put forth their best offers if they don’t know what benefits they will obtain for making concessions.

Third, with Britain’s vote to leave the EU, TTIP has just lost one of its greatest cheerleaders. French and German officials are increasingly expressing concerns about TTIP. Within three days of the Brexit vote, French Prime Minister Manuel Valls dismissed the possibility of a US-EU trade deal, stating TTIP was against ‘EU interests’. In addition, 59 per cent of Germans oppose TTIP – up from 51 per cent – according to the most recent Eurobarometer survey. Britain’s voice for further trade liberalization will be sorely missed by American negotiators eager to strike a deal.

Despite the dark Brexit clouds on the TTIP horizon, there might be a silver lining. Britain’s decision to leave the EU could bring some benefits to the US-EU trade talks in two ways. First, financial services regulation might no longer be a sticking point in the TTIP negotiations. Given London’s role as a financial centre, the UK had insisted on including a financial services chapter in the trade deal. The US, however, has resisted this. The removal of this friction could help move the TTIP negotiations along.

Second, European trade negotiators will no longer have to address British fears that TTIP could put the National Health Service (NHS) at risk. Much of the TTIP-debate in Great Britain has focused on how this deal might impact the NHS. Opponents of TTIP have argued that including healthcare in the agreement could lead to privatization and ultimately the death of the NHS. EU Trade Commissioner Cecilia Malmström spent resources and energy in correcting these misconceptions. UK withdrawal from the EU means that she can now focus on fighting other myths surrounding TTIP, which could potentially help advance the trade deal.

For now and the immediate future, Britain will remain a member of the EU and the European Commission will continue to negotiate trade deals on behalf of all 28 member states. Both the US and EU negotiators are committed to advancing the trade deal despite Brexit. The British decision to leave the EU has not weakened the case for TTIP. Speaking on the outcome of the EU referendum, United States Trade Representative Michael Froman said ‘the economic and strategic rationale for TTIP remains strong’. And his counterpart Cecilia Malmström went even further, saying that the British decision to leave the EU creates more of an impetus for TTIP to be finished this year.

Though this timeline is unlikely to be met, TTIP is likely to survive the British decision to leave the EU. However, Brexit is a serious blow that will probably push back the conclusion of TTIP by at least two years. Any deal will need to take into account the future nature of the UK-EU trade deal, which may not be known before 2018. Meanwhile, elections in Germany and France (two countries with strong public opposition to TTIP) will take place in 2017. On the other side of the Atlantic, the US presidential election adds yet another layer of uncertainty as the trade policy of the next administration remains unknown. When US and EU trade negotiators meet again this week, they should not be too worried about the Brexit storm but rather the changing climate for TTIP in France, Germany and the US.

To comment on this article, please contact Chatham House Feedback




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Does Brexit Mean the Future Is President Trump?

21 July 2016

Dr Jacob Parakilas

Former Deputy Head, US and the Americas Programme

Xenia Wickett

Former Head, US and the Americas Programme; Former Dean, The Queen Elizabeth II Academy for Leadership in International Affairs
The growing anti-establishment backlash on both sides of the Atlantic may not swing November’s election, but the world has fundamentally changed.

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Donald Trump enters the stage on the first day of the 2016 Republican National Convention. Photo by Getty Images.

The British vote to leave the EU is (and should be) seen as a wakeup call for political elites on both sides of the Atlantic. Under normal circumstances, the institutional support that crossed party lines for the Remain campaign should have ensured it a comfortable victory; instead, it lost by a not-insignificant 52−48 per cent margin. Similarly, Donald Trump has alienated the establishment of both American parties – while Democratic dislike is predictable, the extent of the Republican elite’s discomfort with Trump, clearly on display at the party’s convention in Cleveland this week, is extremely unusual at this point in an election campaign which is more typically a display of ‘rally around the candidate’. But as Brexit demonstrated, the conventional logic may not apply in 2016.

There are significant differences between the UK referendum and the US elections. Some of this is structural – a national referendum operates along very different lines than a US presidential election, after all, and the US electorate is much larger and more diverse than its British equivalent. Furthermore, American voters will be making a choice between individuals as well as ideas. This does not necessarily work to the advantage of either Donald Trump or Hillary Clinton (both of whom have the highest unfavourability ratings for presidential candidates seen in decades), but highly individualized questions of personality and temperament will impact voter behaviour in a way that they did not for British referendum voters. Finally, who wins the US election will depend in very large part on state politics and electoral college math – as the 2000 election showed, the candidate who wins the popular vote does not necessarily end up as president.

But there is a far more important message that politicians in the US, UK and, more broadly, Europe, should take away from the Brexit result. Regardless of what happens in the US elections, elites no longer necessarily hold the preponderance of power. The disenfranchised who have historically either not had the mass or the coherence to communicate it now do - at least on occasion.

This is not an ideological split – Brexit voters came together from all parts of the political spectrum. Equally, in the US, Sanders and Trump voters are bucking the system in both the Democratic and Republican parties.

There is a significant backlash under way in both countries towards aspects of globalization, going beyond the traditional right/left divide. Allowing for some differences in specifics, the American and British political establishments have, over the past few decades, broadly eased restrictions on the free movement of capital, goods and people across national borders. There have been notable benefits associated with this approach that have mostly been distributed inclusively, but the costs have typically hit those already less advantaged and without opportunities or skills to mitigate them. Those who have been left out or left behind from these changes are discovering their own political power.

Politicians are going to have to find ways not just to appeal to these voters who feel disenfranchised by existing structures, but also address their legitimate concerns. There will of course be partisan policy solutions put forward on both sides. But inevitably the political leadership is going to have to find ways to bridge party lines to realize solutions to those social and economic inequalities. Ignoring them, as many have in the past, is increasingly a quick path to losing power.

Unless the world wants to turn back to more isolationist and protectionist times, with the slower growth and inequalities that this includes, politicians are also going to have to do a better job of explaining the benefits of globalization. And, more importantly, they will have to ensure that these benefits reach their broader population more equitably and that the costs are better mitigated. 

So the Brexit vote does not necessarily presage a Trump victory on 8 November, but it shows in stark terms that the world has fundamentally changed – the time when elites alone could call the shots is gone. Politicians, including Hillary Clinton, will need to respond proactively to the causes of the dissatisfaction rather than waiting until the next time they need the public vote.

To comment on this article, please contact Chatham House Feedback




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For a US Trade Deal, UK Should Secure Its Spot in TTIP After Brexit

25 August 2016

Marianne Schneider-Petsinger

Senior Research Fellow, US and the Americas Programme
Having Britain as an additional party to a US−EU free-trade agreement would benefit all sides.

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A Union flag hangs in the window of a British grocery store in New York City. Photo by Getty Images.

Even though President Barack Obama cautioned that the UK would be at the ‘back of the queue’ for a trade agreement with the US if the country chose to leave the EU, in the post-Brexit world a deal might be struck more swiftly. Various ideas for bringing the UK and US into a formal trade arrangement have been floated – ranging from a bilateral UK-US trade deal, or the UK joining NAFTA (the North American Free Trade Agreement between the US, Canada and Mexico), to the UK becoming a part of the TPP (the Trans-Pacific Partnership that the US is pursuing with 11 other countries along the Pacific Rim). However, one option stands out: opening the Transatlantic Trade and Investment Partnership (TTIP), which the US and EU are currently negotiating, to the UK after Brexit.

Good reasons for Britain in TTIP

First, from the perspective of the UK, signing up to TTIP would mean a more comprehensive deal with the US than a bilateral UK−US trade agreement. For instance, Britain is very keen to include financial services regulation in any trade agreement with America, but given Washington’s reluctance, this ambition might only be achievable if other countries like France and Germany throw their financial weight into the negotiations.

Second, continuing involvement in the TTIP negotiations allows London to begin securing its trade position with the US now. Though its influence in the EU may weaken as it heads for the exit, Britain could make the best use of influencing the EU position on TTIP while it is still a member. It could then accept the terms of TTIP and accede as a third party relatively quickly after exiting the EU. Official negotiations on a UK−US-only deal would have to wait until the UK has left the EU, as trade talks fall under the exclusive competence of the EU.

Third, for the US and EU, having the UK as a party to TTIP would ensure the scale of the deal is not reduced, and thereby maintain the strategic appeal and ability to set global standards. At the moment, the UK is the EU’s second-largest economy, accounting for approximately 18 per cent of GDP. With Britain in TTIP, the sheer size of the transatlantic market space will have more pull for other countries to adopt the common transatlantic rules in order to gain market access.

Fourth, the UK joining TTIP as a third party would establish the agreement as an ‘open platform’ that is available for other countries to join. Michael Froman, the United States trade representative, has characterized TTIP as being such an open agreement. EU representatives have been more ambivalent, though this is starting to change in the wake of Brexit. David O’Sullivan, the current EU ambassador to the US, recently said that as ‘we’ve always seen TTIP as a potential open platform, [the] UK could still benefit [from it] even not as a member of the European Union’. While now might not be the right time to expand the TTIP bloc beyond its original participants given that negotiations are already complex and drawn out, it would be beneficial for the negotiating partners to send a strong message that countries that are willing and able to commit to the high TTIP standards will be welcomed later on.

Obstacles to Britain in TTIP

But before the UK could be added to TTIP after Brexit, major hurdles will have to be jumped and crucial questions answered. The first obstacle is actually getting a TTIP deal, which will require significant efforts by political leaders and negotiators on both sides of the Atlantic.

Second, selling the ‘UK in TTIP option’ to Brexiteers will not be an easy task. After all, Leave campaigners argued that the US−EU deal might undermine the NHS and was thus presented as one of the reasons to cut loose from Brussels. As the major rationale behind TTIP is regulatory harmonization, if the UK were to sign up to TTIP it would still have to apply many EU rules. This, however, would go counter to the arguments for leaving the EU in the first place.

Third, it will be a challenging job for the UK to untangle its trade relationship with the EU while at the same time negotiating TTIP together with the EU. It would be easiest if the UK decided to remain a member of the EU customs union. Britain would then be required to impose the EU’s external tariffs on countries like the US. This would fit seamlessly with the ‘UK in TTIP’ option. But as the UK will most likely pull out of the customs union, it will be more complicated than that.

Finally, the timing of Brexit and the TTIP negotiations could cause complications. In the unlikely event that a US-EU free trade deal is concluded and ratified while the UK is still a member of the EU, the agreement (or the parts of it that fall under national competence) would most likely continue to apply to Britain after Brexit without the need for accession. If the TTIP negotiations continue beyond Brexit, then the UK would move from negotiating as part of the EU bloc to becoming a third party. This raises the issue of whether the UK and EU continue to negotiate as one bloc vis-à-vis the US.

Special economic relationship

Still, the depth of the economic ties between the US and UK means that the TTIP option is likely to be welcomed favourably by both countries. The US is the most important single export market for the UK, with goods and services worth £45 billion shipped in 2015. Last year, the US ranked third (after Germany and China) as a source for UK imports. With nearly $1 trillion invested in each other’s economies, the US and the UK are also each other’s largest investors. Given this special economic relationship, Britain is unlikely to be at the ‘back of the queue’ in any event. But the TTIP option is the best path to preserving and strengthening the relationship post-Brexit while also realizing the wider strategic benefits of a transatlantic trade agreement.

A version of this article appeared on Real Clear World.

To comment on this article, please contact Chatham House Feedback




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Tackling Toxic Air Pollution in Cities

Members Event

27 November 2019 - 6:00pm to 7:00pm

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Camilla Hodgson, Environment Reporter, Financial Times

Dr Benjamin Barratt, Senior Lecturer in Chinese Environment, KCL

Dr Susannah Stanway MBChB MSc FRCP MD, Consultant in Medical Oncology Royal Marsden NHS Foundation Trust

Elliot Treharne, Head of Air Quality, Greater London Authority

Chair: Rob Yates, Head, Centre on Global Health Security, Chatham House

Air pollution has been classified as a cancer-causing agent with evidence showing an increased risk of lung cancer associated with increasing levels of exposure to outdoor air pollution and particulate matter.

Air pollution is also known to increase risks for other diseases, especially respiratory and heart diseases, and studies show that levels of exposure to air pollution have increased significantly in some parts of the world - mostly in rapidly industrializing countries with large populations.

In coordination with London Global Cancer Week partner organizations, this event outlines the evidence linking air pollution and cancer rates in London and other major cities.

Panellists provide a 360° picture of the impact of the rising incidence of cancer across the world, the challenges the cancer pandemic poses to the implementation of universal health coverage and the existing UK contribution to strengthening capacity in cancer management and research in developing countries.

Department/project

Members Events Team




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Long noncoding RNA pncRNA-D reduces cyclin D1 gene expression and arrests cell cycle through RNA m6A modification [RNA]

pncRNA-D is an irradiation-induced 602-nt long noncoding RNA transcribed from the promoter region of the cyclin D1 (CCND1) gene. CCND1 expression is predicted to be inhibited through an interplay between pncRNA-D and RNA-binding protein TLS/FUS. Because the pncRNA-D–TLS interaction is essential for pncRNA-D–stimulated CCND1 inhibition, here we studied the possible role of RNA modification in this interaction in HeLa cells. We found that osmotic stress induces pncRNA-D by recruiting RNA polymerase II to its promoter. pncRNA-D was highly m6A-methylated in control cells, but osmotic stress reduced the methylation and also arginine methylation of TLS in the nucleus. Knockdown of the m6A modification enzyme methyltransferase-like 3 (METTL3) prolonged the half-life of pncRNA-D, and among the known m6A recognition proteins, YTH domain-containing 1 (YTHDC1) was responsible for binding m6A of pncRNA-D. Knockdown of METTL3 or YTHDC1 also enhanced the interaction of pncRNA-D with TLS, and results from RNA pulldown assays implicated YTHDC1 in the inhibitory effect on the TLS–pncRNA-D interaction. CRISPR/Cas9-mediated deletion of candidate m6A site decreased the m6A level in pncRNA-D and altered its interaction with the RNA-binding proteins. Of note, a reduction in the m6A modification arrested the cell cycle at the G0/G1 phase, and pncRNA-D knockdown partially reversed this arrest. Moreover, pncRNA-D induction in HeLa cells significantly suppressed cell growth. Collectively, these findings suggest that m6A modification of the long noncoding RNA pncRNA-D plays a role in the regulation of CCND1 gene expression and cell cycle progression.




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RNA helicase-regulated processing of the Synechocystis rimO-crhR operon results in differential cistron expression and accumulation of two sRNAs [Gene Regulation]

The arrangement of functionally-related genes in operons is a fundamental element of how genetic information is organized in prokaryotes. This organization ensures coordinated gene expression by co-transcription. Often, however, alternative genetic responses to specific stress conditions demand the discoordination of operon expression. During cold temperature stress, accumulation of the gene encoding the sole Asp–Glu–Ala–Asp (DEAD)-box RNA helicase in Synechocystis sp. PCC 6803, crhR (slr0083), increases 15-fold. Here, we show that crhR is expressed from a dicistronic operon with the methylthiotransferase rimO/miaB (slr0082) gene, followed by rapid processing of the operon transcript into two monocistronic mRNAs. This cleavage event is required for and results in destabilization of the rimO transcript. Results from secondary structure modeling and analysis of RNase E cleavage of the rimO–crhR transcript in vitro suggested that CrhR plays a role in enhancing the rate of the processing in an auto-regulatory manner. Moreover, two putative small RNAs are generated from additional processing, degradation, or both of the rimO transcript. These results suggest a role for the bacterial RNA helicase CrhR in RNase E-dependent mRNA processing in Synechocystis and expand the known range of organisms possessing small RNAs derived from processing of mRNA transcripts.






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A PP2A Phosphatase High Density Interaction Network Identifies a Novel Striatin-interacting Phosphatase and Kinase Complex Linked to the Cerebral Cavernous Malformation 3 (CCM3) Protein

Marilyn Goudreault
Jan 1, 2009; 8:157-171
Research




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Analysis of the Subunit Composition of Complex I from Bovine Heart Mitochondria

Joe Carroll
Feb 1, 2003; 2:117-126
Research




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Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues

Roland Bruderer
May 1, 2015; 14:1400-1410
Research




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High Resolution Clear Native Electrophoresis for In-gel Functional Assays and Fluorescence Studies of Membrane Protein Complexes

Ilka Wittig
Jul 1, 2007; 6:1215-1225
Research




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PaxDb, a Database of Protein Abundance Averages Across All Three Domains of Life

M. Wang
Aug 1, 2012; 11:492-500
Technological Innovation and Resources




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Large Scale Screening for Novel Rab Effectors Reveals Unexpected Broad Rab Binding Specificity

Mitsunori Fukuda
Jun 1, 2008; 7:1031-1042
Research




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Quantitative, Multiplexed Assays for Low Abundance Proteins in Plasma by Targeted Mass Spectrometry and Stable Isotope Dilution

Hasmik Keshishian
Dec 1, 2007; 6:2212-2229
Research




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The Proteome of the Mouse Photoreceptor Sensory Cilium Complex

Qin Liu
Aug 1, 2007; 6:1299-1317
Research




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Comparative Proteomic Analysis of Eleven Common Cell Lines Reveals Ubiquitous but Varying Expression of Most Proteins

Tamar Geiger
Mar 1, 2012; 11:M111.014050-M111.014050
Special Issue: Prospects in Space and Time




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Complementary Profiling of Gene Expression at the Transcriptome and Proteome Levels in Saccharomyces cerevisiae

Timothy J. Griffin
Apr 1, 2002; 1:323-333
Research




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A Tandem Affinity Tag for Two-step Purification under Fully Denaturing Conditions: Application in Ubiquitin Profiling and Protein Complex Identification Combined with in vivoCross-Linking

Christian Tagwerker
Apr 1, 2006; 5:737-748
Research




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Discordant Protein and mRNA Expression in Lung Adenocarcinomas

Guoan Chen
Apr 1, 2002; 1:304-313
Research




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Integrated Genomic and Proteomic Analyses of Gene Expression in Mammalian Cells

Qiang Tian
Oct 1, 2004; 3:960-969
Research




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Trypsin Cleaves Exclusively C-terminal to Arginine and Lysine Residues

Jesper V. Olsen
Jun 1, 2004; 3:608-614
Technology




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Targeted Data Extraction of the MS/MS Spectra Generated by Data-independent Acquisition: A New Concept for Consistent and Accurate Proteome Analysis

Ludovic C. Gillet
Jun 1, 2012; 11:O111.016717-O111.016717
Research




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The Paragon Algorithm, a Next Generation Search Engine That Uses Sequence Temperature Values and Feature Probabilities to Identify Peptides from Tandem Mass Spectra

Ignat V. Shilov
Sep 1, 2007; 6:1638-1655
Technology




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Highly Selective Enrichment of Phosphorylated Peptides from Peptide Mixtures Using Titanium Dioxide Microcolumns

Martin R. Larsen
Jul 1, 2005; 4:873-886
Technology




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Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics

Linn Fagerberg
Feb 1, 2014; 13:397-406
Research




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Exponentially Modified Protein Abundance Index (emPAI) for Estimation of Absolute Protein Amount in Proteomics by the Number of Sequenced Peptides per Protein

Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research




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Multiplexed Protein Quantitation in Saccharomyces cerevisiae Using Amine-reactive Isobaric Tagging Reagents

Philip L. Ross
Dec 1, 2004; 3:1154-1169
Research




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Accurate Proteome-wide Label-free Quantification by Delayed Normalization and Maximal Peptide Ratio Extraction, Termed MaxLFQ

Jürgen Cox
Sep 1, 2014; 13:2513-2526
Technological Innovation and Resources




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Stable Isotope Labeling by Amino Acids in Cell Culture, SILAC, as a Simple and Accurate Approach to Expression Proteomics

Shao-En Ong
May 1, 2002; 1:376-386
Research




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Reply to Cosgrove: Non-enzymatic action of expansins [Letters to the Editor]

In our computational study, we use molecular simulations to substantiate a hypothetical mechanism for glycosidic bond cleavage in the presence of a single catalytic acid at the active site of the mutant D10N HiCel45A. In addition to discussing this plausible mechanism from the context of structurally related MltA lytic transglycosylase and subfamily C GH45s, we also suggest the implications of the plausible mechanism for our current understanding of the action of expansins and lytic transglycosylases. As correctly pointed out by Professor Cosgrove (1), there is large body of evidence, a significant portion of which was regrettably not discussed in our paper, that suggests that expansins are incapable of lytic action on polysaccharide substrates. Whereas these insights do not change the results or the conclusions of our article, we would like to thank Professor Cosgrove for these additional insights. In particular, our main point with respect to expansins is that our results suggest the possibility that expansins are capable of nonhydrolytic lytic activity. Our intention was not to suggest this was the mechanism of expansins, but that it should be considered based on our results and the similarity of the active sites.The molecular mechanisms of how expansins enable cell wall expansion remains to be fully understood. Whereas our proposed mechanism resulting in the formation of the 1,6-anhdro product might be found in expansins and might contribute to the mode of action of expansins, we would like to emphasize that the intent of this study was only to suggest this as a...




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Non-enzymatic action of expansins [Letters to the Editor]

From their simulations of endoglucanase Cel45A, Bharadwaj et al. (1) propose that structurally related expansins and MltA may cut glycan backbones without generating reducing ends. This is tenable for MltA, a peptidoglycan lytic transglycosylase whose action produces nonreducing 1,6-anhydro products, but is untenable for expansins.Expansins loosen plant cell walls and induce wall expansion. Contrary to the assertion by Bharadwaj et al., the conclusion that expansins are not lytic is not merely based on lack of new reducing ends but is supported by multiple (negative) tests for polysaccharide cleavage that do not rely on detection of reducing ends. At least eight studies with three divergent groups of expansins document this point. For instance, α-expansin did not reduce the viscosity of various wall polysaccharide solutions, an endolytic assay that does not rely on measuring reducing ends (e.g. see Ref. 2 and other studies).Walls treated with α-expansin did not release saccharide fragments, measured by pulsed amperometric detection, which can detect nonreducing saccharides (3).In the case of β-expansins, protein treatments did not cleave the backbones of a wide range of dye-coupled cross-linked wall polysaccharides; nor did they cleave backbones of polysaccharides extracted from plant cell walls, measured by gel permeation chromatography (4).For five microbial expansins, tests with a range of dye-coupled cross-linked polysaccharides likewise did not detect lytic activity (e.g. see Ref. 5). Thus, extensive published evidence argues against lytic action by expansins, as proposed by Bharadwaj (1), and attempts to identify 1,6-anhydro products seem unlikely to succeed.




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The hibernating 100S complex is a target of ribosome-recycling factor and elongation factor G in Staphylococcus aureus [Protein Synthesis and Degradation]

The formation of translationally inactive 70S dimers (called 100S ribosomes) by hibernation-promoting factor is a widespread survival strategy among bacteria. Ribosome dimerization is thought to be reversible, with the dissociation of the 100S complexes enabling ribosome recycling for participation in new rounds of translation. The precise pathway of 100S ribosome recycling has been unclear. We previously found that the heat-shock GTPase HflX in the human pathogen Staphylococcus aureus is a minor disassembly factor. Cells lacking hflX do not accumulate 100S ribosomes unless they are subjected to heat exposure, suggesting the existence of an alternative pathway during nonstressed conditions. Here, we provide biochemical and genetic evidence that two essential translation factors, ribosome-recycling factor (RRF) and GTPase elongation factor G (EF-G), synergistically split 100S ribosomes in a GTP-dependent but tRNA translocation-independent manner. We found that although HflX and the RRF/EF-G pair are functionally interchangeable, HflX is expressed at low levels and is dispensable under normal growth conditions. The bacterial RRF/EF-G pair was previously known to target only the post-termination 70S complexes; our results reveal a new role in the reversal of ribosome hibernation that is intimately linked to bacterial pathogenesis, persister formation, stress responses, and ribosome integrity.




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SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation [Protein Synthesis and Degradation]

SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes.




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{gamma}-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion [Signal Transduction]

Hypersecretion of glucagon from pancreatic α-cells strongly contributes to diabetic hyperglycemia. Moreover, failure of α-cells to increase glucagon secretion in response to falling blood glucose concentrations compromises the defense against hypoglycemia, a common complication in diabetes therapy. However, the mechanisms underlying glucose regulation of glucagon secretion are poorly understood and likely involve both α-cell–intrinsic and intraislet paracrine signaling. Among paracrine factors, glucose-stimulated release of the GABA metabolite γ-hydroxybutyric acid (GHB) from pancreatic β-cells might mediate glucose suppression of glucagon release via GHB receptors on α-cells. However, the direct effects of GHB on α-cell signaling and glucagon release have not been investigated. Here, we found that GHB (4–10 μm) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca2+ and cAMP in mouse α-cells. Glucagon secretion from perifused mouse islets was also unaffected by GHB at both 1 and 7 mm glucose. The GHB receptor agonist 3-chloropropanoic acid and the antagonist NCS-382 had no effects on glucagon secretion and did not affect stimulation of secretion induced by a drop in glucose from 7 to 1 mm. Inhibition of endogenous GHB formation with the GABA transaminase inhibitor vigabatrin also failed to influence glucagon secretion at 1 mm glucose and did not prevent the suppressive effect of 7 mm glucose. In human islets, GHB tended to stimulate glucagon secretion at 1 mm glucose, an effect mimicked by 3-chloropropanoic acid. We conclude that GHB does not mediate the inhibitory effect of glucose on glucagon secretion.




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12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2{gamma} knockout [Signal Transduction]

The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions.




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Reduction of protein phosphatase 2A (PP2A) complexity reveals cellular functions and dephosphorylation motifs of the PP2A/B'{delta} holoenzyme [Enzymology]

Protein phosphatase 2A (PP2A) is a large enzyme family responsible for most cellular Ser/Thr dephosphorylation events. PP2A substrate specificity, localization, and regulation by second messengers rely on more than a dozen regulatory subunits (including B/R2, B'/R5, and B″/R3), which form the PP2A heterotrimeric holoenzyme by associating with a dimer comprising scaffolding (A) and catalytic (C) subunits. Because of partial redundancy and high endogenous expression of PP2A holoenzymes, traditional approaches of overexpressing, knocking down, or knocking out PP2A regulatory subunits have yielded only limited insights into their biological roles and substrates. To this end, here we sought to reduce the complexity of cellular PP2A holoenzymes. We used tetracycline-inducible expression of pairs of scaffolding and regulatory subunits with complementary charge-reversal substitutions in their interaction interfaces. For each of the three regulatory subunit families, we engineered A/B charge–swap variants that could bind to one another, but not to endogenous A and B subunits. Because endogenous Aα was targeted by a co-induced shRNA, endogenous B subunits were rapidly degraded, resulting in expression of predominantly a single PP2A heterotrimer composed of the A/B charge–swap pair and the endogenous catalytic subunit. Using B'δ/PPP2R5D, we show that PP2A complexity reduction, but not PP2A overexpression, reveals a role of this holoenzyme in suppression of extracellular signal–regulated kinase signaling and protein kinase A substrate dephosphorylation. When combined with global phosphoproteomics, the PP2A/B'δ reduction approach identified consensus dephosphorylation motifs in its substrates and suggested that residues surrounding the phosphorylation site play roles in PP2A substrate specificity.




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Biophysical characterization of SARAH domain-mediated multimerization of Hippo pathway complexes in Drosophila [Signal Transduction]

Hippo pathway signaling limits cell growth and proliferation and maintains the stem-cell niche. These cellular events result from the coordinated activity of a core kinase cassette that is regulated, in part, by interactions involving Hippo, Salvador, and dRassF. These interactions are mediated by a conserved coiled-coil domain, termed SARAH, in each of these proteins. SARAH domain–mediated homodimerization of Hippo kinase leads to autophosphorylation and activation. Paradoxically, SARAH domain–mediated heterodimerization between Hippo and Salvador enhances Hippo kinase activity in cells, whereas complex formation with dRassF inhibits it. To better understand the mechanism by which each complex distinctly modulates Hippo kinase and pathway activity, here we biophysically characterized the entire suite of SARAH domain–mediated complexes. We purified the three SARAH domains from Drosophila melanogaster and performed an unbiased pulldown assay to identify all possible interactions, revealing that isolated SARAH domains are sufficient to recapitulate the cellular assemblies and that Hippo is a universal binding partner. Additionally, we found that the Salvador SARAH domain homodimerizes and demonstrate that this interaction is conserved in Salvador's mammalian homolog. Using native MS, we show that each of these complexes is dimeric in solution. We also measured the stability of each SARAH domain complex, finding that despite similarities at both the sequence and structural levels, SARAH domain complexes differ in stability. The identity, stoichiometry, and stability of these interactions characterized here comprehensively reveal the nature of SARAH domain–mediated complex formation and provide mechanistic insights into how SARAH domain–mediated interactions influence Hippo pathway activity.




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Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2 [Signal Transduction]

The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, here we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity.




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Five Foreign Policy Questions for the UK’s Next Prime Minister

18 June 2019

Thomas Raines

Director, Europe Programme
Even if most don’t get to vote in the Conservative leadership election, the public deserves serious answers on the foreign policy plans of those who want to lead the country.

2019-06-18-10D.jpg

10 Downing Street. Photo: Getty Images.

In a month’s time, the UK will have a new prime minister. The campaign has been dominated by candidates’ views on how to deliver Britain’s withdrawal from the EU by October, alongside some discussion of domestic issues.

But relatively little has been said about international affairs, despite the fact that foreign policy questions are becoming a more partisan issue and Britain is facing crucial questions around Brexit and the wider international context. These will be waiting for whoever finds themselves in Number 10 on 22 July. 

1. How can Britain influence Europe from outside the EU?

Theresa May was fond of saying that Britain is leaving the EU but not leaving Europe. Britain cannot change its geography. It will continue to share many strategic and security interests with the rest of the continent, but it will be outside of Europe’s central political and economic project. A new PM will not only have to negotiate Britain’s new relationship with the EU, but also think about how to influence it as a third country.

An aspect of this will be finding a new way to work with the EU on foreign, security and defence policy that meets the need for autonomy on both sides. How deep this relationship is or how institutionalized it will be is yet to be negotiated and can be shaped by the next PM.

The UK needs to decide how ambitiously it wants to engage with the new defence agenda in the EU (particularly its industrial components), and how to balance these with key bilateral relationships like France and Germany. Amid uncertainty about American security guarantees and Russian aggression, the next PM must also consider what Britain’s security role in Europe should be and NATO’s place within that.

Beyond conventional foreign policy issues, Britain is also going to be heavily shaped and influenced by the rule-making power of the EU, and how the world’s largest market regulates itself, from energy to financial services, consumer products and the environment.

The UK will need a strategy to influence the EU from the outside – something Swiss, Norwegians and Americans will acknowledge is no easy feat. This could include significantly increasing its diplomatic footprint across Europe, working closely with the UK’s private and non-profit sectors, utilizing Britain’s technical expertise in areas like sanctions, and creating new ad hoc groupings to share perspectives and ideas, building on examples like the Northern Future Forum

2. Should Britain do business with President Trump?

President Trump represents a fundamental challenge to Britain: an American president whose belligerent unilateralism runs counter to many of Britain’s foreign policy objectives. His frequent and often shameless diplomatic faux pas – from proposing Nigel Farage be the British ambassador to his dog-whistle attacks on the mayor of London – are compounded by real differences of substance on issues like trade, climate change and nuclear non-proliferation.

A new prime minister must decide how to manage relations with the US administration, whether to challenge or condemn a US president when he acts against Britain’s interests, or use flattery or quieter diplomacy to seek to influence him. Theresa May’s strategy of staying politically close to the president and playing to his ego has yielded little in policy terms, though other world leaders have fared little better.

A new PM will face some uncomfortable choices. Will they continue to defend the Iran nuclear deal alongside European allies while the US continues to undermine it? Do they believe a trade deal with America is desirable or achievable with the current administration, and what are they willing to sacrifice to achieve it? Is the American security guarantee for Europe secure with Donald Trump as president? Judgements on these questions should inform Britain's wider strategy, and its objectives for a future relationship with the European Union.

3. Should Britain prioritize economics or security in its relations with China?

Britain faces its own version of the challenge that many countries face – how to balance the economic and investment benefits of a positive relationship with China with concerns about repressive domestic politics and a more assertive Chinese role regionally and globally. This tension has become more acute for two reasons.

First, the economic dislocation of leaving the EU may create a greater reliance on Chinese trade and investment. China is already a major investor in the UK. If Brexit proves to be disorderly, Britain’s need may be all the greater (though China faces economic headwinds as well). Some in Brussels even fear that the economic difficulties of Brexit may make the UK a soft touch for emerging powers from which it seeks inward investment and market access.

Second, the deterioration in US–China relations means the UK may come under increasing pressure from the United States to take a tough line with China. The controversy over Huawei’s role in delivering 5G networks may become a more regular feature of transatlantic debates, with Britain facing Chinese economic pressure on one side and a squeeze from America over security issues on the other, without the weight of the EU behind it.  

A new prime minister should consider whether the UK’s interests are served by a security role in east Asia, and whether it has the capability to play one.

The UK remains a party to the Five Power Defence Arrangements. The Royal Navy has conducted freedom of navigation exercises in the South China Sea, prompting a rebuke from Beijing. It has also taken steps to deepen security ties with Japan.

But the UK government has struggled to present a coherent position. Some cabinet ministers have sought to open doors to the Chinese market at the same time as others announced their intentions to send aircraft carriers to the Pacific. The next PM will need to find a balance between China and the US, or accept the consequences of more directly taking sides on disputes about trade, technology, and security.

4. How can the contradictions between UK foreign and domestic policy be reconciled?

One of the many problems with the vague and unhelpful slogan ‘Global Britain’ is how it jars with many aspects of domestic policy. This incoherence reduces Britain’s foreign policy credibility and effectiveness.

Britain has actively supported the UN-led Yemen peace process while continuing to support Saudi Arabia’s military campaign through arms sales. Britain wants to build a new ambitious independent trade policy while restricting the migration that is crucial for services trade. British foreign secretaries trumpet the UK’s soft power while the Home Office deports members of the Windrush generation, bungles EU citizenship applications and sets unreasonable burdens for many people seeking visas simply to visit the country.

Global universities are celebrated while international students had their post-study visas cut (a policy that sensibly is likely to be reversed). Britain advocates international tax compliance and transparency while not taking robust steps to regulate the tax haven role played by crown dependencies and overseas territories.

A new prime minister has the chance to get to grips with these inconsistencies and develop foreign and domestic policies which are more coherent and self-re-enforcing.

5. At what level should Britain’s international ambitions be funded?

Successive governments have celebrated the fact the UK is the only Western country to spend 2% of GDP on defence and 0.7% on development. However, this masks some real pressures in the system.

There are significant problems in the defence budget and a growing gap between commitments and committed funds. Meanwhile, the funding of Britain’s diplomacy has been cut by successive governments – Labour, Conservative and coalition – for much of the last 20 years. Numerous bodies have highlighted the problems facing the overstretched and underfunded Foreign Office. Where would defence and diplomacy sit in the new prime minister’s hierarchy of priorities?

The problem is not purely one of funding, but the gap between ambitions, rhetoric and resources. It is not sustainable for British ministers to trumpet Britain’s global ambitions while not properly funding the tools of its influence abroad.

It would be reasonable and understandable for a new prime minister to adjust that ambition and tone down the rhetoric, or alternatively to address resource pressures by investing in diplomacy and defence. But that choice should be informed by a sober reflection on Britain’s international position and interests as it leaves the EU. Brexit offers a chance to revisit assumptions that have guided British policy for a generation. A new prime minister should seize this opportunity.

A realistic vision for the future

All these issues will be more pronounced if the UK leaves the EU with no deal at the end of October. ‘No deal’ would be not simply an economic shock but a diplomatic rupture that will colour the UK’s capacity to negotiate a new relationship with the EU, which will be the first order of business after a ‘no deal’ exit. Trust will be in short supply.

Even if they don’t get to vote on the new prime minister, the public deserves serious answers to these and other questions from the men who want to lead the country. Not the platitudes of ‘Global Britain’ or a reflexive and unexamined British exceptionalism, but a serious, realistic assessment of how Britain will cope with the disruptions of leaving the EU and how it might thrive outside the regional bloc it has been a part of for more than 45 years.




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EU Security Ambitions Are Hostage to the Brexit Process

25 June 2019

Professor Richard G Whitman

Associate Fellow, Europe Programme
The EU faces a fundamental contradiction in its goals to become more strategically autonomous in defence matters.

2019-06-20-Eurocorps.jpg

Soldiers of a Eurocorps detachment raise the EU flag at the European Parliament in Strasbourg. Photo: Getty Images.

Three years ago, as the UK was holding its referendum on Brexit, the EU was rolling out its Global Strategy for a more cohesive and effective security and defence policy. Since then, EU member states have set impressive goals and, as significantly, taken important practical steps to make an EU defence capability a tangible proposition, despite differing collective defence commitments, traditions of neutrality among some member states and very different strategic cultures.

All of these developments have taken place with the UK as reluctant observer. The UK has been traditionally hostile to a deepening of defence collaboration within the EU (and consistent of the view that Europe’s military security was best provided through NATO). But the Brexit referendum vote has placed the UK as a bystander as EU security and defence initiatives have been pursued which have overridden the past red lines of British governments.

There is, however, a Brexit-related paradox in all these developments.

A central goal of the security and defence-related aspects of the EU Global Strategy is for the EU to have the capacity to act independently of the United States and, through indigenous defence industries, the ability to produce the means to make that possible.

With the UK outside the EU, and its opposition absent, it is easier to create a political consensus to push for more defence integration. But without the UK there are diminished collective defence capabilities which would make European strategic autonomy much harder to achieve.  

The May government has been an enthusiast for preserving close security and defence cooperation with the EU. The Withdrawal Agreement and the Political Declaration both seek to provide for a close EU–UK relationship post-Brexit.

However, the Article 50 negotiations have made clear that the EU’s institutions are hostile to special treatment for the UK beyond that normally accorded to a third country. Disagreements over the terms of the UK’s continuing participation in the Gailleo dual-use satellite system, which has a significant security and defence utility, have signalled that there is a strong lobby in Brussels and some national capitals seeking to significantly circumscribe collaboration with Britain.

The scale and capabilities of the UK’s military, its defence expenditure (notably on defence research and development) and its defence industrial base make any British decoupling from the EU’s security and defence a major issue. Disconnecting the UK from EU developments entirely would be a costly political choice for both sides.

And excluding the UK from new initiatives in defence R&D and new defence procurement arrangements would be suboptimal in delivering a stronger European defence, technological and industrial base. Duplicating existing UK capabilities, especially strategic enablers such as strategic airlift, target acquisition and intelligence, surveillance and reconnaissance capabilities, would be an unnecessary squandering of already hard-pressed European defence budgets.

At present the common procurement and defence industry plans driven by the EU Global Strategy are embryonic. And significant defence capability decisions are taking place detached from the EU’s plans, which could reinforce a divide between the UK and other member states.

As illustrative, the formal agreement this week between France, Germany and Spain on the Future Combat Air System (FCAS) to develop a next-generation stealth fighter is competing with the UK-supported Tempest project that shares the same objective. The 20-year timescales for the delivery of the FCAS and Tempest projects are a reminder that defence procurement decisions are of multi-decade significance.

As the EU’s ambitions are nascent, it is too early to fully assess what might be the impact of any decision by the EU and the UK to keep each other at an arms-length in security and defence cooperation. With a more detached relationship, the UK will have significant concerns if it sees the EU’s common procurement arrangements develop in a manner that actively discriminates against the UK defence industry.

Outside of procurement and defence issues there may be other areas of future concern for the UK – for example, the extent to which the EU might deepen and broaden cooperation with NATO in a manner that makes the collective influence of EU member states within NATO more apparent, or to which the footprint of future EU conflict and security activities in third countries starts to overshadow the activities of the UK.

As the UK has been grappling with Brexit domestically, the EU has been evolving its security and defence policy ambitions. These are developments that will impact on the UK and in which, therefore, it has a stake but as a departing member state it has a weakening ability to shape.

Any aspect of future EU–UK cooperation is hostage to the vagaries of how the Brexit endgame concludes.




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Brexit, Party Politics and the Next Prime Minister

Invitation Only Research Event

15 July 2019 - 8:30am to 9:30am

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Daniel Finkelstein OBE, Associate Editor, The Times; Conservative Member of the House of Lords; Chairman, Onward 
Chair: Thomas Raines, Head, Europe Programme, Chatham House

With the new leader of the Conservative party due to be announced on 23 July, what are the prospects for the party and the country?

On Brexit, the new prime minister faces most of the same challenges and constraints as Theresa May. The leadership contenders have outlined their ambitions for a revised deal, but with the EU insisting negotiations are over, their room for manoeuvre appears to be limited. Furthermore, even with a new leader at the helm, important divisions remain among voters about what shape Brexit and the future UK-EU relationship should take. If the EU won’t change the deal, and parliament won’t accept it, how can the deadlock be broken? Is a 'No Deal' Brexit politically deliverable? Or could there be a general election later in 2019? Can the Conservative party survive a pre-Brexit election intact?

Beyond Brexit, what are the other choices, in both domestic and foreign policy, facing the next prime minister? How might the decisions he makes affect the future of the party and British politics more broadly?

In this session, the speaker will share his reflections on the likely result of the leadership election, and what lies beyond it.

Attendance at this event is by invitation only.

Event attributes

Chatham House Rule

Alina Lyadova

Europe Programme Coordinator




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The Future of Brexit, Britain and Boris

Invitation Only Research Event

17 October 2019 - 8:30am to 9:30am

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Philip Rycroft, Permanent Secretary, Department for Exiting the EU (2017-19)
Chair: Tom Raines, Head, Europe Programme, Chatham House

Once again, Brexit is reaching an important juncture. The European Council on 17 October is seen by many as the last chance for Britain to secure a withdrawal deal or another delay. With parliament and government at loggerheads, it is far from clear what happens at the end of October.
 
In a discussion taking place on the day of the European Summit, the speaker will share his insights on the future of negotiations between the UK and the EU under different scenarios. How do the EU and the UK repair relations after 'No Deal'? Should a withdrawal deal be agreed, what does the second phase of negotiations look like and what lessons can Whitehall draw from phase one? And if there is another delay, what will change over the course of the next three months?
 
Please note attendance at this event is by invitation only and places are now full. 

Event attributes

Chatham House Rule

Alina Lyadova

Europe Programme Coordinator




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Britain, the EU and the Power of Myths: What Does Brexit Reveal about Europe?

Invitation Only Research Event

14 November 2019 - 8:30am to 9:30am

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Kalypso Nicolaïdis, Professor of International Relations, Faculty Fellow, St Antony’s College, University of Oxford; Author, Exodus, Reckoning, Sacrifice: Three Meanings of Brexit
Chair: Hans Kundnani, Senior Research Fellow, Europe Programme, Chatham House

When we look back on Brexit, what will it tell us about Europe? Will it simply be that an insular UK was always different and destined to never fit in? Will it be that the UK's decision to leave revealed deeper problems with the EU? Or will it be that the threat created by the UK's withdrawal united the continent and saved the European project?

The speaker will explore Brexit through the prism of biblical and ancient Greek mythology. She will examine the reasons behind Britain’s decision to leave the EU and imagine a ‘better Europe’ that has learnt the lessons of the past and reconciled the divisions exposed by the Brexit vote. How can the EU reinvent itself and re-engage its citizens? And where does a post-Brexit UK fit?

Attendance at this event is by invitation only. 

Event attributes

Chatham House Rule

Alina Lyadova

Europe Programme Coordinator




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Reflections on the Brexit Election

Invitation Only Research Event

6 December 2019 - 8:30am to 9:30am

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Alistair Burt, Conservative Member of Parliament (1983-97 and 2001-19); Minister of State for the Middle East, UK Foreign & Commonwealth Office and Minister of State at the Department for UK International Development (2017-19)

On 12 December 2019, the United Kingdom will hold one of its most crucial elections in the 21st century. The result will have a direct impact on the Brexit process and will most likely determine the country’s future direction for years to come.  

Yet the final outcome is far from predictable. It seems quite certain that the 2019 election is unlikely to produce a clear two-party share of the vote as happened back in 2017. Public trust in politicians is low and party loyalty is looser than ever. Polls show that Brexit it overwhelmingly considered as the main issue among the electorate alongside a deep concern about the future of public services. This raises multiple questions: can the 2019 election represent a chance to unite the country and move on? Will cross-party identities of ‘Leavers’ and ‘Remainers’ translate to how people vote in the election? And what will the outcome mean for Brexit and the future of party politics in Britain? 

Attendance at this event is by invitation only. 

Event attributes

Chatham House Rule

Alina Lyadova

Europe Programme Coordinator