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Breaking boundaries in our DNA

Marieke Oudelaar from the Weatherall Institute of Molecular Medicine explains how complex folding structures formed by DNA enable genetically identical cells to perform different functions.

Our bodies are composed of trillions of cells, each with its own job. Cells in our stomach help digest our food, while cells in our eyes detect light, and our immune cells kill off bugs. To be able to perform these specific jobs, every cell needs a different set of tools, which are formed by the collection of proteins that a cell produces. The instructions for these proteins are written in the approximately 20,000 genes in our DNA.

Despite all these different functions and the need for different tools, all our cells contain the exact same DNA sequence. But one central question remains unanswered – how does a cell know which combination of the 20,000 genes it should activate to produce its specific toolkit?

The answer to this question may be found in the pieces of DNA that lie between our protein-producing genes. Although our cells contain a lot of DNA, only a small part of this is actually composed of genes. We don’t really understand the function of most of this other sequence, but we do know that some of it has a function in regulating the activity of genes. An important class of such regulatory DNA sequences are the enhancers, which act as switches that can turn genes on in the cells where they are required.

However, we still don’t understand how these enhancers know which genes should be activated in which cells. It is becoming clear that the way DNA is folded inside the cell is a crucial factor, as enhancers need to be able to interact physically with genes in order to activate them. It is important to realise that our cells contain an enormous amount of DNA – approximately two meters! – which is compacted in a very complex structure to allow it to fit into our tiny cells. The long strings of DNA are folded into domains, which cluster together to form larger domains, creating an intricate hierarchical structure. This domain organisation prevents DNA from tangling together like it would if it were an unwound ball of wool, and allows specific domains to be unwound and used when they are needed.

Researchers have identified key proteins that appear to define and help organise this domain structure. One such protein is called CTCF, which sticks to a specific sequence of DNA that is frequently found at the boundaries of these domains. To explore the function of these CTCF boundaries in more detail and to investigate what role they may play in connecting enhancers to the right genes, our team studied the domain that contains the α-globin genes, which produce the haemoglobin that our red blood cells use to circulate oxygen in our bodies.

Firstly, as expected from CTCF’s role in defining boundaries, we showed that CTCF boundaries help organise the α-globin genes into a specific domain structure within red blood cells. This allows the enhancers to physically interact with and switch on the α-globin genes in this specific cell type. We then used the gene editing technology of CRISPR/Cas9 to snip out the DNA sequences that normally bind CTCF, and found that the boundaries in these edited cells become blurred and the domain loses its specific shape. The α-globin enhancers now not only activate the α-globin genes, but cross the domain boundaries and switch on genes in the neighbouring domain.

This study provides new insights into the contribution of CTCF in helping define these domain boundaries to help organise our DNA and restrict the regulation of gene activity within the cells where it is needed. This is an important finding that could explain the misregulation of gene activity that contributes to many diseases. For example in cancer, mutations of these boundary sequences in our DNA could lead to inappropriate activation of the genes that drive tumour growth.

The full study, ‘Tissue-specific CTCF–cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo’, can be read in the journal Nature Cell Biology.

Aerial view of the British Mulberry in operation.

In a guest blog, Professor Thomas Adcock, Associate Professor in Oxford’s Department of Engineering and a Tutorial Fellow at St Peter’s College, discusses his newly published research ‘the waves at the Mulberry Harbours.’

 Professor Adcock’s research focuses on understanding the ocean environment and how this interacts with infrastructure. He has a passionate interest in engineering history, particularly the Mulberry Harbours, which were used during the Second World War as part of Operation Overlord (the invasion of Normandy). His Grandfather was one of the engineers who worked on their design and construction.

Operation Overlord was the invasion of occupied Europe by the Allies in the Second World War. Whilst the Allies' primary enemy was the Axis forces, they also faced another foe — the weather. In particular, given the continuous necessity for personnel and supplies to cross the channel there was serious concern that the sea might cause a breakdown in supply lines. A particular problem was that the enemy would render all ports useless.

 The solution to this was to construct the components of the ports in Britain and take them with them. These temporary harbours were codenamed Mulberry. The plan was ambitious — to have two harbours each twice the size of Dover Harbour — and that these should be operational only 14 days after D-Day and last for 90 days. There were to be two harbours — “Mulberry A” in the American sector and “Mulberry B” in the British sector. Various novel breakwaters and roadways were designed and constructed and floated across to Normandy in the days immediately after D-Day. The American Mulberry was finished ahead of schedule whilst the British harbour was on time. 

However, a fortnight after D-Day a severe storm blew up, almost completely destroying the US harbour and doing serious damage to the British Mulberry. 

Yet the British Mulberry survived and was used (after minor adaptations) for more than twice as long as originally planned. The remains of it can still be seen at Arromanches today. To an engineer a number of questions immediately spring to mind: why did one harbour fail but the other survive; and should the engineers have expected the storm that hit them?

The Mulberry Harbours interest me because they were novel and unusual structures deployed as an integral part of one of the most important operations in military history. We can gain technical insights from what worked and what failed, and learn important lessons by analysing the historical decisions that were made. But my interest is also personal. My Grandfather, Alan Adcock, was one of the engineers who made the Mulberry Harbours a reality. I doubt I would have become an engineer without his influence. 

To answer the question of why the harbours had different fates we needed to understand how big the waves were which hit them.  This was made possible by a wave hindcast carried out by the European Centre for Medium-Range Weather Forecasting.

A hindcast is similar to a weather and wave forecast — point measurements such as atmospheric pressure and wind speed and direction are assimilated into a model run on a supercomputer which predicts how strong and persistent the winds were and how big the waves would be. To model what happens in the English Channel it is necessary to model most of the Atlantic. However, as waves enter shallow water, different physics becomes important — such as wave refraction and breaking.  We took the output of the large-scale  hindcast and used this to drive a local model of the waves close inshore, allowing us to predict what the waves were like when they hit the harbours.

 We found that the waves at the American harbour were significantly larger than those at the British Mulberry — although both experienced waves larger than they were designed to withstand. This goes a long way to explain why the American harbour failed whilst the British one narrowly survived. We also found that a storm of the severity of the 1944 storm would only be expected to occur during the summer once in every 40 years. The Allies were clearly very unlucky to experience a storm this severe only a couple of weeks after D-Day.

The lead author of our recent paper is Zoe Jackson who completed this work as part of her final year undergraduate project under my supervision. The work would not have been possible without the technical expertise of HR Wallingford and the European Centre for Medium-Range Weather Forecasting based in Reading.

 As a final coda, this project used technical knowledge and computing power developed over the more than 70 years since D-Day, and took Zoe about eight months to complete. As I am sure my Grandfather would have observed were he still with us, this is the same period as the original engineers had to design and construct the harbours.

Alan Adcock giving his Grandson early lessons in coastal engineeringAlan Adcock giving his Grandson early lessons in coastal engineering

Image credit: Shutterstock

Oxford Mathematician Neave O'Clery works with mathematical models to describe the processes behind industrial diversification and economic growth. Here she discusses her work in Oxford and previously at Harvard to explain how network science can help us understand why some cities thrive and grow, and others decline, and how they can offer useful, practical tools for policy-makers looking for the formula for success.

No man is an island. English poet John Donne's words have new meaning in a 21st century context as network and peer effects, often amplified by modern technologies, have been acknowledged as central to understanding human behaviour and development. Network analysis provides a uniquely powerful tool to describe and quantify complex systems, whose dynamics depend not on individual agents but on the underlying interconnection structure. My work focuses on the development of network-based policy tools to describe the economic processes underlying the growth of cities.

Urban centres draw a diverse range of people, attracted by opportunity, amenities, and the energy of crowds. Yet, while benefiting from density and proximity of people, cities also suffer from issues surrounding crime, transport, housing, and education. Fuelled by rapid urbanisation and pressing policy concerns, an unparalleled inter-disciplinary research agenda has emerged that spans the humanities, social and physical sciences. From a quantitative perspective, this agenda embraces the new wave of data emerging from both the private and public sector, and its promise to deliver new insights and transformative detail on how society functions today. The novel application of tools from mathematics, combined with high resolution data, to study social, economic and physical systems transcends traditional domain boundaries and provides opportunities for a uniquely multi-disciplinary and high impact research agenda.

One particular strand of research concerns the fundamental question: how do cities move into new economic activities, providing opportunities for citizens and generating inclusive growth? Cities are naturally constrained by their current resources, and the proximity of their current capabilities to new opportunities. This simple fact gives rise to a notion of path dependence: cities move into new activities that are similar to what they currently produce. In order to describe the similarities between industries, we construct a network model where nodes represent industries and edges represent capability overlap. The capability overlap for industry pairs may be empirically estimated by counting worker transitions between industries. Intuitively, if many workers switch jobs between a pair of industries, then it is likely that these industries share a high degree of know-how.

This network can be seen as modelling the opportunity landscape of cities: where a particular city is located in this network (i.e., its industries) will determine its future diversification potential. In other words, a city has the skills and know-how to move into neighbouring nodes. A city located in a central well connected region has many options, but one with only few peripheral industries has limited opportunities.

Such models aid policy-makers, planners and investors by providing detailed predictions of what types of new activities are likely to be successful in a particular place, information that typically cannot be gleaned from standard economic models. Metrics derived from such networks are in-formative about a range of associated questions concerning the overall growth of formal employment and the optimal size of urban commuting zones.


Herd of giraffes

Oxford researchers have found that human ancestors were able to cope with changes in their environment as the climate varied. They developed a new method to measure climate in Africa millions of years ago, using an unexpected source: the fossilised teeth of large mammals.

Hominins lived in Africa from about 7 million years ago, and were the ancestors of all present-day human beings. It’s thought that they evolved many of the distinctive features of modern people, such as sweating and walking upright, but we don’t know exactly what drove these changes. The new research, published in Proceedings of the National Academy of Sciences, investigated whether climate change could have been a factor.

We know that the African landscape was transformed by the spread of tropical grasses, but it’s a challenge to work out why this happened, and how climate change might have affected the evolution of hominins. Obviously, rain doesn’t fossilise, and while some indicators of an arid environment are preserved, they’re very sensitive to other factors which make them difficult to use.

The Oxford team looked at a single area, near Lake Turkana in northern Kenya, where sediments preserve fossilised hominins, as well as evidence of their behaviour such as stone tools. They analysed the teeth of herbivores, including the ancestors of present-day giraffes and hippopotamuses, from the same areas where hominin fossils and tools have been found and ranging in age from about four million to ten thousand years old.

The method is based on correlating oxygen isotope ratios in modern animal teeth and water with climate data at more than 30 sites in eastern and central Africa. In an arid environment, a lot of water evaporates from the ground, leaving behind more of a type of “heavy” oxygen, oxygen-18, relative to the common “light” oxygen, oxygen-16. When animals eat and drink, the ratio of heavy to light oxygen in food and water enters their bodies and is ultimately deposited in their teeth. By measuring oxygen isotope ratios in fossilised teeth, the researchers could determine how arid it was in the past.

They found that hominins were able to survive in both humid and arid environments in eastern Africa. This supports the idea that some of the ways humans changed as they evolved might have helped them to cope with climatic change.

Dr Scott Blumenthal, of the Research Laboratory for Archaeology at Oxford University, said “Researchers have long assumed that a long-term drying trend caused hominin environments to become more open. It was thought that this was what drove many of the fundamental changes in human evolution. We didn’t find evidence for a long-term trend like this. We found that the climate has varied over time from arid to humid, similar to the range of environments you find in eastern Africa today. It may be that this variability of climate was more important in driving evolutionary changes.”

Image credit: Shutterstock

Putting Oxford on the innovation map

Lanisha Butterfield | 26 Jun 2017

Oxford is making waves, economically and academically. Thanks to the thriving Oxford ecosystem, 2016 was a great year for both the city and the University of Oxford.

Oxford Sciences Innovation (OSI), the investment vehicle for Oxford University’s spinout companies, grew to £580 million venture funding, and Oxford University itself doubled its spinout company generation from 10 in 2015 to 21 in 2016, launching OxStem, Oxbotica and Mind Foundry - to name just a few.

Oxford University Innovation, the commercialisation branch of the university and newly crowned tech transfer unit of the year*, is playing a key role in changing the face of the city, and driving a new generation of regional entrepreneurship and investment. OUI play a transformative role in translating academic research into tangible solutions with societal impact. Science Blog talks to OUI’s Chief Executive Officer Matt Perkins and Chief Operating Officer Adam Stoten their role in building the Oxford Ecosystem, and the challenges they are navigating along the way.

For those that don’t know, what is Oxford University Innovation, and what is its relationship to the University?

Matt: OUI is 100% part of the University. Our job is to monitor the University’s innovation agenda, and fulfil these objectives. We find the best commercial outlets to make sure that academic research is commercialised and broadly used, to have as wide an impact on society as possible.

Adam: The University is incredibly diverse, so the needs of one department may be very different to another. It is really important that we develop the right mechanisms and approaches to suit particular cohorts of researchers.

OUI(L-R) Oxford University Innovation's Adam Stoten (Chief Operating Officer) and Matt Perkins (Chief Executive Officer) discuss their role in building the Oxford ecosystem and the challenges that they are navigating along the way.

Oxford has not historically been known for its tech outputs, what are the biggest challenges in building an innovative ecosystem?

Matt: There are a lot of good entrepreneurial services available in Oxford, and they aren’t always clearly signposted. For us, it is about making it simple and easy for people to understand and navigate the ecosystem, supporting the inventors and innovators of tomorrow to get started.

We have our Start-up Incubator, which supports companies that have been established by either students or alumni. We call these businesses start-ups, rather than spinouts.

Said Business School have their Launchpad and will soon open the Foundry, and they are both work spaces for budding entrepreneurs to achieve their ambitions and develop their inventions.

The links may not be as explicit as they could be, but each facility is related to the other, and more relationships will be established moving forward.

Helping people to find their way around the services available is a key element that OUI can bring. We can give the outside world a shop window into the Oxford University ecosystem. But one of the things we need to get better at doing is integrating ourselves and working more closely with people outside of the university environment, spreading this message more broadly.

There are some great organisations out there, such as the Oxford Investment Opportunity Network (OION). We need to find ways of reaching out to and working with them.

Are you able to share how you will go about that?

Adam: A cohesive regional voice is key, and being more collaborative is a big part of our plan for the future.

Cambridge University has done a really good job of acting regionally. Oxford is much more connected than we were a few years ago, but there remains an opportunity for all the different actors from the Oxford cluster to better market themselves, their outcomes and capacity from this region. I think that is great, and a great opportunity.

Matt: Oxford University is part of the community.  We are not the whole community. We play a very strong and important part in it, but everyone will benefit from the whole region developing. The University has tremendous global reach, and that is a massive benefit for the city. We need to make sure the region understands what we can do, that the country understands what we can do. And then reach out to the rest of the world.

Image credit: YASA MotorsOUI's varied portfolio of spinouts include YASA Motors, which provides e-motors for hybrid or truly electronic vehicles Image credit: YASA Motors

Innovation and spinouts are talked about a lot, but for many their meanings can be a bit clear, can you breakdown the jargon?

Adam: A spinout is a new company that is formed and founded by University academics, with the intention of developing a product or service(s), with societal impact.

The product itself can be anything, providing it is utilising intellectual property (IP) and is tangible for consumers. That could take the form of a patent, or it could mean channelling know-how and expertise into providing a service.

And what does innovation mean to you?

Matt: For me, it is the practical application of knowledge. Taking something you know and using it differently to achieve something that you couldn’t do before. That can take many forms: intellectual property, providing a service, reaching new markets - these are just as innovative as developing a new technology.

Adam: In our context it comes down to any way that we can help translate the outputs of university research into some kind of societal impact. That could be a new gene therapy to cure blindness, or a new smartphone game to help train healthcare workers in the developing world so they can respond to acute paediatric emergencies. That is actually a project called LIFE, which was the first to be successfully funded from our new crowdfunding platform, OxReach. It was launched with colleagues from the University last year and went on to hit its crowdfunding target of £60,000, and then to leverage almost a quarter of a million more from other investors.

No obvious economic value, but the project had massive impact potential, and could actually help save lives in sub-Saharan Africa. That is the kind of impact that we want to have.

Image credit: NightstaRxThe spinout company Nightstarx is developing an ophthalmology gene therapy that can not only halt the progression of a particular disease, but restore a patient’s sight. Image credit: NightstaRx

Are there any projects in the pipeline that have a strong potential for impact that you are particularly excited about?

Matt: On top of having created 21 spinouts in the last year, we are working on 65-70 more. By the end of the year we will have created somewhere in the region of 20 spinouts. It is an incredible and wide ranging portfolio.

Nightstar is developing an ophthalmology gene therapy that has already shown in clinical trials that it not only can halt the progression of a particular disease, but restore a patient’s sight. We have very high expectations that this research will translate into a new drug with incredible impact.

First Light Fusion is a really interesting organisation that is looking to develop a form of nuclear fusion. The scale of their ambition is enormous, they have some really smart ideas, and we look forward to seeing what will happen.

Yasa motors is also very exciting. It provides e-motors for hybrid or truly electronic vehicles. Their motors are excellent and lead the world in terms of performance per unit weight.

It’s also important to remember that innovation isn’t just about tech. We are also talking to people about running spinouts from the humanities division, which is fantastic! Things like training people to speak new languages. There are some incredibly smart people out there who are coming up with good ideas which have commercial value, and our job is to provide a service to all of them.

Adam: Traditionally our focus has been with medical sciences and MPLS, but more than half of the companies that have been generated through our incubator have been based on social science research. This comes down to us thinking of different ways of commercialising outputs of research and generating impact. It might not be through patented technology, it could be more about consultancy, which is another big opportunity for us to expand our services to the University.

How do you think Oxford compares to other tech clusters and academic ecosystems, in terms of innovation?

Matt: There are lots of great universities out there, but Oxford University is overflowing with intellectual property (IP). University research now underpins around 75 per cent of the world’s key inventions, so no matter where you are geographically, any organisation would like access to that.

Cambridge have a great history of producing companies that have been successful. They started earlier and were the first British institution in that space. They are also doing a great job. This combination has attracted investment and it has attracted great people.

Oxford may have joined the game later, but we are now creating more spinouts a year than Cambridge are, substantially more. The quality of the academic researchers is as good at both universities.

I think the media sometimes like to pigeonhole people.  They see Cambridge as the business university and Oxford as the place for technical experts. We have to find a way of making sure that people understand that we do the business bit just as well. That will take some effort - a combined effort across the university. We are operating at a level which is equivalent with the best universities in the US as well. But it is about raising people’s awareness as much as anything else.

What is the one thing that you would like people to know about the Oxford ecosystem?

Matt: More than anything else I would like people to understand that Oxford is the most vibrant ecosystem in the UK, Europe and probably the US. And it is only going to get better. The more that we can get that out to people, the better. I hope people will see that there is opportunity to create companies, for licensing and for investors to come in and be a part of that success story.

Adam: In the UK and Europe the Oxford ecosystem is unparalleled. You have the powerhouse of the University research, combined with access to the world’s largest investment fund dedicated to a single institution. And there is what I would consider to be the best tech transfer office working in Europe, supporting it all. I think that is an incredibly powerful combination.