Plant scientists at the University of Cambridge have found that the cucumber mosaic virus (CMV) alters gene expression in the tomato plants it infects, causing changes to air-borne chemicals – the scent – emitted by the plants. Bees can smell these subtle changes, and glasshouse experiments have shown that bumblebees prefer infected plants over healthy ones.

Scientists say that by indirectly manipulating bee behaviour to improve pollination of infected plants by changing their scent, the virus is effectively paying its host back. This may also benefit the virus: helping to spread the pollen of plants susceptible to infection and, in doing so, inhibiting the chance of virus-resistant plant strains emerging.

The authors of the new study, published today in the journal PLOS Pathogens, say that understanding the smells that attract bees, and reproducing these artificially by using similar chemical blends, may enable growers to protect or even enhance yields of bee-pollinated crops.

“Bees provide a vital pollination service in the production of three-quarters of the world’s food crops. With their numbers in rapid decline, scientists have been searching for ways to harness pollinator power to boost agricultural yields,” said study principal investigator Dr John Carr, Head of Cambridge’s Virology and Molecular Plant Pathology group.

“Better understanding the natural chemicals that attract bees could provide ways of enhancing pollination, and attracting bees to good sources of pollen and nectar – which they need for survival,” Carr said.

He conducted the study with Professor Beverley Glover, Director of Cambridge University Botanic Garden, where many of the experiments took place, and collaborators at Rothamsted Research.

CMV is transmitted by aphids – bees don’t carry the virus. It’s one of the most prevalent pathogens affecting tomato plants, resulting in small plants with poor-tasting fruits that can cause serious losses to cultivated crops.

Not only is CMV one of the most damaging viruses for horticultural crops, but it also persists in wild plant populations, and Carr says the new findings may explain why:

“We were surprised that bees liked the smell of the plants infected with the virus – it made no sense. You’d think the pollinators would prefer a healthy plant. However, modelling suggested that if pollinators were biased towards diseased plants in the wild, this could short-circuit natural selection for disease resistance,” he said.

“The virus is rewarding disease-susceptible plants, and at the same time producing new hosts it can infect to prevent itself from going extinct. An example, perhaps, of what’s known as symbiotic mutualism.”

The increased pollination from bees may also compensate for a decreased yield of seeds in the smaller fruits of virus-infected plants, say the scientists.

The findings also reveal a new level of complexity in the evolutionary ‘arms race’ between plants and viruses, in which it is classically believed that plants continually evolve new forms of disease-resistance while viruses evolve new ways to evade it.

“We would expect the plants susceptible to disease to suffer, but in making them more attractive to pollinators the virus gives these plants an advantage. Our results suggest that the picture of a plant-pathogen arms race is more complex than previously thought, and in some cases we should think of viruses in a more positive way,” said Carr.

Plants emit ‘volatiles’, air-borne organic chemical compounds involved in scent, to attract pollinators and repulse plant-eating animals and microbes. Humans have used them for thousands of years as perfumes and spices.

The researchers grew plants in individual containers, and collected air with emissions from CMV-infected plants, as well as ‘mock-infected’ control plants.

Through mass spectrometry, researchers could see the change in emissions induced by the virus. They also found that bumblebees could smell the changes. Released one by one in a small ‘flight arena’ in the Botanic Gardens, and timed with a stopwatch by researchers, the bees consistently headed to the infected plants first, and spent longer at those plants.

“Bees are far more sensitive to the blends of volatiles emitted by plants and can detect very subtle differences in the mix of chemicals. In fact, they can even be trained to detect traces of chemicals emitted by synthetic substances, including explosives and drugs,” said Carr.

Analysis revealed that the virus produces a factor called 2b, which reprograms genetic expression in the tomato plants and causes the change in scent.

Mathematical modelling by plant disease epidemiologist Dr Nik Cunniffe, also in the Department of Plant Sciences at Cambridge, explored how the experimental findings apply outside the glasshouse. The model showed how pollinator bias for infected plants can cause genes for disease-susceptibility to persist in plant populations over extremely large numbers of generations.

The latest study is the culmination of work spanning almost eight years (and multiple bee stings). The findings will form the basis of a new collaboration with the Royal Horticultural Society, in which they aim to increase pollinator services for cultivated crops.

With the global population estimated to reach nine billion people by 2050, producing enough food will be one of this century’s greatest challenges. Carr, Glover and Cunniffe are all members of the Cambridge Global Food Security Initiative at Cambridge, which is involved in addressing the issues surrounding food security at local, national and international scales.

The use of state-of-the-art experimental glasshouses at Cambridge Botanic Garden, and equipment at Cambridge and Rothamsted, was funded by the Leverhulme Trust.

Researchers have discovered a gene signature in healthy brains that echoes the pattern in which Alzheimer’s disease spreads through the brain much later in life. Thefindings, published in the journal Science Advances, could help uncover the molecular origins of this devastating disease, and may be used to develop preventative treatments for at-risk individuals to be taken well before symptoms appear.

The results, by researchers from the University of Cambridge, identified a specific signature of a group of genes in the regions of the brain which are most vulnerable to Alzheimer’s disease. They found that these parts of the brain are vulnerable because the body’s defence mechanisms against the proteins partly responsible for Alzheimer’s disease are weaker in these areas.

Healthy individuals with this specific gene signature are highly likely to develop Alzheimer’s disease in later life, and would most benefit from preventative treatments, if and when they are developed for human use.

Alzheimer’s disease, the most common form of dementia, is characterised by the progressive degeneration of the brain. Not only is the disease currently incurable, but its molecular origins are still unknown. Degeneration in Alzheimer’s disease follows a characteristic pattern: starting from the entorhinal region and spreading out to all neocortical areas. What researchers have long wondered is why certain parts of the brain are more vulnerable to Alzheimer’s disease than others.

“To answer this question, what we’ve tried to do is to predict disease progression starting from healthy brains,” said senior author Professor Michele Vendruscolo of the Centre for Misfolding Diseases at Cambridge’s Department of Chemistry. “If we can predict where and when neuronal damage will occur, then we will understand why certain brain tissues are vulnerable, and get a glimpse at the molecular origins of Alzheimer’s disease.”

One of the hallmarks of Alzheimer’s disease is the build-up of protein deposits, known as plaques and tangles, in the brains of affected individuals. These deposits, which accumulate when naturally-occurring proteins in the body fold into the wrong shape and stick together, are formed primarily of two proteins: amyloid-beta and tau.

“We wanted to know whether there is something special about the way these proteins behave in vulnerable brain tissue in young individuals, long before the typical age of onset of the disease,” said Vendruscolo.

Vendruscolo and his colleagues found that part of the answer lay within the mechanism of control of amyloid-beta and tau. Through the analysis of more than 500 samples of healthy brain tissues from the Allen Brain Atlas, they identified a signature of a group of genes in healthy brains. When compared with tissue from Alzheimer’s patients, the researchers found that this same pattern is repeated in the way the disease spreads in the brain.

“Vulnerability to Alzheimer’s disease isn’t dictated by abnormal levels of the aggregation-prone proteins that form the characteristic deposits in disease, but rather by the weaker control of these proteins in the specific brain tissues that first succumb to the disease,” said Vendruscolo.

Our body has a number of effective defence mechanisms which protect it against protein aggregation, but as we age, these defences get weaker, which is why Alzheimer’s generally occurs in later life. As these defence mechanisms, collectively known as protein homeostasis systems, get progressively impaired with age, proteins are able to form more and more aggregates, starting from the tissues where protein homeostasis is not so strong in the first place.

Earlier this year, the same researchers behind the current study identified a possible ‘neurostatin’ that could be taken by healthy individuals in order to slow or stop the progression of Alzheimer’s disease, in a similar way to how statins are taken to prevent heart disease. The current results suggest a way to exploit the gene signature to identify those individuals most at risk and who would most benefit from taking a neurostatin in earlier life.

Although a neurostatin for human use is still quite some time away, a shorter-term benefit of these results may be the development of more effective animal models for the study of Alzheimer’s disease. Since the molecular origins of the disease have been unknown to date, it has been difficult to breed genetically modified mice or other animals that repeat the full pathology of Alzheimer’s disease, which is the most common way for scientists to understand this or any disease in order to develop new treatments.

“It is exciting to consider that the molecular origins identified here for Alzheimer’s may predict vulnerability for other diseases associated with aberrant aggregation – such as ALS, Parkinson’s and frontotemporal dementia,” said Rosie Freer, a PhD student in the Department of Chemistry and the study’s lead author. “I hope that these results will help drug discovery efforts – that by illuminating the origin of disease vulnerability, there will be a clearer target for those working to cure Alzheimer’s.”

“The results of this particular study provide a clear link between the key factors that we have identified as underlying the aggregation phenomenon and the order in which the effects of Alzheimer’s disease are known to spread through the different regions of the brain,” said study co-author Professor Christopher Dobson, who is Master of St John’s College, Cambridge. “Linking the properties of specific protein molecules to the onset and spread of neuronal damage is a crucial step in the quest to find effective drugs to combat this dreadful neurodegenerative condition, and potentially other diseases related to protein misfolding and aggregation.”

Addressing these problems represents the core programme of research of the Centre for Misfolding Diseases, which is directed by Chris Dobson, Tuomas Knowles and Michele Vendruscolo. The primary mission of the Centre is to develop a fundamental understanding of the molecular origins of the variety of disorders associated with the misfolding and aggregation of proteins, which include Parkinson’s disease, ALS and type II diabetes as well as Alzheimer’s disease, and then to use such understanding for the rational design of novel therapeutic strategies.

Reference:
R. Freer et. al. ‘A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease.’ Science Advances (2016). DOI:10.1126/sciadv.1600947

Researchers have built a miniature electro-optical switch which can change the spin – or angular momentum – of a liquid form of light by applying electric fields to a semiconductor device a millionth of a metre in size. Their results, reported in the journal Nature Materials, demonstrate how to bridge the gap between light and electricity, which could enable the development of ever faster and smaller electronics.

There is a fundamental disparity between the way in which information is processed and transmitted by current technologies. To process information, electrical charges are moved around on semiconductor chips; and to transmit it, light flashes are sent down optical fibres. Current methods of converting between electrical and optical signals are both inefficient and slow, and researchers have been searching for ways to incorporate the two.

In order to make electronics faster and more powerful, more transistors need to be squeezed onto semiconductor chips. For the past 50 years, the number of transistors on a single chip has doubled every two years – this is known as Moore’s law. However, as chips keep getting smaller, scientists now have to deal with the quantum effects associated with individual atoms and electrons, and they are looking for alternatives to the electron as the primary carrier of information in order to keep up with Moore’s law and our thirst for faster, cheaper and more powerful electronics.

The University of Cambridge researchers, led by Professor Jeremy Baumberg from the NanoPhotonics Centre, in collaboration with researchers from Mexico and Greece, have built a switch which utilises a new state of matter called a Polariton Bose-Einstein condensate in order to mix electric and optical signals, while using miniscule amounts of energy.

Polariton Bose-Einstein condensates are generated by trapping light between mirrors spaced only a few millionths of a metre apart, and letting it interact with thin slabs of semiconductor material, creating a half-light, half-matter mixture known as a polariton.

Putting lots of polaritons in the same space can induce condensation – similar to the condensation of water droplets at high humidity – and the formation of a light-matter fluid which spins clockwise (spin-up) or anticlockwise (spin-down). By applying an electric field to this system, the researchers were able to control the spin of the condensate and switch it between up and down states. The polariton fluid emits light with clockwise or anticlockwise spin, which can be sent through optical fibres for communication, converting electrical to optical signals.

“The polariton switch unifies the best properties of electronics and optics into one tiny device that can deliver at very high speeds while using minimal amounts of power,” said the paper’s lead author Dr Alexander Dreismann from Cambridge’s Cavendish Laboratory.

“We have made a field-effect light switch that can bridge the gap between optics and electronics,” said co-author Dr Hamid Ohadi, also from the Cavendish Laboratory. “We’re reaching the limits of how small we can make transistors, and electronics based on liquid light could be a way of increasing the power and efficiency of the electronics we rely on.”

While the prototype device works at cryogenic temperatures, the researchers are developing other materials that can operate at room temperature, so that the device may be commercialised. The other key factor for the commercialisation of the device is mass production and scalability. “Since this prototype is based on well-established fabrication technology, it has the potential to be scaled up in the near future,” said study co-author Professor Pavlos Savvidis from the FORTH institute in Crete, Greece.

The team is currently exploring options for commercialising the technology as well as integrating it with the existing technology base.

The research is funded as part of a UK Engineering and Physical Sciences Research Council (EPSRC) investment in the Cambridge NanoPhotonics Centre, as well as the European Research Council (ERC) and the Leverhulme Trust.

Reference:
A. Dreismann et al. ‘A sub-femtojoule electrical spin-switch based on optically trapped polariton condensates.’ Nature Materials (2016). DOI: 10.1038/nmat4722

Our brains naturally shrink with age, but scientists are increasingly recognising that obesity – already linked to conditions such as diabetes, cancer and heart disease – may also affect the onset and progression of brain ageing; however, direct studies to support this link are lacking.

In a cross-sectional study – in other words, a study that looks at data from individuals at one point in time – researchers looked at the impact of obesity on brain structure across the adult lifespan to investigate whether obesity was associated with brain changes characteristic of ageing. The team studied data from 473 individuals between the ages of 20 and 87, recruited by the Cambridge Centre for Aging and Neuroscience. The results are published in the journal Neurobiology of Aging.

The researchers divided the data into two categories based on weight: lean and overweight. They found striking differences in the volume of white matter in the brains of overweight individuals compared with those of their leaner counterparts. Overweight individuals had a widespread reduction in white matter compared to lean people.

Comparison of grey matter (brown) and white matter (yellow) in sex-matched subjects A (56 years, BMI 19.5) and B (50 years, BMI 43.4). Credit: Lisa Ronan

The team then calculated how white matter volume related to age across the two groups. They discovered that an overweight person at, say, 50 years old had a comparable white matter volume to a lean person aged 60 years, implying a difference in brain age of 10 years.

Strikingly, however, the researchers only observed these differences from middle-age onwards, suggesting that our brains may be particularly vulnerable during this period of ageing.

“As our brains age, they naturally shrink in size, but it isn’t clear why people who are overweight have a greater reduction in the amount of white matter,” says first author Dr Lisa Ronan from the Department of Psychiatry at the University of Cambridge, “We can only speculate on whether obesity might in some way cause these changes or whether obesity is a consequence of brain changes.”

Senior author Professor Paul Fletcher, from the Department of Psychiatry, adds: “We’re living in an ageing population, with increasing levels of obesity, so it’s essential that we establish how these two factors might interact, since the consequences for health are potentially serious.

“The fact that we only saw these differences from middle-age onwards raises the possibility that we may be particularly vulnerable at this age. It will also be important to find out whether these changes could be reversible with weight loss, which may well be the case.”

Despite the clear differences in the volume of white matter between lean and overweight individuals, the researchers found no connection between being overweight or obese and an individual’s cognitive abilities, as measured using a standard test similar to an IQ test.

Co-author Professor Sadaf Farooqi, from the Wellcome Trust–Medical Research Council Institute of Metabolic Science at Cambridge, says: “We don’t yet know the implications of these changes in brain structure. Clearly, this must be a starting point for us to explore in more depth the effects of weight, diet and exercise on the brain and memory.”

The research was supported by the Bernard Wolfe Health Neuroscience Fund, the Wellcome Trust and the Biotechnology and Biological Sciences Research Council.

Reference
Ronan, L et al. Obesity associated with increased brain-age from mid-life.Neurobiology of Aging; e-pub 27 July 2016; DOI: 10.1016/j.neurobiolaging.2016.07.010

To date, researchers have identified hundreds of genetic variants that increase or decrease the risk of developing diseases from cancer and diabetes to tuberculosis and mental health disorders. However, for the majority of such genes, scientists do not yet know how the variants contribute to disease – indeed, scientists do not even understand how many of the genes function.

One such gene is C13orf31, found on chromosome 13. Scientists have previously shown that variants of the gene in which a single nucleotide – the A, C, G and T of DNA – differs are associated with risk for the infectious disease leprosy, and for the chronic inflammatory diseases Crohn’s disease and a form of childhood arthritis known as systemic juvenile idiopathic arthritis.

In a study published today in the journal Nature Immunology and led by the University of Cambridge, researchers studied how this gene works and have identified a new mechanism that drives energy metabolism in our immune cells. Immune cells help fight infection, but in some cases attack our own bodies, causing inflammatory disease.

Using mice in which the mouse equivalent of the C13orf31 gene had been altered, the team showed that the gene produces a protein that acts as a central regulator of the core metabolic functions in a specialist immune cell known as a macrophage (Greek for ‘big eater’). These cells are so named for their ability to ‘eat’ invading organisms, breaking them down and preventing the infection from spreading. The protein, which the researchers named FAMIN (Fatty Acid Metabolic Immune Nexus), determines how much energy is available to the macrophages.

The researchers used a gene-editing tool known as CRISPR/Cas9, which acts like a biological ‘cut and paste’ tool, to edit a single nucleotide in the risk genes within the mouse’s genome to show that even a tiny change to our genetic makeup could have a profound effect, making the mice more susceptible to sepsis (blood poisoning). This showed that FAMIN influences the cell’s ability to perform its normal function, controlling its capacity to kill bacteria and release molecules known as ‘mediators’ that trigger an inflammatory response, a key part of fighting infection and repairing damage in the body.

Professor Arthur Kaser from the Department of Medicine at the University of Cambridge, who led the research, says: “By taking a disease risk gene whose role was completely unknown and studying its function down to the level of a single nucleotide, we’ve discovered an entirely new and important mechanism that affects our immune system’s ability to carry out its role as the body’s defence mechanism.”

Dr Zaeem Cader, the study’s first author, adds: “Although it’s too early to say how this discovery might influence new treatments, genetics can provide invaluable insights that might help in identifying potential drug targets for so-called precision medicines, tailored to an individual’s genetic make-up.”

The research was largely funded by the European Research Council and the Wellcome Trust, with support from National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.

Reference
Cader, MZ et al. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nature Immunology; 1 Aug 2016; DOI: 10.1038/ni.3532

The majority of the exhibits are from the Museum’s own rich collections, and those from the founding bequest of Viscount Fitzwilliam in 1816 can never leave the building and can only be seen at the Museum. For the first time, the secrets of master illuminators and the sketches hidden beneath the paintings will be revealed in a major exhibition presenting new art historical and scientific research.

Spanning the 8th to the 17th centuries, the 150 manuscripts and fragments in COLOUR: The Art and Science of Illuminated Manuscripts guide us on a journey through time, stopping at leading artistic centres of medieval and Renaissance Europe. Exhibits highlight the incredible diversity of the Fitzwilliam’s collection: including local treasures, such as the Macclesfield Psalter made in East Anglia c.1330-1340, a leaf with a self-portrait made by the Oxford illuminator William de Brailes c.1230-1250, and a medieval encyclopaedia made in Paris c.1414 for the Duke of Savoy.

Four years of cutting-edge scientific analysis and discoveries made at the Fitzwilliam have traced the creative process from the illuminators’ original ideas through their choice of pigments and painting techniques to the completed masterpieces.

“Leading artists of the Middle Ages and early Renaissance did not think of art and science as opposing disciplines,” said curator, Dr Stella Panayotova, Keeper of Manuscripts and Printed Books. “Instead, drawing on diverse sources of knowledge, they conducted experiments with materials and techniques to create beautiful works that still fascinate us today.”

Merging art and science, COLOUR shares the research of MINIARE (Manuscript Illumination: Non-Invasive Analysis, Research and Expertise), an innovative project based at the Fitzwilliam. Collaborating with scholars from the University of Cambridge and international experts, the Museum’s curators, scientists and conservators have employed pioneering analytical techniques to identify the materials and methods used by illuminators.

“This has been an exciting project,” said research scientist, Dr Paola Ricciardi. “By combining imaging and spectroscopic analysis — methods more commonly associated with remote sensing and analytical chemistry — and by exploring such a diverse range of manuscripts, we can begin to understand how illuminators actually worked.”

“A popular misconception is that all manuscripts were made by monks and contained religious texts, but from the 11th century onwards professional scribes and artists were increasingly involved in a thriving book trade, producing both religious and secular texts. Scientific examination has revealed that illuminators sometimes made use of materials associated with other media, such as egg yolk, which was traditionally used as a binder by panel painters.”

Book of Hours illuminated by Vante di Gabriello di Vante Attavanti (act. c.1480-1485), Florence, c.1480 – c.1490 © Fitzwilliam Museum, Cambridge1 of 6

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Other discoveries include pigments rarely associated with manuscript illumination – such as the first ever example of smalt detected in a Venetian manuscript. Smalt, obtained by grinding blue glass, was found in a Venetian illumination book made c.1420. Evidently, the artist who painted it had close links with the famed glassmakers of Murano. This example predates by half a century the documented use of smalt in Venetian easel paintings.

Analyses of sketches lying beneath the paint surfaces, and of later additions and changes to paintings help to shed light on manuscripts and their owners. One French prayer book, made c.1430, was adapted over three generations to reflect the personal circumstances and dynastic anxieties of a succession of aristocratic women.

Adam and Eve were originally shown naked in an ABC commissioned c.1505 by the French Queen, Anne of Brittany (1476-1514) for her five-year-old daughter. However, a later owner, offended by the nudity, gave Eve a veil and Adam a skirt. Infrared imaging techniques and mathematical modelling have made it possible to reconstruct the original composition without harming the manuscript.

The Museum’s treasures will be displayed alongside carefully selected loans — celebrated manuscripts from Cambridge libraries as well as other institutions in the UK and overseas. These include an 8th century Gospel Book from Corpus Christi College, the University Library’s famous Life of Edward the Confessor, magnificent Apocalypses from Trinity College and Lambeth Palace, London, and a unique model book from Göttingen University.

Visitors will be encouraged to make their own discoveries in the exhibition galleries and online through a new, free digital resource: ILLUMINATED: Manuscripts in the Making. With hundreds of high resolution digital images and infrared photographs, this interactive, cross-disciplinary resource offers users in-depth information on the manuscripts’ contents, patrons, cultural and historical contexts, as well as scientific data relating to artists’ techniques and materials.

With over 300 illustrations in full colour, the authoritative exhibition catalogue encompasses subjects as diverse as the trade in pigments, painting techniques, the medieval science of optics and modern-day forgeries. Catalogue entries and essays by leading experts offer readers insight into all aspects of colour from the practical application of pigments to its symbolic meaning.

“We are delighted to be presenting this exhibition in our bicentenary year,” said director, Tim Knox. “Ten years ago The Cambridge Illuminations was the Museum’s first ever record-breaking exhibition, attracting over 80,000 visitors. People were enchanted by the remarkable beauty and delicacy of the manuscripts. I am convinced that our bicentenary visitors will again be equally inspired by the superb illuminations collected and treasured at the Fitzwilliam for 200 years, and will value this rare opportunity to find out how they were made and how we are preserving them for the future.”

COLOUR: The Art and Science of Illuminated Manuscripts will run during the second half of the Fitzwilliam’s bicentenary year, from 30 July to 30 December 2016. Admission is free.

New research on the financial practices surrounding a ‘wonder drug’ with a more than 90% cure rate for hepatitis C – a blood-borne infection that damages the liver over many years – shows how this medical breakthrough, developed with the help of public funding, was acquired by a major pharmaceutical company following a late-stage bidding war.

The research shows how that company more than doubled the drug’s price over original pricing estimates, calculating “how much health systems could bear” according to researchers, and channelled billions of dollars in profits into buying its own shares rather than funding further research.

In this way, the company, Gilead Sciences, passed significant rewards on to shareholders while charging public health services in the US up to $86k per patient, and NHS England almost £35k per patient, for a three month course of the drug.

The high prices have contributed to a rationing effect: many public systems across the US and Europe treat only the sickest patients with the new drug, despite its extraordinary cure rate, and the fact that earlier treatment of an infectious disease gives it less opportunity to spread.

Gilead’s strategy of acquisitions and buybacks is an example of an industry-wide pattern, say the researchers. Many big pharmaceutical companies now rely on innovation emerging from public institutes, universities, and venture-capital supported start-ups – acquiring the most promising drug compounds once there is a level of “certainty”, rather than investing in their own internal research and development.

The researchers, from Cambridge University’s Department of Sociology, say this effectively leaves the public “paying twice”: firstly for the initial research, and then for patent-protected high priced medications. A summary of their research has been commissioned by the British Medical Journal (BMJ) and is published today.

“Large pharmaceutical companies rarely take a drug from early stage research all the way to patients. They often operate as regulatory and acquisition specialists, returning most of the subsequent profits to shareholders and keeping some to make further acquisitions,” said lead researcher Victor Roy, a Cambridge Gates Scholar.

The study’s senior author, Prof Lawrence King, said: “Drug research involves trial and error, and can take years to bear fruit – too long for companies that need to show the promise of annual growth to investors, so acquisitions are often the best way to generate this growth.”

There are an estimated 150 million people worldwide chronically infected with hepatitis C. It disproportionately affects vulnerable groups such as drug users and HIV sufferers, and can ultimately lead to liver failure through cirrhosis if left untreated.

Roy and King’s article tells the story of the curative drug Sofosbuvir. The compound was developed by a start-up that emerged from an Emory-based laboratory that received funding from the US National Institutes of Health and the US Veterans Administration.

The start-up, Pharmasset, eventually raised private funding to develop sofosbuvir. When Phase II trials proved more promising than Gilead’s in-house hepatitis C prospects, it acquired Pharmasset for $11bn following a bidding war – the final weeks of which saw Pharmasset’s valuation rocket by nearly 40%.

“The cost of this late stage arms race for revenues has become part of the industry justification for high drug prices,” write Roy and King.

Once Sofosbuvir was market-ready in 2013, Gilead set a price of $84k. A US Senate investigation later revealed that Pharmasset had initially considered a price of $36k.

By the first quarter of 2016, Gilead had accumulated over $35bn in revenue from hepatitis C medicines in a little over two years – nearly 40 times Gilead and Pharmasset’s combined reported costs for developing the medicines.

Last year, Gilead announced that a lion’s share of those profits – some $27bn – will go towards ‘share buybacks’: purchasing its own shares to increase the value of the remaining ones for shareholders. By contrast, between 2013 and 2015 Gilead increased research investment by $0.9bn to $3bn total.

“Share buybacks are a financial manoeuvre that emerged during the early 1980s due to a change in rules for corporations by the Reagan administration. The financial community now expects companies to reward shareholders with buybacks, but directing profit into buybacks can mean cannibalising innovation,” said Roy.

A further example they cite is that of Merck, who spent $8.4bn in 2014 to acquire a drug developer specialising in staph infections. The next year they closed the developer’s early stage research unit, laying off 120 staff. Three weeks after that, Merck announced an extra $10bn in share buybacks.

In the BMJ article, the researchers set out a number of suggestions to counter the consequences of the current financial model. These include giving health systems greater bargaining power to negotiate deals for breakthrough treatments, and limiting share buybacks.

Roy and King also highlight a possible future model that uses a mix of grants and major milestone prizes to “push” and “pull” promising therapies into wider application, and, crucially, uncouples drug prices from supposed development costs, including those added by shareholder expectations. They write that this approach may be attempted for areas of major public health concern.

“The treatments for Hepatitis C may portend a future of expensive therapies for Alzheimer’s to many cancers to HIV/AIDS. Health systems and patients could face growing financial challenges,” said King.

“We need to recognise what current business models around drug development might mean for this future.”

New research shows that natural accumulations of carbon dioxide (CO₂) that have been trapped underground for around 100,000 years have not significantly corroded the rocks above, suggesting that storing CO₂ in reservoirs deep underground is much safer and more predictable over long periods of time than previously thought.

These findings, published today in the journal Nature Communications, demonstrate the viability of a process called carbon capture and storage (CCS) as a solution to reducing carbon emissions from coal and gas-fired power stations, say researchers.

CCS involves capturing the carbon dioxide produced at power stations, compressing it, and pumping it into reservoirs in the rock more than a kilometre underground.

The CO₂ must remain buried for at least 10,000 years to avoid the impacts on climate. One concern is that the dilute acid, formed when the stored CO₂ dissolves in water present in the reservoir rocks, might corrode the rocks above and let the CO₂ escape upwards.

By studying a natural reservoir in Utah, USA, where CO₂ released from deeper formations has been trapped for around 100,000 years, a Cambridge-led research team has now shown that CO₂ can be securely stored underground for far longer than the 10,000 years needed to avoid climatic impacts.

Their new study shows that the critical component in geological carbon storage, the relatively impermeable layer of “cap rock” that retains the CO₂, can resist corrosion from CO₂-saturated water for at least 100,000 years.

“Carbon capture and storage is seen as essential technology if the UK is to meet its climate change targets,” says principle investigator Professor Mike Bickle, Director of the Cambridge Centre for Carbon Capture and Storage at the University of Cambridge.

“A major obstacle to the implementation of CCS is the uncertainty over the long-term fate of the CO₂ which impacts regulation, insurance, and who assumes the responsibility for maintaining CO₂ storage sites. Our study demonstrates that geological carbon storage can be safe and predictable over many hundreds of thousands of years.”

The key component in the safety of geological storage of CO₂ is an impermeable cap rock over the porous reservoir in which the CO₂ is stored. Although the CO₂ will be injected as a dense fluid, it is still less dense than the brines originally filling the pores in the reservoir sandstones, and will rise until trapped by the relatively impermeable cap rocks.

“Some earlier studies, using computer simulations and laboratory experiments, have suggested that these cap rocks might be progressively corroded by the CO₂-charged brines, formed as CO₂ dissolves, creating weaker and more permeable layers of rock several metres thick and jeopardising the secure retention of the CO₂,” explains lead author Dr Niko Kampman.

“However, these studies were either carried out in the laboratory over short timescales or based on theoretical models. Predicting the behaviour of CO₂ stored underground is best achieved by studying natural CO₂ accumulations that have been retained for periods comparable to those needed for effective storage.”

To better understand these effects, this study, funded by the UK Natural Environment Research Council and the UK Department of Energy and Climate Change, examined a natural reservoir where large natural pockets of CO₂ have been trapped in sedimentary rocks for hundreds of thousands of years. Sponsored by Shell, the team drilled deep down below the surface into one of these natural CO₂ reservoirs to recover samples of the rock layers and the fluids confined in the rock pores.

The team studied the corrosion of the minerals comprising the rock by the acidic carbonated water, and how this has affected the ability of the cap rock to act as an effective trap over geological periods of time. Their analysis studied the mineralogy and geochemistry of cap rock and included bombarding samples of the rock with neutrons at a facility in Germany to better understand any changes that may have occurred in the pore structure and permeability of the cap rock.

They found that the CO₂ had very little impact on corrosion of the minerals in the cap rock, with corrosion limited to a layer only 7cm thick. This is considerably less than the amount of corrosion predicted in some earlier studies, which suggested that this layer might be many metres thick.

The researchers also used computer simulations, calibrated with data collected from the rock samples, to show that this layer took at least 100,000 years to form, an age consistent with how long the site is known to have contained CO₂.

The research demonstrates that the natural resistance of the cap rock minerals to the acidic carbonated waters makes burying CO₂ underground a far more predictable and secure process than previously estimated.

“With careful evaluation, burying carbon dioxide underground will prove very much safer than emitting CO₂ directly to the atmosphere,” says Bickle.

The Cambridge research into the CO₂ reservoirs in Utah was funded by the Natural Environment Research Council (CRIUS consortium of Cambridge, Manchester and Leeds universities and the British Geological Survey) and the Department of Energy and Climate Change.

The project involved an international consortium of researchers led by Cambridge, together with Aarchen University (Germany), Utrecht University (Netherlands), Utah State University (USA), the Julich Centre for Neutron Science, (Garching, Germany), Oak Ridge National Laboratory (USA),  the British Geological Survey, and Shell Global Solutions International (Netherlands).

Reference:

N. Kampman, et al. “Observational evidence confirms modelling of the long-term integrity of CO2-reservoir caprocks” Nature Communications 28 July 2016.

In a study published today in the Proceedings of the National Academy of Sciences, researchers from the University of Cambridge and University College London (UCL) used magnetic resonance imaging (MRI) to study the brain structure of almost 300 individuals aged 14-24 years old.

By comparing the brain structure of teenagers of different ages, they found that during this important period of development, the outer regions of the brain, known as the cortex, shrink in size, becoming thinner. However, as this happens, levels of myelin – the sheath that ‘insulates’ nerve fibres, allowing them to communicate efficiently – increase within the cortex.

Previously, myelin was thought mainly to reside in the so-called ‘white matter’, the brain tissue that connects areas of the brain and allows for information to be communicated between brain regions. However, in this new study, the researchers show that it can also be found within the cortex, the ‘grey matter’ of the brain, and that levels increase during teenage years. In particular, the myelin increase occurs in the ‘association cortical areas’, regions of the brain that act as hubs, the major connection points between different regions of the brain network.

Dr Kirstie Whitaker from the Department of Psychiatry at the University of Cambridge, the study’s first author, says: “During our teenage years, our brains continue to develop. When we’re still children, these changes may be more dramatic, but in adolescence we see that the changes refine the detail. The hubs that connect different regions are becoming set in place as the most important connections strengthen. We believe this is where we are seeing myelin increasing in adolescence.”

The researchers compared these MRI measures to the Allen Brain Atlas, which maps regions of the brain by gene expression – the genes that are ‘switched on’ in particular regions. They found that those brain regions that exhibited the greatest MRI changes during the teenage years were those in which genes linked to schizophrenia risk were most strongly expressed.

“Adolescence can be a difficult transitional period and it’s when we typically see the first signs of mental health disorders such as schizophrenia and depression,” explains Professor Ed Bullmore, Head of Psychiatry at Cambridge. “This study gives us a clue why this is the case: it’s during these teenage years that those brain regions that have the strongest link to the schizophrenia risk genes are developing most rapidly.

“As these regions are important hubs that control how regions of our brain communicate with each other, it shouldn’t be too surprising that when something goes wrong there, it will affect how smoothly our brains work. If one imagines these major hubs of the brain network to be like international airports in the airline network, then we can see that disrupting the development of brain hubs could have as big an impact on communication of information across the brain network as disruption of a major airport, like Heathrow, will have on flow of passenger traffic across the airline network.”

The researchers are confident about the robustness of their findings as they divided their participants into a ‘discovery cohort’ of 100 young people and a ‘validation cohort’ of almost 200 young people to ensure the results could be replicated.

The study was funded by a Strategic Award from the Wellcome Trust to the Neuroscience in Psychiatry Network (NSPN) Consortium.

Dr Raliza Stoyanova in the Neuroscience and Mental Health team at Wellcome, which funded the study, comments: “A number of mental health conditions first manifest during adolescence. Although we know that the adolescent brain undergoes dramatic structural changes, the precise nature of those changes and how they may be linked to disease is not understood.

“This study sheds much needed light on brain development in this crucial time period, and will hopefully spark further research in this area, and tell us more about the origins of serious mental health conditions such as schizophrenia.”

Reference
Whitaker, KJ, Vertes, PE et al. Adolescence is associated with genomically patterned consolidation of the hubs of the human brain connectome. PNAS; 25 July 2016; DOI: 10.1073/pnas.1601745113

One of the world’s largest anti-poverty measures – a scheme designed to guarantee 100 days’ work to poor, rural households in India – has become bogged down in a bureaucratic quagmire, according to recently-published research.

The Mahatma Gandhi National Rural Employment Guarantee Act, 2005 (MNREGA) is the subject of Paper Tiger by Cambridge anthropologist Nayanika Mathur. The Act covers all of India’s rural population (or about 70% of India’s 1.3 billion people) and is supposed to guarantee work for unskilled labourers at the minimum wage.

Launched amid huge fanfare in February 2006, MNREGA’s performance continues to be the object of strenuous debate in India. “MNREGA was put forward as a radical, progressive move, enshrining the right to work,” said Mathur. “This was a sophisticated legislation that potentially has a lot of promise. But I wanted to see first hand how a law authored by elites in New Delhi, in English, gets put into practice in one of the poorest parts of India.”

Mathur chose to study this welfarist statute through an innovative anthropological method: embedding herself within the development bureaucracy of the state in a remote and impoverished Himalayan district.

She spent a total of 18 months following the implementation of MNREGA through different levels of the Indian state. Almost a year was spent living in the town of Gopeshwar in Chamoli district, in the remote central Himalayan state of Uttarakhand. With its high levels of poverty, unemployment and distress out-migration, Mathur chose to base her research in the Himalaya to see how MNREGA was – or wasn’t – being put into practice at a local level.

“The locals thought I was very odd,” said Mathur. “They weren’t suspicious of me, but they couldn’t understand why I was there in the first place. The bureaucrats, in particular, didn’t think anything they do is of worth and feel very neglected and distant from the centre. It took months for the awkwardness to subside and for me to be accepted. But the surprise they felt at having someone take (what they consider) their dull, repetitive bureaucratic work seriously, never quite left them.”

As Mathur followed the MNREGA around the high Himalaya she was surprised to hear it described as an “unimplementable” programme. Despite the desperate need for employment opportunities in rural Himalaya, the welfare scheme was conspicuous by its absence. Paper Tiger, as it meticulously traces the implementation of the MNREGA, presents some surprising findings.

The book argues that MNREGA has largely failed, not because of corruption (as is commonly assumed), but because of its anti-corruption measures. In her role as a participant-observer in small, crumbling government offices in Himalayan India, Mathur found that the legal requirement for transparent functioning had led to an exponential increase in the paperwork demanded of the state bureaucracy. Along with its sheer laboriousness and complexity, this paperwork was intervening in the traditional system of operation of welfare leading to a complete paralysis in welfare.

The extreme reliance on paper, documents, and files in the Indian bureaucracy has a complicated history in India and can be traced back to the operations of the British colonial state in India. Mathur argues that the seemingly-new drive to hold the contemporary Indian state accountable to its citizenry is, in fact, aggravating the documentary foundations of its bureaucracy.

“Ironically, it is the requirements to render the Indian state transparent and accountable that introduced a crisis of implementation with MNREGA,” notes Mathur.

The drive for transparency at a national level also produced problems specific to the region where Mathur conducted her research. In order to stem corruption, a directive was issued asking for all wages to be paid through bank accounts. This created huge problems in the Himalayas where there are very few bank branches, and those that do exist were located miles away from most villages.

Most problematically, women were at risk of losing control over their own wages as they became dependent either on middlemen or male relatives to operate bank accounts for them. Unwittingly, the push for financial transparency had ended up creating an anti-women system.

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Despite its evident problems, Mathur believes the Act is a clever, canny piece of legislation. In Paper Tiger, she uses the crisis in the implementation of MNREGA as a case study that helps make broader arguments about the nature of the state – and what it means when welfare schemes are found not to be working as they should.

Added Mathur: “My study of the operations of the state in the Indian Himalaya, allows for an understanding of the failure of the developmental Indian state that is not predicated upon corruption, violence, incapacity, sloth, or simple dysfunction.”

“Rather, my attempt here is to make us understand what the welfare state in practice is. For it is only when we really get our heads round the very nature of the beast can we hope to ever reform it.”

Warm Jupiters are large, gas-giant exoplanets—planets found around stars other than the Sun. They are comparable in size to Jupiter and Saturn in our Solar System. But unlike the Sun’s family of giant planets, Warm Jupiters orbit their parent stars at roughly the same distance that Mercury, Venus and the Earth circle the Sun. They take ten to two hundred days to complete a single orbit instead of decades. Their origin is heavily debated topic of research.

It is generally thought that Warm Jupiters cannot form on the orbits that we find them on today; they are too close to their parent stars to have accumulated enough mass, and sufficient gas. Instead, it appeared more likely that they had formed in the outer reaches of their planetary systems and had migrated inward to their current positions. However such a migratory history would also leave a trace. The large gravity of any migrating Warm Jupiter would have disturbed any neighbouring or companion planets, ejecting them from the system.

But, instead of finding “lonely”, companion-less Warm Jupiters, the team found that 11 of the 27 targets they studied have companions ranging in size from Earth-like to Neptune-like.

The team’s analysis, published this week in the Astrophysical Journal, demonstrates the existence of two distinct types of warm Jupiters, each with their own formation and dynamical history.

The two types include those that have smaller planetary companions and thus, likely formed near to where we find them today; and warm Jupiters without any companions indicating that they likely migrated to their current positions.

The presence of many smaller sized planetary companions to warm Jupiters provides our strongest evidence that planets similar to Jupiter and Saturn can assemble on orbits shorter than the Earth’s. “And when we take into account that there is more analysis to come,” says lead-author Chelsea Huang, “the number of Warm Jupiters with smaller neighbours may be even higher. We may find that more than half have companions.”

This result came as a “surprise” according to Amaury Triaud, now a research fellow at the Institute of Astronomy, in Cambridge. “Before starting this study, we had not anticipated this remarkable result. This challenges our ideas about which conditions are sufficient for the formation of planets. It reinforces the view that planets form in richer and more diverse ways than what can be glimpsed from the sole study of the Solar system planets.”

Reference

Huang, C et al. Warm Jupiters are less lonely than Hot Jupiters: close neighbors. Astrophysical Journal; 6 July 2016; DOI:10.3847/0004-637X/825/2/98

Based on a press release prepared by the University of Toronto.

The World Health Organization estimates that 1.3 billion adults worldwide are overweight, and that a further 600 million are obese. The prevalence of adult obesity is 20% in Europe and 31% in North America.

“On average, overweight people lose about one year of life expectancy, and moderately obese people lose about three years of life expectancy,” says Dr Emanuele Di Angelantonio from the University of Cambridge, the lead author. “We also found that men who were obese were at much higher risk of premature death than obese women. This is consistent with previous observations that obese men have greater insulin resistance, liver fat levels, and diabetes risk than women.”

The study found an increased risk of premature death for people who were underweight, as well as for people classed as overweight. The risk increased steadily and steeply as BMI increased. A similar trend was seen in many parts of the world and for all four main causes of death.

Where the risk of death before age 70 would be 19% and 11% for men and women with a normal BMI, the study found that it would be 29.5% and 14.6% for moderately obese men and women. The authors defined premature deaths as those at ages 35-69 years.

The new study brings together information on the causes of any deaths in 3.9 million adults from 189 previous studies in Europe, North America and elsewhere. At entry to the study all were aged between 20 and 90 years old, and were non-smokers who were not known to have any chronic disease when their BMI was recorded. The analysis is of those who then survived at least another five years.

The authors say that assuming that the associations between high BMI and mortality are largely causal, if those who were overweight or obese had WHO-defined normal levels of BMI, then one in 7 premature deaths in Europe and one in 5 in North America would be avoided.

Reference
The Global BMI Mortality Collaboration. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents.Lancet; 13 July 2016; DOI: 10.1016/S0140-6736(16)30175-1

Adapted from a press release from The Lancet

Matter falling into a black hole heats up as it plunges to its doom. Before it passes into the black hole and is lost from view forever, it can reach millions of degrees. At that temperature it shines x-rays into space.

In the 1980s, astronomers discovered that the x-rays coming from black holes vary on a range of timescales and can even follow a repeating pattern with a dimming and re-brightening taking 10 seconds to complete. As the days, weeks and then months progress, the pattern’s period shortens until the oscillation takes place 10 times every second. Then it suddenly stops altogether.

This phenomenon was dubbed a Quasi Periodic Oscillation (QPO). During the 1990s, astronomers began to suspect that the QPO was associated with a gravitational effect predicted by Einstein’s general relativity which suggested that a spinning object will create a kind of gravitational vortex. The effect is similar to twisting a spoon in honey: anything embedded in the honey will be ‘dragged’ around by the twisting spoon. In reality, this means that anything orbiting around a spinning object will have its motion affected. If an object is orbiting at an angle, its orbit will ‘precess’ – in other words, the whole orbit will change orientation around the central object. The time for the orbit to return to its initial condition is known as a precession cycle.

In 2004, NASA launched Gravity Probe B to measure this so-called Lense-Thirring effect around Earth. By analysing the resulting data, scientists confirmed that the spacecraft would turn through a complete precession cycle once every 33 million years. Around a black hole, however, the effect would be much stronger because of the stronger gravitational field: the precession cycle would take just a matter of seconds to complete, close to the periods of the QPOs.

An international team of researchers, including Dr Matt Middleton from the Institute of Astronomy at the University of Cambridge, has used the European Space Agency’s XMM-Newton and NASA’s NuSTAR, both x-ray observatories, to study the effect of black hole H1743-322 on a surrounding flat disc of matter known as an ‘accretion disk’.

Close to a black hole, the accretion disc puffs up into a hot plasma, a state of matter in which electrons are stripped from their host atoms – the precession of this puffed up disc has been suspected to drive the QPO. This can also explain why the period changes – the place where the disc puffs up gets closer to the black hole over weeks and months, and, as it gets closer to the black hole, the faster its Lense-Thirring precession becomes.

The plasma releases high energy radiation that strikes the matter in the surrounding accretion disc, making the iron atoms in the disc shine like a fluorescent light tube. Instead of visible light, the iron releases X-rays of a single wavelength – referred to as ‘a line’. Because the accretion disc is rotating, the iron line has its wavelength distorted by the Doppler effect: line emission from the approaching side of the disc is squashed – blue shifted – and line emission from the receding disc material is stretched – red shifted. If the plasma really is precessing, it will sometimes shine on the approaching disc material and sometimes on the receding material, making the line wobble back and forth over the course of a precession cycle.

It is this ‘wobble’ that has been observed by the researchers.

“Just as general relativity predicts, we’ve seen the iron line wobble as the accretion disk orbits the black hole,” says Dr Middleton. “This is what we’d expect from matter moving in a strong gravitational field such as that produced by a black hole.”

This is the first time that the Lense-Thirring effect has been measured in a strong gravitational field. The technique will allow astronomers to map matter in the inner regions of accretion discs around back holes. It also hints at a powerful new tool with which to test general relativity. Einstein’s theory is largely untested in such strong gravitational fields. If astronomers can understand the physics of the matter that is flowing into the black hole, they can use it to test the predictions of general relativity as never before – but only if the movement of the matter in the accretion disc can be completely understood.

“We need to test Einstein’s general theory of relativity to breaking point,” adds Dr Adam Ingram, the lead author at the University of Amsterdam. “That’s the only way that we can tell whether it is correct or, as many physicists suspect, an approximation – albeit an extremely accurate one.”

Larger X-ray telescopes in the future could help in the search because they could collect the X-rays faster. This would allow astronomers to investigate the QPO phenomenon in more detail. But for now, astronomers can be content with having seen Einstein’s gravity at play around a black hole.

Adapted from a press release by the European Space Agency.

Image: ESA/ATG medialab.

The study, published in Science by researchers at University of Cambridge, Queen Mary University of London (QMUL) and King’s College London, shows that the genetic variation of ribosomal DNA (rDNA) could be driving how the environment within the womb determines an offspring’s attributes. rDNA is the genetic material that forms ribosomes – the protein building machines within the cell.

Lead researcher Professor Vardhman Rakyan from QMUL said: “The fact that genetic variation of ribosomal DNA seems to play such a major role suggests that many human genetics studies in humans could be missing a key part of the puzzle. These studies only looked at a single copy part of individuals’ genomes and never at ribosomal DNA.

“This could be the reason why we’ve only so far been able to explain a small fraction of the heritability of many health conditions, which makes a lot of sense in the context of metabolic diseases, such as type 2 diabetes.”

The environmental factors that play a role alongside genetic factors in determining a person’s attributes are also present in the in-utero environment. When offspring are in the womb, the environment experienced by their mothers (for example, diet, stress, smoking), influences the attributes of their offspring when they are adults. This ‘developmental programming’ is thought to contribute to the obesity and type 2 diabetes epidemic seen today.
A major contributor to this process is ‘epigenetics’. This describes naturally-occurring modifications to genes that control how they are expressed. One such modification involves tagging DNA with chemical compounds called methyl groups. These epigenetic markers determine which genes are expressed or not expressed. Liver cells and kidney cells are genetically identical in terms of their DNA sequence but differ in their epigenetic marks. It has been proposed that in response to a poor in-utero environment, an offspring’s epigenetic profile will change.

The team compared the offspring of pregnant mice when given a low protein diet (8 per cent protein) and a normal diet (20 per cent protein). After they were weaned, all offspring were given a normal diet, and the team then looked at the difference in the offspring’s DNA methylation, from mothers exposed to a low protein diet and those that were not.

Professor Rakyan said: “When cells are stressed, for example when nutrient levels are low, they alter protein production as a survival strategy. In our low protein mice mothers, we saw that their offspring had methylated rDNA. This slowed the expression of their rDNA, which could be influencing the function of ribosomes, and resulted in smaller offspring – as much as 25 per cent lighter.”

These epigenetic effects occur during a critical developmental window while the offspring is in-utero but is a permanent effect that remains into adulthood. A mother’s diet while pregnant is therefore likely to have more severe consequence on the offspring’s epigenetic state than an offspring’s own diet after it has been weaned.

Professor Susan Ozanne from the University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit added: “Perhaps our most surprising finding was that, despite all of our mice being bred to be genetically identical, their rDNA was different. In fact, even within an individual mouse, different copies of rDNA were genetically distinct.”

In any given genome, there are many copies of rDNA, and the researchers found that not all copies of the rDNA were responding in the same way epigenetically. In offspring from mothers who were fed a low protein diet, it was only one form of rDNA – the ‘A-variant’ – that appeared to undergo methylation and affect weight. Professor Ozanne added: “This variation in rDNA appears to be playing a large role in determining the response of the fetus to the in utero environment and therefore its phenotype later in life.”

This means that the epigenetic response of a given mouse is determined by the genetic variation of the rDNA – those who have more A-variant rDNA end up being smaller.

Heritability (how much the risk of a disease is explained by genetic factors) of type 2 diabetes has been estimated to be between 25 and 80 per cent in different studies. However, less than 20 per cent of the heritability of type 2 diabetes has been explained by genome studies of people with the disease. The major role played by genetic variation of rDNA, together with the fact that rDNA analysis would not have been included in these studies, could explain some of this missing heritability.

The findings also complement other studies that have found that mice that are put on high fat diets have offspring who show increased rDNA methylation. This suggests that methylation is a general stress response and may also explain the rise in obesity that is happening across the world.

The study was funded by the Biotechnology and Biological Sciences Research Council, Research Councils UK, the European Union, British Heart Foundation and Medical Research Council.

Reference
Holland, ML et al. Early life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice. Science; 7 July 2016; DOI: 10.1126/science.aaf7040

Adapted from a press release from Queen Mary University of London

The point in our development when the whole body plan is set, just before individual organs start to develop, is known as gastrulation. Understanding this point in very early development is vital to understanding how humans and animals develop and how things go wrong. One of the biggest challenges in studying gastrulation is the very small number of cells that make up an embryo at this stage.

“If we want to better understand the natural world around us, one of the fundamental questions is, how do animals develop?” says Professor Bertie Gottgens from the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute at the University of Cambridge. “How do you turn from an egg into an animal, with all sorts of tissues? Many of the things that go wrong, like birth defects, are caused by problems in early development. We need to have an atlas of normal development for comparison when things go wrong.”

Today, thanks to advances in single-cell sequencing, the team was able to analyse over 1000 individual cells of gastrulating mouse embryos. The result is an atlas of gene expression during very early, healthy mammalian development.

“Single-cell technologies are a major change over what we’ve used before – we can now make direct observations to see what’s going on during the earliest stages of development,” says Dr John Marioni, Research Group Leader at EMBL-EBI, the Wellcome Trust Sanger Institute and the University of Cambridge. “We can look at individual cells and see the whole set of genes that are active at stages of development, which until now have been very difficult to access.

“Once we have that, we can take cells from embryos in which some genetic factors are not working properly at a specific developmental stage, and map them to the healthy atlas to better understand what might be happening.”

To illustrate the usefulness of the atlas, the team studied what happened when a genetic factor essential for the formation of blood cells was removed.

“It wasn’t what we expected at all. We found that cells which in healthy embryos would commit to becoming blood cells would actually become confused in the embryos lacking the key gene, effectively getting stuck,” says Dr Marioni. “What is so exciting about this is that it demonstrates how we can now look at the very small number of cells that are actually making the decision at the precise time point when the decision is being made. It gives us a completely different perspective on development.”

“What is really exciting for me is that we can look at things that we know are important but were never able to see before – perhaps like people felt when they got hold of a microscope for the first time, suddenly seeing worlds they’d never thought of,” says Professor Gottgens. “This is just the beginning of how single cell genomics will transform our understanding of early development.”

The study was made possible by a Wellcome Trust Strategic Award to study Gastrulation and by the Sanger/EBI Single Cell Genomics Centre.

Reference
Scialdone A, et al. Resolving early mesoderm diversification through single-cell expression profiling. Nature; 6 July 2016; DOI: 10.1038/nature18633

Adapted from a press release from the European Bioinformatics Institute.

Why we live in a universe made of matter, rather than a universe with no matter at all, is one of science’s biggest questions. The behaviour of antimatter, a rare oppositely charged counterpart to normal matter, is thought to be key to understanding why. However, the nature of antimatter is a mystery. Scientists use data from the LHCb and ALPHA experiments at CERN to study antiparticles and antiatoms in order to learn more about it. Some of these scientists, from the University of Cambridge and other UK institutions, will present their work at the Royal Society’s annual Summer Science Exhibition which opens to the public tomorrow (5 July 2016).

At CERN’s Large Hadron Collider particle accelerator, matter and antimatter versions of fundamental particles are produced when the accelerator beams smash into each other. The LHCb experiment records the traces these particles leave behind as they fly outwards from the beam collisions with exquisite precision, enabling scientists to identify the particles and deduce whether they are matter or antimatter. At larger scales, antimatter is studied in CERN’s antiproton decelerator complex, when antiprotons are joined with antielectrons to form anti-hydrogen atoms. The ALPHA experiment holds these antiatoms in suspension so that their structure and behavior can be studied. Both experiments are currently recording data that will enable scientists to carefully build up an understanding of why antimatter appears to behave the way it does.

The University of Cambridge is a founder institute of the LHCb experiment and plays a major part in the construction and operation of the detectors that determine the identity of particles. The detectors use the Ring-Imaging Cherenkov radiation technique via which particles emit radiation as they travel faster than the speed of light in the material of the detectors. The principles behind this technique and the data produced will be on view in the Royal Society Summer Science Exhibition for visitors to examine.

Professor Val Gibson of the University of Cambridge and former UK Spokesperson for the experiment said: “Antimatter might sound like science fiction, but it is one of the biggest mysteries in science today. We’re going to show everyone just why it matters so much – from what it can tell us about the earliest universe, to how we study it at the frontiers of research, to how it has everyday uses in medical imaging.“

Visitors to the Exhibition will also be able to see how fundamental particles and antiparticles are identified with the LHCb experiment, talk to researchers to discover what this science is like, try the experimental techniques used to hold and study anti-atoms with the ALPHA experiment, and move, image and locate antimatter within a PET scanner system.

The Royal Society’s Summer Science Exhibition is weeklong festival of cutting edge science from across the UK, featuring 22 exhibits which give a glimpse into the future of science and tech. Visitors can meet the scientists who are on hand at their exhibits, take part in activities and live demonstrations and attend talks. Entrance is free.