The Future of Investment Dispute Settlement Regimes 30 June 2020 — 2:00PM TO 3:30PM Anonymous (not verified) 9 February 2021 Online

This event is part of the Inclusive Governance Initiative, which is examining how to build more inclusive models and mechanisms of global governance fit for purpose in today’s world.

Is an ‘atomized’ approach to cross-border investment dispute resolution inevitable? Has the multiplicity of mechanisms helped or hindered inclusivity in and transparency in governance? Is there a need for, and scope to, increase the international coordination of dispute resolution mechanisms? If so, what form should it take? What could be the implications for international economic law?

Insights from Climate Policy: Engaging Subnational Governments in Global Platforms 10 June 2020 — 2:45PM TO 6:00PM Anonymous (not verified) 9 February 2021 Online

How have subnational governments shaped the global agenda and created momentum on climate change where national and international governance processes could not?

Can these advances be converted into meaningful collaboration channels for policy development? What works, or does not, when it comes to engagement with multilateral negotiation processes? What ingredients are necessary for success? What are the broader implications of these trends for inclusivity and innovation in international governance?

This event is part of the Inclusive Governance Initiative, which is examining how to build more inclusive models and mechanisms of global governance fit for purpose in today’s world.

Innovating Governance: Examples from the Digital Arena 25 February 2020 TO 26 February 2020 — 10:00AM TO 11:30AM Anonymous (not verified) 9 February 2021 Chatham House

The Inclusive Governance Initiative is launched with this roundtable on digital governance.

The Inclusive Governance Initiative, a centenary project which is examining how to build more inclusive models and mechanisms of global governance fit for purpose in today’s world, is launched with this roundtable on digital governance.

The event brings together a diverse and multidisciplinary group of leading experts to consider where and how early initiatives around governance of the digital sphere have succeeded – or not – and how they are evolving today.

The conversation will include the debate between multilateral and multi-stakeholder approaches, the opportunities and challenges of collective non-binding commitments, and converting civil society collaboration into policy contribution.

The Implication of Greater Use of Investment Screening 26 June 2020 — 9:00AM TO 10:30AM Anonymous (not verified) 11 February 2021 Online

What is driving the trend towards greater use of investment screening by nation states and regional economic groupings?

• How is the COVID-19 crisis affecting this trend?
• What will the economic implications be?
• Will this help or hinder inclusivity and transparency in investment governance?
• Is there a role for international safeguards and/or international coordination of national/regional approaches to investment screening?

This event is part of the Inclusive Governance Initiative, which is examining how to build more inclusive models and mechanisms of global governance fit for purpose in today’s world.

Rebuilding trust is central to the UN’s future Expert comment NCapeling 25 March 2021

António Guterres is under scrutiny as he prepares to report on the future of the United Nations, with a renewed focus on trust, resilience and prevention.

The United Nations Secretary-General’s inbox is full as his organization celebrates its 75th anniversary. Trust must be rebuilt amid increased geo-political rivalry, North-South divisions, and sceptical citizens left behind by globalization. The international community has manifestly underinvested in institutional resilience and prevention. Better partnerships are needed with the private sector, and innovative forms of cross-regional cooperation fostered.

There are positive signs UN member states want things to change. They unanimously agreed a Political Declaration last September strongly reaffirming multilateralism, and they gave António Guterres one year to present a roadmap on how to respond, ‘building back better’ in the face of climate change and COVID-19.

A key challenge is to steer mandates and resources towards prevention. The World Bank-WHO Global Preparedness Monitoring Board, which eerily predicted the pandemic in its inaugural report in September 2019, reminds us successful prevention rests not on warning alone, but on aligned incentives for early action.

Geopolitical tensions persist

China has invested significantly in the multilateral system over the last decade, both in formal organizations such as the UN and the African Union, and in fostering a set of China-centred ‘mini-lateral’ fora such as the SCO, BRICS and BRI. It has also deepened its ties with Russia in the UN Security Council. Western countries both begrudgingly admire and deeply distrust China’s nimbleness in advancing its interests and values in this way but are divided on how to respond.

The Biden administration has recommitted itself to multilateral processes but US bilateral relations are likely to remain the main foreign policy driver. The UK has sought to convert the G7 into an enlarged summit-level meeting for democracies but Europe is divided over the wisdom of formalizing a group which may increase divisions with China, and some major democracies – India for example – have divergent approaches on issues such as trade protection.

An increase in cross-regional informal caucusing within the UN system to advance norms and progress around specific common objectives is likely. Guterres can encourage smaller powers to become ‘bridge builders’ sitting in the middle of a ‘Venn diagram’ of such new member state constellations at the UN.

Guterres can also build on the recent Abraham Accords to encourage cross-regional cultural, political and security relationships on the back of trade and investment, and map practical opportunities for strategic cooperation between China and the West in health and food security, climate and biodiversity, and global macroeconomic management, while fostering new normative frameworks to manage strategic competition in artificial intelligence (AI), big data, cyber resilience, gene-editing, and automation.

North-South mistrust

Realizing the Sustainable Development Goals (SDGs) and climate objectives rests in part in mobilizing the expertise and resources of sub-state actors such as business and city and regional authorities. However, developing countries remain wary of granting the UN Secretary-General a greater role in fostering partnerships with the private sector and mobilizing private finance, out of fear this may overshadow the global North’s promises to provide aid and create fairer trade and debt conditions.

In addition, African governments are expressing growing frustration at their continued lack of ‘agency’ in UN decision-making, the reneging of promises on climate financing by the global North, and the slow rollout of the COVAX facility to developing countries.

Progress may lie in two areas. First, developing country leadership of initiatives – such as the Friends Group on SDG financing established by the Jamaican and Canadian ambassadors to the UN – can help build trust and allay concerns, which is vital to incentivise transformative investment by sovereign wealth, pension, and insurance funds in pro-poor low carbon infrastructure in developing countries.

The second area is curating multi-stakeholder initiatives outside the UN framework and then linking them back to the organization once they have proven to be beneficial to both developed and developing countries. Successful initiatives such as the Vaccine Alliance can be a model of how to do this while not detracting from state obligations.

Scepticism among citizens

Trust in governance also needs rebuilding at the level of the individual citizen. Mobilized by populist movements and ‘fake news’ online, individuals left behind by the uneven economic benefits of globalization view governments and international organizations as unaccountable and lacking their interests at heart.

Guterres has called for a new ‘social contract’ between governments and their citizens, and for ‘Multilateralism 2.0’ to demonstrate a practical ‘hard interest’ as well as a ‘values’ case for why international cooperation inclusively benefits individuals as well as states. And technological innovation can also help citizens hold governments to account. As the first Secretary-General with a science and engineering background, Guterres has championed how technology enhances UN delivery of its objectives.

The pairing of artificial intelligence (AI) with satellites and drones for geospatial insight has been pioneered by both the United Nations Environment Programme (UNEP) and the Food and Agriculture Organization (FAO) to help communities preserve ecosystems and agricultural productivity. The resultant data, accessible on smart phones and computers, enables civil society to measure governments’ promises against real-time progress, through monitoring greenhouse gas emissions from power stations.

Alongside trust and accountability, fostering inclusiveness is likely to be central to Guterres’ report as he navigates how the UN can legitimize multi-stakeholder partnerships, enhance transparency, and bring coherence to diverse ‘mini-lateral’ initiatives.

These themes are explored further in the forthcoming synthesis paper ‘Reflections on building more inclusive global governance: Ten insights into emerging practice’

Geopolitical shifts and evolving social challenges – what role for human rights? 29 June 2021 — 3:00PM TO 4:30PM Anonymous (not verified) 10 June 2021 Online

Speakers reflect on some of the key themes that will influence the future of human rights.

Please click on the below link to confirm your participation and receive your individual joining details from Zoom for this event. You will receive a confirmation email from Zoom, which contains the option to add the event to your calendar if you so wish.

Shifts in geopolitical power and the rise of authoritarianism are disrupting the dynamics for making progress on human rights globally.

At the same time, the relevance of the global human rights framework is being called into question by some of our most acute social challenges – rapidly evolving technology, deepening inequality and the climate crisis.

Chatham House’s Human Rights Pathways project is exploring how alliances, strategies and institutions are adapting, and will need to evolve, to strengthen human rights protection in this increasingly contested and complex global environment.

At this panel event speakers reflect on some of the key themes that will influence the future of human rights, including the long-term impacts of the pandemic, the place of human rights diplomacy in the new geopolitics, the relevance of human rights to social movements, and the potential of human rights law to galvanise efforts on urgent challenges such as the climate crisis.

Influence of soft law grows in international governance Expert comment NCapeling 17 June 2021

Soft law is increasingly being used by policymakers to enable greater cooperation and inclusivity, and its role is here to stay in creating effective regimes.

As the UK government’s recent Integrated Review points out, international law-making in a fragmented international order is becoming increasingly difficult.

Geopolitical tensions, and the length of time required to agree multilateral treaties – typically decades – make it challenging to reach binding agreements in complex and fast-evolving policy areas such as climate change and technology governance.

As a result, the regulation of international behaviour through soft law – meaning non-binding instruments such as principles, codes of conduct or declarations – is starting to assume greater significance. And states increasingly find soft law-making attractive because there are relatively fewer decision costs involved.

Soft law also lays the ground for the possibility of transforming into hard law if, over time, its principles become widely accepted and it is evident states are treating them as legal obligations. And the emergence of a hybrid of both soft and hard law components in treaties has started to develop in recent years, such as the Paris Agreement on Climate Change.

Opening access to global governance

A major attraction of soft law-making is that it provides for non-traditional, non-state actors to take part in the process of global governance. Non-governmental organizations (NGOs), social movements, corporate sector, and individuals are more easily drawn into soft law-making compared to treaties, to which only states can be party.

This holds out the promise for greater inclusiveness in global rulemaking and governance, but soft law processes also pose many challenges. Soft law provides an avenue for states to avoid legal obligations on important subjects and developing rules in such an informal manner can lead to fragmentation and a lack of coherence in the international system.

As noted in dialogues held under Chatham House’s Inclusive Governance Initiative, some areas of international interaction require hard law, such as economic competition, certain international security issues, and aspects of the global commons. In these areas, soft law is just not appropriate or enough.

Soft law measures such as codes of conduct may be useful in rapidly developing areas such as technology, as they are more flexible and adaptable than hard law. And they may be particularly effective if used in conjunction with binding regulation, and subject to monitoring and enforcement by a regulator, as in recent proposals by the European Union (EU) for a Digital Services Act.

The Chatham House Inclusive Governance Initiative report highlights that the proliferation of soft law does not necessarily have to compete with the existing system of hard law, so long as soft law solutions do not conflict with, or undermine, hard law such as existing treaty provisions.

Case study: Business and human rights

The UN Guiding Principles on Business and Human Rights (UNGPs) are an interesting example of both the promise of soft law-making, and its challenges. Officially adopted by the UN General Assembly in 2011, the UNGPs set out the global standard of what is expected of companies as regards human rights due diligence (HRDD) to prevent and address business-related human rights harms.

The sections on HRDD in the UNGPs have been constructed as a non-binding ‘social’ standard of conduct, though with the expectation that this would eventually be reinforced through a “smart mix” of both soft law and hard law initiatives. Arguments in favour of the predominantly soft law approach at the time – subsequently borne out in practice – were that this would encourage a higher level of participation, by states and businesses in particular, and better foster creativity and innovation in a still-developing field.

The UNGPs recognize and reinforce the importance of meaningful and inclusive stakeholder engagement for both the credibility and legitimacy of processes, and for the quality of substantive outcomes. The Ruggie process which led to the UNGPs, drew extensively from a wide range of stakeholder engagement processes covering many different jurisdictions and all UN regional groupings. The importance of deep and inclusive stakeholder engagement is also recognized in the mandate of the UN Working Group on Business and Human Rights.

The annual UN Forum on Business and Human Rights is one of the largest and most vibrant multi-stakeholder events in the UN calendar. Now in its tenth year, the forum provides an opportunity for an annual review by stakeholders – government, business and civil society – of past achievements in implementing the UNGPs and knowledge sharing on ways to address more persistent, underlying challenges.

Its relatively informal approach to agenda setting has, year on year, enabled an increasingly diverse array of stakeholder-organized sessions, supporting a ‘bottom up’ approach which raises awareness of under-reported issues and undervalued solutions.

In addition, while the UNGPs provide the substantive framework for discussion, flexible governance arrangements allow for rapid reorientation to respond to present and emerging crises, such as COVID-19 pandemic and climate change.

However, the sluggish responses of many companies, coupled with revulsion at reports of serious abuses in the value chains of many well-known brands, have prompted some governments to seek ways of translating some aspects of HRDD methodologies into binding legal standards. France passed a Corporate Duty of Vigilance Law in 2017 and Germany adopted a new law on supply chain due diligence in June 2021 which is to enter into effect on 1 January 2023. The European Commission is also working up proposals for an EU-wide regime to be unveiled in mid-2021.

Soft law versus hard law

At the international level, there are signs of divergence between those states which see value in persevering with the soft law route towards better regulation and corporate standards, and those which want to move as rapidly as possible to a hard law framework for business and human rights, enshrined in treaty, to improve domestic-level regulation and access to effective remedies.

Those supporting the hard law route – largely less industrialized states – received a boost in 2016 when the UN Human Rights Council mandated an Intergovernmental Working Group to explore options for a new treaty on business and human rights.

This initiative, known as the ‘treaty process’, has completed six rounds of negotiations. Despite the necessarily greater formality, these treaty negotiation sessions continue to emphasize the importance of stakeholder consultation. NGOs with ECOSOC status are invited to contribute views on the framing and content of draft treaty provisions immediately following the interventions by states, intergovernmental organizations and national human rights institutions, in that order.

The key question is whether this dynamism and inclusivity can be preserved as the transition is made from soft law to more binding approaches. Translating soft law standards into binding regimes inevitably means making hard choices, and different stakeholder groups have different views as to where legal lines should be drawn, how key concepts should be defined, and where the balance between legal certainty and flexibility should be struck.

The negotiations needed to strike an effective balance between competing objectives and needs can be challenging and time-consuming, as experiences with the treaty process have shown. But stakeholder demand for inclusive processes to help shape the law remains strong. Stakeholder groups clearly want a say in how the new EU-wide regime for ‘mandatory human rights due diligence’ will work in practice. A recent online ‘stakeholder survey’ garnered more than 400,000 responses.

Ultimately, the most effective domestic regimes are likely to be a mix of hard law standards supported by more flexible standards and guidance. Civil society organizations and trade unions will continue to have a multi-faceted role to play. Not only are they vital sources of expertise on human rights challenges connected to business activities, at home and abroad, they can also act as private enforcers of standards and advocates for affected people and communities.

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

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

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

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

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

Human rights policies and the online environment

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

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

International cooperation for human rights protection

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

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

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

Awareness of the interconnectivity of global problems

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

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

Capturing the next generation’s potential

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

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

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

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

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

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

Undercurrents: The Oversight Board's Trump decision, and Merkel's legacy Audio bhorton.drupal 25 June 2021

Was Facebook right to suspend Trump? And how will Merkel be remembered?

In the wake of the storming of Capitol Hill on 6 January 2021, social media platforms took steps to remove former President Donald Trump from their websites for infringing community standards. This step was welcomed by many, but also raised serious questions about the power of social media companies to limit free speech and censor elected officials. The suspension of President Trump from Facebook was referred to the Oversight Board, an independent body of experts set up to scrutinise the platform’s content moderation decisions.  

In this episode, Ben speaks to Thomas Hughes and Kate Jones about the outcome of the Oversight Board’s inquiry into the Trump suspension, and the wider implications for content moderation on social media.  

Then Lara is joined by Hans Kundnani to assess the political outlook in Germany and reflect on the legacy of outgoing Chancellor Angela Merkel.  

Strengthening Transatlantic Digital Cooperation

This project explores opportunities for increased cooperation via the transatlantic ‘tech triangle’ of the European Union, United Kingdom and United States.

This project serves as a cross-house initiative (involving the US and Americas Programme, the Europe Programme, the International Law Programme, the Digital Society Initiative and the International Security Programme).

Its long-term goal is to support the emergence of a global vision for technology governance: a vision drawing on democratic values and human rights principles. The project aims to extend the application of these principles to the digital space.

The first phase centres around a knowledge-exchange series, with findings and recommendations disseminated around targeted multilateral events such as G7, the United Nations General Assembly and the 2021 Internet Governance Forum.

Building on this exchange, the second phase will shift its focus to other democratic states and broaden digital cooperation dialogues from like-minded countries in the OECD, in addition to non-Western democracies and under-represented stakeholders from developing countries.

Counter-terrorism measures and sanctions: How to avoid negative consequences for humanitarian action? 9 September 2021 — 2:00PM TO 3:30PM Anonymous (not verified) 21 July 2021 Online

Exploring current endeavours to address the tensions between counter-terrorism measures, sanctions and humanitarian action.

Counter-terrorism measures  address broad forms of support to terrorist acts. Their expansion, internationally and domestically, has given rise to new points of friction with international humanitarian law. Unless the measures include adequate safeguards, they  can impede humanitarian action. Country-specific sanctions imposed for other objectives, such as ending conflicts or protecting civilians, raise similar challenges for humanitarian action. 

These problems are not new, but solutions at international and national level remain elusive. 

At this panel event, which marks the launch of a new Chatham House research paper, panellists explore current endeavours to address the tensions between counter-terrorism measures, sanctions and humanitarian action.

• What are the current dynamics and developments at Security Council level?  
• What are the opportunities now that the UK is developing its independent sanctions strategy? 
• What challenges do counter-terrorism requirements in funding agreements for humanitarian action  pose? 
• What is necessary to make progress?

Elizabeth Wilmshurst CMG appointed Honorary Queen’s Counsel News release jon.wallace 14 January 2022

Founder of the International Law Programme at Chatham House recognized for her major contribution to the law of England and Wales.

Elizabeth Wilmshurst CMG, distinguished fellow of Chatham House’s International Law Programme, has been awarded the title of Honorary Queen’s Counsel (QC Honoris Causa), recognizing her major contribution to the law of England and Wales, outside practice in the courts. The Lord Chancellor will preside over an appointment ceremony at Westminster Hall on 21 March 2022.

Elizabeth founded the International Law Programme at Chatham House and is an academic expert member of Doughty Street Chambers. She was a legal adviser in the United Kingdom diplomatic service between 1974 and 2003. Between 1994 and 1997 she was the Legal Adviser to the United Kingdom mission to the United Nations in New York. She also took part in the negotiations for the establishment of the International Criminal Court.

Throughout her career, Elizabeth has worked to strengthen the role of international law in reducing global tensions, addressing cross-border challenges and promoting individual liberty, including through influential publications at the Institute such as The Chatham House Principles of International Law on the Use of Force in Self-Defence. 

Robin Niblett CMG, Director and Chief Executive of Chatham House said:

‘We are delighted by this award which recognizes Elizabeth’s outstanding contribution to the field of international law, both in government and – on a continuing basis – through the International Law Programme at Chatham House.’

Challenges of AI Explainer jon.wallace 22 March 2022

What are the practical, legal and ethical implications of artificial intelligence (AI) and how can regulation help meet these challenges?

This article explains the challenges associated with the funding, development, supply and regulation of artificial intelligence (AI). It deals with narrow AI, that is systems and applications that are task-specific.

The article is not concerned with the concept of artificial general intelligence, or AGI, that is an AI which could meet and exceed the full capabilities of the human mind in the future.

Definition of AI

There is no universally accepted definition of AI, but in the UK’s Industrial Strategy White Paper, AI is defined as ‘technologies with the ability to perform tasks that would otherwise require human intelligence’. 

AI makes decisions using algorithms that either follow rules or, in the case of machine learning, review large quantities of data to identify and follow patterns. Because machine learning consists of multiple layers, and machines develop their own learning and patterns, it is opaque compared to traditional rule-following computing.

Today AI applications are common in many economic activities including online shopping and advertising, web search, digital personal assistants, language translation, smart homes and infrastructure, health, transport and manufacturing. 

Risks and benefits of AI

AI has the potential to bring huge advantages, for example in medical science, education, food and aid distribution, more efficient public transport and in tackling climate change. 

Used well, it could help humanity meet the UN’s 2030 Sustainable Development Goals and make many processes swifter, fairer and more efficient. It is a technology which is likely to be as transformative to human history as was the Industrial Revolution.

However, there are serious ethical, safety and societal risks associated with the rapid growth of AI technologies. 

Will AI be a tool that makes rich people richer? Will it exaggerate bias and discrimination? Will AI decision-making create a less compassionate society? Should there be limits to what decisions an AI system can take autonomously, from overtaking a car on the motorway to firing a weapon?

And if AI goes wrong – for example if a self-driving car has an accident – who should be liable? 

To ensure AI is used safely and fairly, up-to-date and rigorous regulation is needed. 

Regulation of AI

AI creates serious regulatory challenges due to the way it is funded, researched and developed.  

The private sector drives progress in AI, and governments mostly rely on big tech companies to build their AI software, furnish their AI talent, and achieve AI breakthroughs. In many respects this is a reflection of the world we live in, as big tech firms have the resources and expertise required.

However, without government oversight the future application of AI’s extraordinary potential will be effectively outsourced to commercial interests. That outcome provides little incentive to use AI to address the world’s greatest challenges, from poverty and hunger to climate change.

Government policy on AI

Currently governments are playing catch-up as AI applications are developed and rolled out. Despite the transnational nature of this technology, there is no unified policy approach to AI regulation, or to the use of data. 

It is vital that governments provide ‘guardrails’ for private sector development through effective regulation. But this is not yet in place, either in the US (where the largest amount of development is taking place) or in most other parts of the world. This regulation ‘vacuum’ has significant ethical and safety implications for AI. 

Some governments fear that imposing stringent regulations will discourage investment and innovation in their countries and lose them a competitive advantage. This attitude risks a ‘race to the bottom’, where countries compete to minimize regulation in order to lure big tech investment. 

The EU and UK governments are beginning to discuss regulation but plans are still at an early stage. Probably the most promising approach to government policy on AI is the EU’s proposed risk-based approach. It would ban the most problematic uses of AI, such as AI that distorts human behaviour or manipulates citizens through subliminal techniques. 

And it would require risk management and human oversight of AI that poses high risk to safety or human rights, such as AI used in critical infrastructure, credit checks, recruitment, criminal justice, and asylum applications.

Meanwhile, the UK is keen to see the establishment of an AI assurance industry that would provide kitemarks (or the equivalent) for AI that meets safety and ethical standards.

Despite these policy developments, there remain fundamental questions about how to categorize and apply risk assessments, what an AI rights-based approach could look like, and the lack of inclusivity and diversity in AI.

AI ethical issues

AI has serious ethical implications. Because AI develops its own learning, those implications may not be evident until it is deployed. The story of AI is littered with ethical failings: with privacy breaches, with bias, and with AI decision-making that could not be challenged.

It’s therefore important to identify and mitigate ethical risks while AI is being designed and developed, and on an ongoing basis once it is in use. 

But many AI designers work in a competitive, profit-driven context where speed and efficiency are prized and delay (of the kind implied by regulation and ethical review) is viewed as costly and therefore undesirable. 

Designers may also not have the training, tools or capacity to identify and mitigate ethical issues. The majority are from an engineering or computing background, and do not reflect the diversity in society.

Shareholders and senior management will also naturally be hostile to criticism which could affect profits.

Once an AI application has been designed, it is often sold to companies to fulfil a task (for example, sifting employment applicants) without the buyer being able to understand how it works or what risks may come with it.

Ethical frameworks for AI

Some international bodies have made efforts to create an ethical framework for AI development, including UNESCO’s Recommendation on the Ethics of Artificial Intelligence, and the IEEE’s Global Initiative on Ethics of Autonomous and Intelligent Systems. And some companies have developed their own ethical initiatives.

But each of these proposals naturally overlaps, is slightly different and is voluntary. They set out principles for creating ethical AI, but provide no accountability in the event that an AI goes wrong.

Ethical roles in the AI industry are a potentially important new profession, but the field is underfunded and under resourced. There is widespread agreement that ethics is important, but a lack of consensus on how it should be enforced.

Government use of AI

It’s equally important that the way governments use AI is understood, consensual and ethical, complying with human rights obligations. Opaque practices by governments may feed the perception of AI as a tool of oppression. 

China has some of the clearest regulation of AI private industry in the world, but the way the government has deployed AI tools in the surveillance of its citizens has serious civil liberties implications.

China’s exports of AI to other countries are increasing the prevalence of government surveillance internationally.

Privacy and AI

Probably the greatest challenge facing the AI industry is the need to reconcile AI’s need for large amounts of structured or standardized data with the human right to privacy. 

AI’s ‘hunger’ for large data sets is in direct tension with current privacy legislation and culture. Current law, in the UK and Europe limits both the potential for sharing data sets and the scope of automated decision-making. These restrictions are limiting the capacity of AI. 

During the COVID-19 pandemic, there were concerns that it would not be possible to use AI to determine priority allocation of vaccines. (These concerns were allayed on the basis that GPs provided oversight on the decision-making process.)

More broadly, some AI designers said they were unable to contribute to the COVID-19 response due to regulations that barred them from accessing large health data sets. It is at least feasible that such data could have allowed AI to offer more informed decisions about the use of control measures like lockdowns and the most effective global distribution of vaccines.

Better data access and sharing are compatible with privacy, but require changes to our regulation. The EU and UK are considering what adjustments to their data protection laws are needed to facilitate AI while protecting privacy.

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

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

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

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

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

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

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

Designations can reduce options for support

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

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

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

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

Risk-averse commercial partners

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

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

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

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

Time for the UK to follow others

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

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

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

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

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

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

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

What is happening in Sri Lanka? Explainer Video aboudiaf.drupal 15 July 2022

Chanu Peiris reflects on the unfolding political and economic crisis in Sri Lanka and its impact on human rights.

What is happening in Sri Lanka?

Sri Lanka has been a leader in South Asia on many human development indicators including health and education. Until recently, it was considered an upper middle-income country. Its GDP, when adjusted for purchasing power, was on par with South Africa’s.  

But the country is now experiencing economic collapse. The crisis has its roots in economic mismanagement by multiple governments. This was made worse by global market disruptions and by internal security emergencies including the 2019 Easter bombings.  

What rights are being impacted?   

The current situation is impacting the full range of human rights for people in Sri Lanka. According to the World Food Programme, over a third of people are now facing moderate to severe hunger.

Shortages of other essentials including cooking gas, fuel and lifesaving medicines are disrupting the normal functioning of society and causing loss of life, enormous hardship, mental distress and social unrest.

There are serious concerns about the long-term impacts to the more vulnerable members of Sri Lanka society – including children, whose development due to lack of proper nutrition and disruptions to schools will be affected.  

The global human rights community has called attention to rights violations by the government, which has been seen to be slow to take the necessary steps to rectify the economic situation. It has also used lethal force and social media blackouts in response to protests. 

What are the broader human rights implications? 

The country is seeing the most widespread and diverse mass demonstrations in its history. So far they have led to the resignation of Prime Minister Mahinda Rajapaksa and the cabinet. They have also resulted in President Gotabaya Rajapaksa leaving the country. 

The scale of the protests signals an important shift in the social contract. The crisis has united people who were previously divided and there are demands for the abolition of the executive presidency.   

It is also significant that people are calling for more than the economic issues to be addressed. They are focusing on the need for systemic changes, including accountability and transparency within a government which has long resisted both.

In other words, what we are seeing is a clear assertion from the streets of the indivisibility of human rights – that access to food, water, and electricity rely on the safeguarding of civil and political rights and proper accountability.

They are making a powerful argument in favour of human rights-sensitive governance – something that has been in short supply around the world. 

Seven ways Russia’s war on Ukraine has changed the world Feature jon.wallace 17 February 2023

Chatham House experts examine the shifts in geopolitical alliances, security, energy, and supply chains and whether these changes are likely to be long-lasting.

President Vladimir Putin’s decision to launch a full-scale re-invasion of Ukraine one year ago was a global shock which ‘marked an abrupt end to 30 years of globalization and all the international co-operation that made that possible’ with serious implications for countries around the world, outlined Chatham House director Bronwen Maddox in her inaugural lecture.

Not only has the war threatened the stability of Europe but it has also impacted food and energy security globally including in the Middle East and Africa, creating shock waves in a world barely recovering from the COVID-19 pandemic.

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

Reactive oxygen species (ROS) are an unavoidable host environmental cue for intracellular pathogens such as Mycobacterium tuberculosis and Mycobacterium bovis; however, the signaling pathway in mycobacteria for sensing and responding to environmental stress remains largely unclear. Here, we characterize a novel CmtR-Zur-ESX3-Zn2+ regulatory pathway in M. bovis that aids mycobacterial survival under oxidative stress. We demonstrate that CmtR functions as a novel redox sensor and that its expression can be significantly induced under H2O2 stress. CmtR can physically interact with the negative regulator Zur and de-represses the expression of the esx-3 operon, which leads to Zn2+ accumulation and promotion of reactive oxygen species detoxication in mycobacterial cells. Zn2+ can also act as an effector molecule of the CmtR regulator, using which the latter can de-repress its own expression for further inducing bacterial antioxidant adaptation. Consistently, CmtR can induce the expression of EsxH, a component of esx-3 operon involved in Zn2+ transportation that has been reported earlier, and inhibit phagosome maturation in macrophages. Lastly, CmtR significantly contributes to bacterial survival in macrophages and in the lungs of infected mice. Our findings reveal the existence of an antioxidant regulatory pathway in mycobacteria and provide novel information on stress-triggered gene regulation and its association with host–pathogen interaction.

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

Stop codon read-through (SCR) is a process of continuation of translation beyond a stop codon. This phenomenon, which occurs only in certain mRNAs under specific conditions, leads to a longer isoform with properties different from that of the canonical isoform. MTCH2, which encodes a mitochondrial protein that regulates mitochondrial metabolism, was selected as a potential read-through candidate based on evolutionary conservation observed in the proximal region of its 3' UTR. Here, we demonstrate translational read-through across two evolutionarily conserved, in-frame stop codons of MTCH2 using luminescence- and fluorescence-based assays, and by analyzing ribosome-profiling and mass spectrometry (MS) data. This phenomenon generates two isoforms, MTCH2x and MTCH2xx (single- and double-SCR products, respectively), in addition to the canonical isoform MTCH2, from the same mRNA. Our experiments revealed that a cis-acting 12-nucleotide sequence in the proximal 3' UTR of MTCH2 is the necessary signal for SCR. Functional characterization showed that MTCH2 and MTCH2x were localized to mitochondria with a long t1/2 (>36 h). However, MTCH2xx was found predominantly in the cytoplasm. This mislocalization and its unique C terminus led to increased degradation, as shown by greatly reduced t1/2 (<1 h). MTCH2 read-through–deficient cells, generated using CRISPR-Cas9, showed increased MTCH2 expression and, consistent with this, decreased mitochondrial membrane potential. Thus, double-SCR of MTCH2 regulates its own expression levels contributing toward the maintenance of normal mitochondrial membrane potential.

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

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

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

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Histone recognition by “reader” modules serves as a fundamental mechanism in epigenetic regulation. Previous studies have shown that Spindlin1 is a reader of histone H3K4me3 as well as “K4me3-R8me2a” and promotes transcription of rDNA or Wnt/TCF4 target genes. Here we show that Spindlin1 also acts as a potent reader of histone H3 “K4me3-K9me3/2” bivalent methylation pattern. Calorimetric titration revealed a binding affinity of 16 nm between Spindlin1 and H3 “K4me3-K9me3” peptide, which is one to three orders of magnitude stronger than most other histone readout events at peptide level. Structural studies revealed concurrent recognition of H3K4me3 and H3K9me3/2 by aromatic pockets 2 and 1 of Spindlin1, respectively. Epigenomic profiling studies showed that Spindlin1 colocalizes with both H3K4me3 and H3K9me3 peaks in a subset of genes enriched in biological processes of transcription and its regulation. Moreover, the distribution of Spindlin1 peaks is primarily associated with H3K4me3 but not H3K9me3, which suggests that Spindlin1 is a downstream effector of H3K4me3 generated in heterochromatic regions. Collectively, our work calls attention to an intriguing function of Spindlin1 as a potent H3 “K4me3-K9me3/2” bivalent mark reader, thereby balancing gene expression and silencing in H3K9me3/2-enriched regions.

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

DNA polymerases are today used throughout scientific research, biotechnology, and medicine, in part for their ability to interact with unnatural forms of DNA created by synthetic biologists. Here especially, natural DNA polymerases often do not have the “performance specifications” needed for transformative technologies. This creates a need for science-guided rational (or semi-rational) engineering to identify variants that replicate unnatural base pairs (UBPs), unnatural backbones, tags, or other evolutionarily novel features of unnatural DNA. In this review, we provide a brief overview of the chemistry and properties of replicative DNA polymerases and their evolved variants, focusing on the Klenow fragment of Taq DNA polymerase (Klentaq). We describe comparative structural, enzymatic, and molecular dynamics studies of WT and Klentaq variants, complexed with natural or noncanonical substrates. Combining these methods provides insight into how specific amino acid substitutions distant from the active site in a Klentaq DNA polymerase variant (ZP Klentaq) contribute to its ability to replicate UBPs with improved efficiency compared with Klentaq. This approach can therefore serve to guide any future rational engineering of replicative DNA polymerases.

RecQ family helicases are highly conserved from bacteria to humans and have essential roles in maintaining genome stability. Mutations in three human RecQ helicases cause severe diseases with the main features of premature aging and cancer predisposition. Most RecQ helicases shared a conserved domain arrangement which comprises a helicase core, an RecQ C-terminal domain, and an auxiliary element helicase and RNaseD C-terminal (HRDC) domain, the functions of which are poorly understood. In this study, we systematically characterized the roles of the HRDC domain in E. coli RecQ in various DNA transactions by single-molecule FRET. We found that RecQ repetitively unwinds the 3'-partial duplex and fork DNA with a moderate processivity and periodically patrols on the ssDNA in the 5'-partial duplex by translocation. The HRDC domain significantly suppresses RecQ activities in the above transactions. In sharp contrast, the HRDC domain is essential for the deep and long-time unfolding of the G4 DNA structure by RecQ. Based on the observations that the HRDC domain dynamically switches between RecA core- and ssDNA-binding modes after RecQ association with DNA, we proposed a model to explain the modulation mechanism of the HRDC domain. Our findings not only provide new insights into the activities of RecQ on different substrates but also highlight the novel functions of the HRDC domain in DNA metabolisms.

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