Tuesday, 6 September 2016

Sharing clinical data: everyone wins

Patients who contribute their data to research are primarily motivated by a desire to help others with the same plight, through the development of better treatments or even a cure. Out of respect for these individuals, and to uphold the fundamental tenets of the scientific process, I’d like the clinical trials community to shift its default position on data sharing and reuse to align to data availability on publication, similar to the life science community. This will enable more robust, rigorous research, create new opportunities for discovery and build trust between patients and scientists.

This aspiration is widely shared in the basic research community, and has been well articulated in considered and public discussions such as a series led by the National Academy of Sciences in 2003. Nevertheless, recent articles in the New England Journal of Medicine have pushed against data sharing, calling those who reuse data “research parasites” (followed by a bit of clarification) and concern about how best to structure clinical trial data sharing with a lengthy and complex embargo procedure, potentially including payment.

A tradition of sharing

Sharing tools has been the norm (mostly) for genetics and molecular biology since the early days of genetics, mainly because you couldn’t really get anything done unless people let you use their reagents. This has persisted for over a century, from the first studies of fly lines to cDNA clones, enzymes, antibodies and, now, ‘omics datasets.

The Protein Data Bank in the 1970s, the EMBL Bank (now ENA) and GenBank nucleotide collections in the 1980s and the Human Genome Project in the 1990s all thrived thanks to the norms of reagent sharing and data deposition, and the returns to science were - and are still - huge. Such practices are pragmatic in terms of both data quality and author credit, each of which provides incentives for researchers.

I am perhaps painting a beautiful picture of an imperfect world – there is still much to be done to ensure all this data sharing can work. Compliance, agreeing on things like adaptable standards, and keeping the infrastructure humming are all challenges we grapple with on a daily basis in molecular biology. But we have much to be proud of, and embracing the ethos of sharing has brought us a long way in a short time.

Data release: why?

Releasing data when you publish a paper isn’t about giving things up – although I can see that for some, the lack of instant reward might make one feel that way. Data release is not about rewarding a single PI; it’s about benefitting the clinical research community as a whole, and making the most of the data entrusted to you by patients. So - why release data?

We are custodians, not owners, of patient data.

Patients participate in trials to further medical research, benefit from new medicines (potentially) and gain from focused care and advice. But numerous surveys have shown that participants are primarily motivated to share their data – the most valuable aspect of a clinical trial – by the altruistic desire help others in the future.

So it is very strange that some researchers feel justified in assuming the data produced in a clinical trial is somehow their own scientific property. From the perspective of patient care, this position is particularly questionable when it impedes the ability of other scientists to re-examine the data for additional studies, which would contribute to the progress so eagerly desired by the participants.

If we’re not doing all this research to improve patient care, then probably we should change the consent process.

Challenging the interpretation of observations is fundamental to the scientific process.

Evidence is a wonderful thing. Our freedom to base our arguments on reproducible experiments dates back to the 17th Century, when people in Europe were finally permitted to openly discuss and debate science based on direct observation. Evidence is the backbone of scientific discourse, so it follows that papers without data can be easily dismissed as well-articulated speculation.

When a dataset is published, readers are then able to drill down to raw observations, and can verify methods or explore alternative explanations. Yes, this means they can potentially expose errors in your work and your thinking. But it’s far more common for readers to double-check the work against other published datasets, which can answer lots of different questions. Ultimately, this is a good thing for science.

Sharing data sharpens the mind.

The very real anxieties that come with data sharing are both individual and collective, because we are building knowledge together. Professional pride dictates that if your data will be open for inspection, you will be much more careful about the details. (After all that data cleaning and fixing, confounder/covariate discovery and adjustment, you do not want to be the one who left a howler for others to discover.)

Everyone knows there are skeletons in the data closet, mostly down to the complications of running real-life experiments, so current analyses make use of several approaches to boost confidence in the results. But generally speaking, just knowing your peers could be wandering through your data sharpens your mind and makes you focus on handling and presenting your analysis properly.
When an entire community does this, it benefits from a deeper consensus on what a “good study” looks like. That matters a lot.

Meta-analysis and Serendipity

When it can be done, meta-analysis (the combining of datasets) is a win–win–win (funders, scientists, patients). It’s about building on studies, combining them to gain new insights, asking different questions and finding new leads. Meta-analysis isn’t always possible – clinical trials often look at entirely different things, and even when they do study the same thing, they can’t always be aligned very well. But meta-analysis is only possible when people share their datasets.

Serendipity is another benefit of data sharing – I am always amazed at how important it is for science. Serendipity has guided us to some seriously profound insights, for example the relationship between the Malaria parasite and plants, or how metabolic enzymes can be used as lens crystals. It’s been behind many of the completely weird discoveries that make biology so wonderful, and many practical discoveries, such as CRISPR, that push the frontiers of possibility.

I’ve stumbled happily upon Serendipity many times, and very often others have made serendipitous discoveries based on data or methods I have published. You’d have to be pretty cynical to begrudge your fellow scientists such pleasure, and, frankly, a bit petty to fret over whether they’ll remember to credit you (nearly all scientists carefully reference their sources, if only to reassure reviewers of the credibility of the data they use).

For funders, both meta-analysis and serendipitous discoveries compound their return on investment and make them look good. For scientists, being able to make use of comparable data to verify or cross-validate their work, or to make unplanned discoveries, is invaluable. For patients, knowing their contribution is being used in lots of different and useful ways can give a sense of pride.

Sceptical about whether this really applies to clinical research? Well, without having access to a large number of trials, I doubt anyone could say.

Having more large datasets on hand for meta-analysis can only benefit those planning and analysing the results of clinical trials. And as clinical trials begin to incorporate more high-dimensional, data rich datasets (e.g. imaging, metabolomics, multi-omics) – and to share them – there will be plenty of opportunities to carry out sophisticated meta-analysis.

As for Serendipity, well, it can strike at any time.

The scoop

It is hardly possible for anyone to “scoop” you simply because you released your data on publication – particularly if that dataset represents only what is needed to support your paper. If someone else looks at that data and comes up with an interesting observation you missed, they can potentially make that corner of science a little bit better. Dwelling on the negatives will get you nowhere, but looking on the bright side may land you a new collaborator.

If the only datasets you share at publication time are those that relate specifically to that paper, there is no need for complicated embargo rules that provide authors enough time to perform a full analysis on all the data collected (as proposed in the most recent NEJM editorial). Tracking and versioning might become more complicated with later papers, but this approach does the important job of tying the datasets to the publication in a reasonable timeframe, opening up that piece of science for proper verification and discourse.

If you really believe you are going to be scooped for some missing analysis on a dataset, the solution is to delay publication. If you’re worried that making your data public will expose you to undue criticism, make your analysis bulletproof. That will be good for you and for the system as a whole, as understanding the strengths and weaknesses of different analyses only makes the community stronger.

When data sharing is not straightforward

Human subjects

No matter what, we have to honour patient consent. As scientists we may wish such agreements were more future-proof, but when those consents preclude data sharing beyond the study group, we have to accept it and move on.

Exactly how to future-proof consents for clinical trials is no simple matter. One solution would be for funding agencies or regulators to begin insisting that consent forms provide a reasonable level of research access, which would facilitate research but respect the privacy of individuals.

Currently, for genetic studies, there is a lightweight vetting process, involving both individual and institutional sign off, which assures patients that the researchers will perform appropriate research on the dataset. This is a clunky approach and it certainly needs improvement, but it is functional.

Standards and infrastructure

Data sharing is only feasible if the parties involved are able to do it, without worrying that they’ll run into trouble transferring files from one site to another, or that their data will disappear into some kind of black hole.

A robust, global archive for this kind of information would be one important piece of a larger infrastructure that would make biomedical data sharing straightforward. The EMBL-EBI model – biomolecular archives supported by international collaborations – is a solid example. Funding for infrastructure like this is huge value for money, and costs little in the context of global clinical research funding.

CDISC standards are functional, and well used by the clinical trials community. But there is a constant need to review standards and establish new ones for emerging technologies. This work never ends, but the end goal of harmonisation (i.e. to support meta-analysis) is a good one, and the whole process helps us along on our eternal quest for a shared language.

Regulatory and commercial concerns

I do not have a lot of experience in this area, but it’s clear that regulation of clinical trials is a huge deal for the pharmaceutical industry. Any data release policy needs to work well for the regulators, and for commercial interests, who can have different concerns from academia. For both, the science performed in clinical trials must be very sound, so that mind-sharpening step of data release is certainly of value, but most companies that I know are delighted when other science happens from the data they release. 

Evidence is beautiful

In this on-going debate about data, let us base our arguments on… data. We are all likely to change our views view when presented with compelling data and well-reasoned analysis, which is one of the nice things about being a scientist.

Refreshingly, for the most part I do not think this debate is one of those boring political ones where everyone chooses a side, closes their ears and steels themselves for uncomfortable dinner-table discussions. Scientists already working in an open-data environment understandably campaign for everyone to join them – though they are full aware of the downsides. Scientists working in clinical trials can see there are advantages to sharing data, but have neither the time nor the inclination to sort out the myriad details that would make it workable.

As a starting point, we can focus on the simplest, tried-and-tested approach of publishing your data alongside your narrative – a practice that has served science well for over 300 years. But more importantly, we can keep the discussion going, and work with one another to overcome the barriers to realising the full potential of biomedical research. That would be a win for scientists, their funders and, most importantly, patients themselves.

Tuesday, 14 June 2016

The EU Referendum in the UK: A very personal view

I have tweeted prolifically about the UK Referendum on membership in the European Union, strongly supporting the REMAIN (staying in the EU) campaign. In response to requests for a more substantial explanation of my position, I present here a short version and a long version of my views.

Short view

I am voting to REMAIN IN the EU for four main reasons:

  1. It will be at best bad and at worst catastrophic for the UK economy to vote "leave".
  2. The trade deal we have as part of the EU is sensible. Bizarrely, the current trade deal (somewhat sweetened by David Cameron's efforts) is really having our cake and eating it, too. The EU deal we have is nothing close to resembling the 'EU super state' people worried about in the 1990s. The Eurozone is the closest thing to such a state - but we are clearly not part of the Euro. For those who want to be part of the common market only, the trade deal brokered by Cameron is what we have on the table.
  3. Immigration is big, complex issue that modern societies, including the UK, have tackled rather clumsily and not managed well. However, leaving the EU will not improve our ability to handle immigration. If anything, it will worsen it.
  4. We are fundamentally linked to Europe: our borders, our electricity, our science and arts, our pollution, our friends and family who have settled in other countries. We are not going to physically change the location of our islands, and as this no longer the 19th Century, we are no longer in the business of building an Empire. Our future is here, in this place. We've got to be a strong part of Europe's future, keep our place at the table and argue for what we think is right. Spinning our wheels trying to recreate the glory of 19th Century Britain, in isolation from our nearest neighbours, is mad and regressive. 

Longer view

Before I unpack my four major reasons for remaining in the EU, some "meta" points to consider:

1. As an individual, I am clearly pro-Europe. 

I am a Director of the European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI). This is a scientific International Treaty Organisation that, while not being directly linked to the EU (for example, Israel is a member country of EMBL), keeps me very closely involved with issues affecting science in the EU and Europe (e.g, discussing shared challenges with Italian, French, German and other researchers and policymakers involved in genomics and big data analysis). This position has given me unique insights into issues that affect the scientific community throughout Europe, and over the past decade I have come to understand and deeply appreciate the value of blending different approaches of other (non-UK) European countries with our own. 

The criticism that I am biased may be true, if it is based on my genuine warmth for all the different, complex facets of Europe, without thinking they are in any way perfect. Everyone brings their own biases to the discussion, whether they are due to position, experience or job. Understanding our own biases and setting them aside to explore the issue from different viewpoints is valuable, and will make this discussion about the EU richer.

2. I do not think the EU is perfect. 

I am passionate about the UK staying in the EU, but that's not to say I believe the EU it is perfect. There are small niggles and annoyances where I think it could do better, and some gaping issues that it needs to confront. That said, I cannot think of any national government (including ours) that could be held up as an example of perfection for the EU to emulate. (For those who put forward the UK Parliamentary system as a perfect system, consider the House of Lords... Would you even think about creating such a body today?)

I get to see quite a bit of national governments and transnational schemes close up, through the lens of science (which is inherently international). Seen in this way, the EU is neither the worst nor the best bureaucracy. It is simply unique, with uneasy tensions between Brussels and various coalitions of nation states, and amongst the nation states themselves. This is no more odd than the familiar tensions between England, Scotland, Wales and Northern Ireland in the UK, or those between the German Länder or Chinese provinces. It is the dynamic of the EU that is unique, both because of its geographical spread and the power distribution of its Member States.

Despite what the UK press might have you believe, the EU centre is far less powerful than those of equivalent national systems, for example in the UK or Germany. The European Council, where all the democratically elected Heads of State have either an explicit or an implicit veto, has a massive influence in Europe, and each European nation state gets its vote.

The EU's lack of perfection does not justify leaving it; if anything, its imperfections are to be tackled directly and with representation. There is every reason to continue to strive to reform the EU.

3. I do not think it's crazy to ask the question. 

I'm not sure that a referendum is the best way to get a considered answer, but I don't think it's crazy for citizens to question governmental structures, or to question whether the EU's structure is "good for Britain" from a purely self-centred British perspective. It is in fact very good for people to be engaged enough to ask what this transnational body is really trying to achieve, in a general sense (more on this below). One should never have a system that cannot be sensibly challenged.

I have some good friends who are committed to voting "out", sometimes in the interests of sovereignty and libertarian values, and sometimes (often my parents' generation) out of concern for cultural changes brought about by immigration. I feel strongly that we all owe it to each other to hash it out with good, considered arguments, based as much as possible on evidence. What we will all be proud of in end is how we treat each other with respect and listen to one another, even when we disagree. There is no place for derision or contempt here - the stakes are simply too high.

4. This is a personal view. 

This is not the EMBL view. I am not representing anybody else but myself in this post.

Unpacking my "Remain" suitcase

I've heard plenty of reasons cited for voting "out" - here are my "vote in" arguments, in much more detail.

1. It will be at best bad and at worst catastrophic for the UK economy if our citizens vote "out".

Leave campaigners take umbrage at this, positing, "We are a great trading nation, and economically we will be the same or better out of the EU". Not so. We are a great trading nation, and that's precisely thanks to making pragmatic decisions when presented with important ones, like this referendum.

I am not an economist, but then neither are most people flinging about fantasies about some sort of panglossian world of trade for the UK outside of the EU.

Straightforward facts:

  • More than 40% of our trade is with Europe. Perhaps that proportion might be a bit lower in the future, but it's never going to be below 30%, if only for geographic convenience and the sheer sizes of Germany and France. 

There is simply no way that the EU is going to offer us a better deal once we've flounced off in a huff. Cross-border service agreements and trade without freedom of movement? I don't think so. Why? First, all the other EU agreements (e.g. EEA, Swiss) require free movement in exchange for free trade. Second, excluding London's financial services will only be a big win for Paris and Frankfurt. Expect massive lobbying, pushing hard on an open door to prevent any trade deal including financial services.

Take an example of a German company wanting to be competitive in the UK: BMW may sell so many cars in the UK, but it will be in the EU's interest to negotiate BMW to sell many, many more cars to the US and China (that's what really keeps the BMW people in Munich up at night). Also, BMW doesn't care as much about having tariffs for their expensive cars entering the UK as they do about the market distribution of those tarrifs, and whether they make BMW less competitive as a brand in the UK compared to other car makers. They may lose a little market share if Jaguar continues to have a UK manufacturing base, but it's not really enough to swing a trade deal one way or the other.

Making new trade deals with China, India and the USA on our terms? The bigger economy always sets the terms, always has done (I refer you to the Swiss/China deal) and always will. The UK might be the 5th (nominal) or 9th (PPP) biggest economy in the world, but the first non-NAFTA, non-EU economy smaller than us (on PPP terms) is South Korea, then Saudi Arabia, Turkey and Iran. Even with those countries, it is very hard to imagine that the EU trade block negotiators will allow a better deal to be struck with the UK than with the EU. Let us please, please not snooker ourselves in a negotiation before we've even started. Embarrassing.

  • In the best case, negotiations will take around 5 years. It is more likely they will take closer to 10 years. During all that time, our first priority will be to sort our relationship with the EU (where we have ~40% of our trade now). 

In the best possible scenario, our new, crack team of trade negotiators will be moving on from their discussion with the EU within 5 years, talking next to South Korea and Turkey, both of which may well be happily bargaining to compete with the UK's freshly negotiated position with the EU, for another 5 years. Perhaps we'd get a good deal eventually, perhaps not.

Our points of leverage - international finance, pharmaceuticals - have a strong track record of moving their centre of gravity, and multinationals can reasonably be expected to position themselves to minimise the risk of screwing this up and, at the very least, de-emphasing Britain. Far worse, they might be expected to withdraw completely during this time. This would mean even less leverage for Britain, not more.

  • In the best case, after 10 years any loss in our economy might be mitigated by freer terms of trade with Turkey, South Korea, Saudi Arabia and Iran (n.b. we will not get a better deal than the EU with NAFTA or China), assuming the EU's negotiators with those countries tank and really screw up their competitive position. 

Really? South Korea, Turkey, Saudi Arabia and Iran? Does this sound like a better alternative to free trade with Germany?

  • In the worst case, after 10 years we would be kicked around in trade deals and forced to accept the terms on offer from countries/trading blocks that, understandably, put their own interests first. 

None of these countries or trading blocks would shed a single tear over the great trading nation that the UK used to be. They'll get the best deal for themselves, and move on. That's what trade negotiators do. Of course this sounds all rather grubby, realpolitik and unfair, but the reality is that, as always, we must choose our battles carefully. Very carefully.

Why on earth would we voluntarily suffer certain short-term pain, and risk catastrophic long term pain? What is the motivation behind this self-destructive impulse?

2. With the current offer, we have our cake and eat it, too.

There are some who argue, "We don't want to be part of an EU super-state". This is usually combined with statements asserting, "The EU is undemocratic," and "We should reclaim our sovereignty". The dismaying thing about these arguments is that they are part of an old fight, and one that has already been won. Britain is not in the Eurozone, where much of the further integration is happening. The UK is clearly outside - in effect, it leads (or could lead if it wasn't so self-obsessed) the non-euro component of the EU.


During the 1980s and the 1990s there was an EU roadmap, which had it evolving into an explicit federal structure with a common currency and a political union across Europe. European Heads of State and government leaders decided to attempt monetary union first, before political union. However, a series of events radically changed the course of this strategy, affecting the whole of the EU but the UK in particular. There were three major changes: the treaty of Maastrict in 1992, the French and Dutch referenda on the European constitution in 2005, and the recent agreement brokered by David Cameron for the UK.

The Maastrict treaty of 1992 involved the UK and Denmark's opt-out of the euro. All of the other EU Member States agreed to either adopt the currency together, or to "eventually" adopt it. The start of the euro was an exciting turning point, as it provided a "fair weather" monetary union and agreements about fiscal policies underpinning it.

It was partly bloody-mindedness and partly thorough economic analysis that got the UK an opt-out of the euro. The UK Treasury argued that a successful currency union required fiscal (i.e. 'what state spends') union, and fiscal union requires political union to work properly. For the UK, it was all (monetary, fiscal and political), or nothing. This position was defended during the Labour years by Gordon Brown at the Treasury against the political direction of Tony Blair, an episode often forgotten about Brown's legacy.

European constitution? Eurozone?

That this monetary union was intended to pave the way for a political union was enshrined in a "European Constitution", which was put to a vote in 2005. But a resounding "Non" from France and "Nee" from the Netherlands stopped the constitution in its tracks. The Treaty of Lisbon 'tidy-up' treaty left the Eurozone with a monetary union but no strong fiscal system. In this state the Eurozone entered the 2008 crash (to be fair, not caused by Europe), when the "fair weather" rules were tested almost to destruction. This unhappy state of affairs is still unresolved today.

Respected economists and political analysts agree that the Eurozone must either break up or become nation-like, with enforceable, federal-scale rules and a quid-pro-quo arrangement whereby wealthier countries fund substantial public works and establish safety nets in poorer countries in exchange for stability. Breakup would involve a reversion to a zone of German influence, wherein countries that trade most with Germany will voluntarily link to its currency (with all the headaches that implies). Frankly, both options look impossible at the moment, but maintaining status quo is equally impossible. Surely, something must give. Whatever happens, the UK remains outside of it all.

Possibly the only major concession secured by David Cameron was an agreement to change the European Union from operating as a single currency block (i.e. euro) with some unmerged secondary currencies (e.g. pound, kroner) to explicitly acknowledging that the EU will be a multi-currency union. This is a profound win. It reverses the part of the Maastrict treaty in which all states except the UK and Denmark were going join the Eurozone. It officially separates the boundaries of the Eurozone from the boundaries of the EU, and limits the Eurozone in regards to regulation of the currency/trade processes. I am sure there is a whole host of technical details about this that I don't understand, but for sure this is an important change.

So - given all of this - the EU can no longer be considered a 'European super-state'. The Eurozone might emerge as a 'super-state of the future', but the agreement is clear that the UK will not be part of that. The current deal we are being offered is a rather too-good-to-be-true offer.

Many northern Europeans think the UK is already being offered a very sweet deal. Eurosceptics of the 1990s should appreciate this - that there is a free trade area made up of nation states, and it is called the EU. Freedom of movement still a concern? Read on.


As for the democratic credentials of the EU, it is not for want of trying, as demonstrated by the European Parliament. National politics (in the UK and in many other places) treats the European Parliament as an irrelevance, a scapegoat and object of derision. But honestly, its structure is no more odd than, say, having the second chamber of a national parliament composed of life-appointed peers and hereditary peers who vote internally on who gets to vote. For the UK to be indifferent to the democratic systems of the EU and then complain about its lack of democracy is a bit weird.

The European Council (confusingly, completely different from the Council of Europe) is where the Heads of State/Government meet, and has equal power to the European Parliament. These democratically elected individuals feel quite strongly about their mandate. There is no pretending that this is somehow a clear governance situation; it has developed organically and, with all its different layers, attempts to balance the different sizes, political styles and cultures of the EU Member States. As a Brit well accustomed to complex constitutions and evolution rather than revolution in government, I find this organic approach somewhat comforting. It's certainly more baroque than many (most?) systems, but it's hardly unique in Europe, where the accidents of history have a way of creating political structure.

It is not the time to reform these structures, and it won't be until the final end point of the Eurozone is clarified. In the event a federal fiscal system emerges, better structures must be hammered out, in which the EU's relationship to non-Eurozone countries is spelled out. A big bun fight is inevitable, but the first bun will not soar until the question of whether the Eurozone is going to be a federal state is resolved. In the event no such state emerges, the dismantling of the Euro will give rise to new structures during a time of great disruption.

3. Leaving the EU will not improve our ability to handle immigration.

A small number of older people I meet sometimes rage against modern Britain, incenses about immigration. "We must control our borders and immigration better," goes the chorus. "We are losing our country," goes the verse. This is hard to talk about sensibly, because what triggers this gut reaction is so amorphous.

My main answer is that leaving the EU will not fundamentally change these issues for the UK, and that poorer countries outside of the EU need to resolve some of the serious issues that are putting pressure on their people to leave. Over half of the immigration into the UK is not from the EU, so in terms of numbers, half the problem is completely unrelated to our membership.

It is easy to miss that 5% of NHS staff (10% of NHS doctors) are non-UK EU citizens, paying taxes and keeping our health system afloat. You might not notice the millions of young EU citizens - from waiters to engineers - working, paying UK taxes and, mainly thanks to their youth, making very few demands in return (one estimate puts increased demand on the NHS from non-UK EU citizens at 1%).

A laissez-faire approach to cultural integration is unlikely to work, as described by commentators such as Trevor Philips. But EU migrants integrate well, so that's not really the challenge here. British culture is no more or less quirky than any other northern European culture - just open a can of Swedish surströmming (fermented herring) if you don't believe me. In my experience, when you push people on the cultural integration of Europeans in different European countries, they are not just tolerant, they actively like their Italian / French / Swedish / Maltese neighbours, delight in explaining English peculiarities to them. and enjoy learning a bit about other cultural quirks. Polish builders/plumbers, a favourite immigration example of yore, get quite good press these days, having demonstrated a couple of decades' worth of hard work and pragmatism. So cultural integration is mainly a non-issue when it comes to other European cultures.

Lower-skilled people in the UK often voice feelings that they have had opportunities taken away from them from low-skilled (or more skilled but happy to work cheaply) people from elsewhere in the EU. Certainly over the past 50 years there has been a levelling out of developed and developing nations, with shifting patterns of employment where large-scale manufacturing happens and job opportunities open up. This is not my field of expertise, but it would seem sensible in this shifting environment to agree on minimum conditions and wages across as broad an area as possible to minimise any potential negative impacts of this kind of movement.

It would not, however, seem sensible to assume that leaving the EU would result in a sudden resurgence of semi-skilled jobs in the UK.

4. Our future is with Europe.

Like it or lump it, we are just 21 miles from France, connected by a tunnel. We continue to have massive, regular trade in goods, people and ideas with the Netherlands, France, northern Germany and many other parts of the EU.

Our history is intimately linked with those of France, Holland and Germany, from the Plantangents through Protestantism to the English coronation of Hanoverian kings.

Ours are important islands in Europe, but by no means the only ones, joining Ireland, Malta, Sardinia, Corsica, the Majorcas, the Azores, Copenhagen and Gotland who could point to clear blue water separating "them" from the "rest of Europe".

In terms of everything that matters - culture, trade, electricity, pollution, holidays, food, football, rugby, tennis, language - we are European, definitely part of the broader sweep of northern nations with strong Anglo, Celtic, Viking and Protestant traditions.

Like every other major European nation, we can be proud of our contributions to the world and, like every other European nation, be proud to learn from our mistakes. We can perhaps indulge in being slightly more proud than others about certain things (Most Nobel Prizes in Europe?  Longest-running Parliament? Rule of Law?). But we could never pretend that French poets, philosophers and mathematicians (leaving aside Napoleon) haven't had an impact, or that the French revolution did not leave its mark on the world. Europe suffers no shortage of impressive achievements. So why on earth would putting two fingers up to the EU suddenly make our achievements seem more important?

We will inevitably need to agree on many things with our fellow European nations. We do not generate electricity consistently enough to unlink our electrical grid from Europe. We do not have enough gas from the North Sea to avoid trading for it. We do not produce enough food to sustain ourselves and eschew the produce of other countries. Viruses, bacteria, pollution will never submit themselves to border controls. Our parents might retire (or have retired already) to sunnier shores outside the UK, in other parts of the EU, and we will doubtless wish to (or need to) visit them easily. Our children will seek to enrich their lives by living in another country for a time, whether it's for a summer or a couple of years.

We must have a sensible level of agreement with the largest grouping of developed nations in the world, and the largest pool of educated, qualified people on our doorstep.

For better or for worse, the EU, with all its faults, is the place to make these agreements. We will not dodge trips to Brussels, or arguments with our peers in Paris or Berlin, by leaving the EU. We have already changed the EU, partly through sheer bloody-mindedness, and partly by thoroughly analysing what is working and what could work better. Us being out of the Euro and showing that there is a productive non-Euro, inside EU life is key. If we stay engaged and keep our seat at the table, there is much more we can change for the benefit of all. What is on offer - to be part of the EU and not part of the Eurozone - is a remarkable opportunity. We'd be fools not to take it.