UK University News

A new book co-authored by Professor Barbara Sahakian explores ‘hot’ and ‘cold’ decision-making and the possible improvement of bad or risky decisions with cognitive enhancing drugs. The book, 'Bad Moves: How decision making goes wrong and the ethics of smart drugs', co-authored with Jamie Nicole LaBuzetta, also discusses the increasing lifestyle use of ‘smart drugs’ by healthy people.

Professor Sahakian says the role of emotions in decision-making is not fully understood, but that knowledge about it is increasing. For example, she says, we know that we have to exert cognitive control by our prefrontal cortex over emotional areas of the brain such as the amygdala in order to have good emotional regulation. We also know that there are two forms of decision making: ‘hot’ cognition, which includes emotional and risky decisions, and ‘cold’ cognition, which includes rational or non-emotional decisions.

She says: “Understanding the differences between these two forms of cognition can help us to further discover how emotions are involved in decision making.” In healthy students, an example of ‘hot’ decision-making could be opting to go out the night before an exam which could affect their exam grade. An example of a problem of ‘hot’ cognition could be highly risky behaviour such as when a patient who is in the manic phase of bipolar disorder maxes out their credit cards. In contrast, ‘cold’ cognition might include such decisions as how to organise your day in the most effective way or deciding on ingredients for a meal.

She will be speaking about her research for ‘Bad Moves’ as part of the Cambridge series of talks at this year's Hay Festival. Professor Sahakian directs a laboratory of psychopharmacology at the University of Cambridge which uses cognitive enhancing drugs (‘smart drugs’) and psychological treatments to improve cognition, including decision-making, in patients with psychiatric disorders including Alzheimer’s disease, frontotemporal dementia, attention deficit hyperactivity disorder (ADHD), mania and depression.

Her aim is to improve the ability of patients to function successfully in their daily living at school, university, work or home, and to have a better quality of life and wellbeing. Given that 16% of people in the UK have a common mental health problem, such as depression, she feels it is important that there is a better understanding of difficulties people face which hopefully may lead to reduced stigmatisation.

She also has a strong interest in the safety and ethical issues with regard to the increasing lifestyle use of ‘smart drugs’ by healthy people. In particular, she is concerned about safety as there are no long term studies of the use of ‘smart drugs’ in healthy people. Another concern is the accessing of these ‘smart drugs’ over the Internet. Furthermore, there are ethical issues involved in the use of these drugs by healthy people, such as coercion, ‘cheating’ in competitive situations such as exams and the impact this will have on our society. These issues need to be discussed by an informed public.

*“Bad moves. How decision making goes wrong and the ethics of smart drugs” by Barbara J Sahakian and Jamie Nicole LaBuzetta is published by Oxford University Press.

Hospital performance has rarely been out of the news in recent months, following the conclusion of a public inquiry into Mid Staffordshire NHS Foundation Trust that argued for “fundamental change” in the culture of the NHS to make sure patients are put first. The news casts a spotlight on what measures the government might take to combat poor care.

One emerging movement in hospital health services is the adoption of pay-for- performance (P4P) schemes to reward better-performing hospitals with cash incentives. In the USA, for instance, the government’s social insurance programme Medicare has launched P4P in efforts to encourage better and more standardised care, and to penalise hospitals with high re-admission rates.

However, it remains unclear as to whether P4P schemes improve patient outcomes, explained Professor Martin Roland, Director of the Cambridge Centre for Health Services Research (CCHSR): “P4P is being widely implemented, especially in the United States, despite a scant evidence base.”

The idea behind P4P is to reward healthcare providers based on how well they perform against a set of pre-agreed criteria, such as whether anti-clotting medication has been given within 30 minutes following a heart attack and how quickly antibiotics are given for patients with pneumonia.

In the first evaluation of a P4P scheme (Advancing Quality) in the UK, a report has suggested that 890 lives were saved across 24 hospitals in the northwest of England over an 18-month period. The analysis of the NHS scheme was carried out by a team of researchers at CCHSR, the University of Manchester and Nottingham University Business School, and was published in the New England Journal of Medicine.

The Advancing Quality scheme used a ‘tournament’ system, in which only the top performers received a bonus. The researchers evaluated the number of in-hospital deaths due to pneumonia, heart failure and heart attack within 30 days of admission following the scheme’s introduction, compared with the 18 months preceding it, among a total of 134,435 patients admitted for these conditions and controls across the country.

A scheme similar to Advancing Quality had failed to show any improvement in outcomes in the USA. Speculating on reasons for the difference, Roland said: “The context is really important – the level of the incentives, how they are structured and whether clinicians from different hospitals meet together to discuss how they were improving care face to face as they did in the UK, or through ‘webinars’ as in the US.”

Extensive work by CCHSR evaluating P4P programmes has shown that these incentives can have benefits, but also unintended consequences. For instance, care for non-incentivised health problems may be neglected if there are powerful incentives to concentrate time on other conditions.

The CCHSR is a collaboration between the Health Services Research Group in the University’s Institute of Public Health and the Health and Healthcare Policy Programme at the independent and not-for-profit research institution RAND Europe. The centre was recently placed second in a world ranking of health policy think tanks. “The collaboration between the University and RAND Europe has been a great success,” said Roland, “bringing together expertise from two complementary organisations as well as bringing in experts from the US to collaborate on our research.”

“As new ways of delivering health services develop, and public expectations change, it becomes ever more important to evaluate how effectively organisations in primary, secondary, community and social care are performing,” he added. “These are significant contributions to the healthcare debate because only then will policy makers have the knowledge to determine where best to place limited resources.”

Living in a multicultural, globalised world, it’s hard to imagine the moment when different cultures first met, or a time when people’s knowledge of each other’s worlds was nonexistent.

Yet, on 12 October 1769, seven Maori canoes paddled out from the east coast of New Zealand south of Poverty Bay to investigate a large ship. The vessel was the HMS Endeavour, captained by Captain James Cook, and this was the first time the Maori people had encountered a European.

They were at first reluctant to approach the ship but then, according to the diary of ship’s surgeon William Monkhouse, “very soon enter’d into a traffick with our people for [Tahitian] cloth… giving in exchange their paddles (having little else to dispose of) and hardly left themselves sufficient number to paddle a shore.”

A set of these finely carved and decorated paddles is now housed in the University of Cambridge’s Museum of Archaeology and Anthropology, where an innovative research project ‘Artefacts of Encounter’ has been working with Polynesian communities to understand what the earliest Europeans to visit the Pacific Islands made of the people they met, and what those people made of them.

Rather than turning to the written evidence of Europeans, the researchers have placed at the heart of their investigation the objects the Polynesians gave in exchange for goods. For the Polynesians, the paddles and pots, feathered cloaks and woven helmets, nose whistles and shell horns are often the only surviving evidence of a contact with other cultures that happened centuries ago.

“Artefacts help us to study what parties on either side of the encounters were trying to achieve through these seminal transactions,” explained researcher Dr Julie Adams. “They help us to consider new evidence of the nature of these encounters and of the changes in social practices, ideas and beliefs they engendered, both in the Pacific and in Europe. Artefacts are key to understanding how socio-cultural change unfolds.”

But with more than 650 voyages from Europe and the Americas entering Polynesia between 1765 and 1840, the artefacts the explorers brought back are both plentiful and largely scattered throughout museums of the world. Artefacts were divided up between crew members as ships returned home; today, no single museum houses the bounty of any single expedition.

Focusing initially on 40 ‘priority’ voyages – among them those of Cook (1768-80), Malaspina (1789-94), d’Entrecasteaux (1791-1793) and d’Urville (1822-40) – the team has re-analysed over 1,000 objects from 30 museums and Carl Hogsden has built a digital research environment that brings them back together for the first time.

Named KIWA after the great Polynesian navigator, the digital resource manages a wealth of widely dispersed data through a series of active collaborations with holding institutions, scholars and Polynesian communities, “enabling the discovery of new connections between hard-to-access material,” as Hogsden explained. KIWA is designed to enable the sharing of data and research insights among the geographically dispersed project team (based in the UK, New Zealand and Brazil) as well as between research and curatorial staff worldwide.

For the Maori wooden paddles, for instance, the researchers have traced back almost 250 years from the artefact to the first encounter – through close study of the wooden paddles themselves, which are intricately decorated in red ochre, as well as through sea charts, ship’s log records, diary entries, inventories and, significantly, discussions with a Maori kin-group whose ancestors may have been among those who exchanged paddles for goods with Cook’s crew.

“The paddles would have been part of a set used to paddle a waka taua, a large canoe embodying the spiritual potency (mana) of a kin-group personified by their chief,” explained Adams. “They were probably given as a gift to Tupaia, the Tahitian priest-navigator-interpreter who accompanied Cook and his men to New Zealand, possibly in an effort to bind him and his own mana to the local genealogical networks.”
Tupaia was to die of typhus at Batavia and his possessions were brought back to Britain, where they were sent by Lord Sandwich, then Lord of the Admiralty and Cook’s patron, to Trinity College, Cambridge, in October 1771. After being exhibited for many decades in Trinity College Library, they were deposited in the Museum in 1914.

Adams, who with Dr Amiria Salmond and others has helped amass the object-centric evidence that underpins the digital resource, explained the resource’s significance: “For the very first time, it is now possible for researchers to reassemble all of the artefacts collected on a certain expedition – such as the Bellingshausen voyage from Russia to the Marquesas Islands in 1803. These are now dispersed across various institutions and have never been studied in their entirety.

“Or researchers could ask the database to show all the carved wooden clubs collected from Tonga, or all objects made from barkcloth, dog skin or feathers, or all the objects collected by an individual, such as the missionary George Bennet who toured Polynesia in the 1820s.”

One aim of the project, which is led by Professor Nicholas Thomas and funded by the Economic and Social Research Council, is to expose variations in patterns of exchange among different island groups (including Tonga, the Society Islands and New Zealand) as well as between different voyages over time. Such a comparative approach will enable new conclusions to be drawn not only about the voyages themselves and their immediate aftermath, but about the divergent trajectories of first imperial, then (post-)colonial relationships.

The project has taken a lead from present-day Polynesians, who assert strong ancestral interests in these encounters and their artefacts. A key aspect of the project has been collaboration with a Māori tribal group, Te Aitanga a Hauiti (represented by the arts management group Toi Hauiti) – whose forefathers encountered early European explorers from the arrival of Cook in 1769. For six months, Hogsden worked with Toi a Hauiti to help create a digital research network that allows the Cambridge-based system to share content with a digital archive under development by the Maori community and local web developers, CodeShack.

“This work forms the basis for a reciprocal relationship between networked research hubs where ownership and control of information lies with the source,” explained Hogsden. “Although the networked content is collaboratively produced, the interpretation of digital objects differs. This is important because the Maori community views objects in a highly relational way – everything is connected to everything else – and so whereas our database is object-centric, theirs is relationship-centric. The two databases can nonetheless talk to each other and share content.”

For the paddles, members of the project team visited New Zealand to discuss the objects with the Ngai Tamanuhiri tribe, whose ancestors were probably part of the party who paddled out to the Endeavour in 1769. The importance of the paddles as early examples of kowhaiwhai painting has been recognised by those engaged in the revitalisation of Maori arts, and research is in progress to establish their genealogical connections to present-day Maori communities.

The Museum of Archaeology and Anthropology holds a world-class collection of Oceanic, Asian, African and Native American artefacts and has been shortlisted for the Art Fund’s Museum of the Year 2013.
For more information, please visit the Artefacts of Encounter project website http://maa.cam.ac.uk/aofe

Much work in the humanities could not be done without scholarly editions, and producing such editions consumes vast amounts of time and energy. Apocryphal stories abound about academics whose editorial labours have consumed their careers.

“Scholarly editing has traditionally been about coming up with a stable, pristine text,” explained Dr Jason Scott-Warren, Director of the Cambridge Centre for Material Texts in the Faculty of English. “The greater the cultural significance of a work, the more important it becomes to identify distortions and to correct those distortions, so as to produce a single, perfected version for modern readers.”

Where conventional editing seeks to reconcile conflicting versions for the reader, digital editing, unconstrained by the spatial limitations of the printed page, is about “giving readers access to the material in all its multiplicity,” he continued. “It offers the prospect of ‘un-editing’.”

New digital projects at Cambridge are making what Scott-Warren refers to as the true “mess of history” available in ways hitherto impossible, and are creating opportunities to explore the past lives of texts in ways previously unimaginable.

The medieval and early modern ‘commonplace book’ exemplifies the multiplicity of the raw materials that inform our literary histories. These domestic journals – scrapbooks, essentially, dating from the 15th to the 18th centuries – form the basis of Scriptorium, a digital archive produced by the Faculty of English with funding from the Arts and Humanities Research Council. These volumes bring together disparate texts, such as household accounts, sonnets, prayers and jokes, in unexpected and illuminating ways. “In this rich mulch of materials,” said Scott-Warren, “we might find the scaffold speeches of convicted traitors juxtaposed with contemporary political satires, or medical instructions mingled with proverbs and drinking songs. We begin to understand some of the interactions between genres, and to sense the import of a text in its moment.”

It is the connections across the texts as much as the messages they individually convey that enable Scriptorium’s users to shine a light onto the past. The same principles of deep and lateral connectivity characterise the array of digital editions emerging at Cambridge today, materials ranging from cardinal religious texts to foundational scientific treatises; from the music of Fryderyk Chopin to the plays of Arthur Schnitzler. These new editions feature analytical tools as well as annotations and contextual information that enable users to draw connections between – and so forge new paths of enquiry through – disparate parts of our cultural heritage.

The Cambridge Digital Library, a powerful platform being developed by Cambridge University Library (with funding from the Polonsky Foundation), is further enriching its digital editions by re-presenting their content in innovative ways that transcend boundaries between archive and edition, between traditional roles (librarian, editor, publisher, reader) and between institutions.

A new digital edition of the Board of Longitude archive, for instance, charting the development of science and technology in the 18th century, will incorporate objects – telescopes, clocks, chronometers – from the National Maritime Museum along with abstracts, biographies and essays from experts in the Department of History and Philosophy of Science.

The University Library is amalgamating its online Newton Papers with the fruits of the University of Sussex’s Newton edition and is beginning to link its own Darwin Correspondence edition with the digital archive. It is also employing text-mining techniques to enrich the descriptions of its Genizah collection of 190,000 medieval manuscript fragments documenting the lives of Mediterranean Jews, Arabs and Christians. This will enable the mapping of new relationships between the documents.

“Our next step,” said Digital Library Manager Grant Young, “is to empower readers themselves to annotate, tag, converse with and challenge each other – and us. It’s about leveraging information that will augment the content and establish new connections, building in feedback mechanisms, interactivity and a recommendation facility.”

Where the edition has traditionally been regarded as tantamount to a bible, now the reader can access materials that show that the Bible is, in fact, an edition. Young’s team, in collaboration with the University of Birmingham, has recently released the first major edition in over 100 years of the 5th-century Codez Bezae Cantabrigiensis, one of the handful of manuscripts used to establish the text of the New Testament.

This plurality and the potential eclecticism that results – with fully personalised editions standing at one extreme – can be unsettling. “Perhaps print provides the stability that is necessary for intellectual life to proceed, so that we will need to work out compromises between print and digital media,” suggested Scott-Warren. Through a Digital Humanities Network launched in 2011 by the University, academics, librarians and technicians are looking critically at digital editions in production, and exploring their implications for editorial theory.

The potential empowerment, however, in accessing what Scott-Warren described as “the instability that lies beneath the surface of the text” is clearly apparent in a project devoted to the flux at the heart of the creative process: the Online Chopin Variorum Edition (OCVE), funded by the Andrew W. Mellon Foundation.

Chopin’s music is subject to the variations that occur when transmitting any text in musical notation or performances, but further variants arise from his own, perpetual revisions of his works. Not only is it impossible to determine a neat chronology across his versions: it is not valid to assume that Chopin was refining his work towards a point of perfection. Each version may be understood as definitive in its moment.

The OCVE enables users to compare and annotate passages across sources ranging from Chopin’s manuscripts to revised impressions of the first editions. We can trace, for example, where an altered chord inflects the music with new meaning; or how the absence of a pedal release sign at the end of a piece, interpreted by many modern editors as an omission, can in fact be an instruction to keep the pedal down after the final cadence and allow the music to fade into silence, beyond the limits of the double bar-line.

While this project makes conventional editing far more straightforward, “the really exciting thing about the digital future,” said Professor John Rink, Director of the OCVE, “is the creation of a new understanding of what an edition is, and what it can do. For a user of the OCVE to trace the creative evolution of an idea across sources results in an understanding that potentially is an edition, in and of itself.”

Moreover, the form of an edition in the digital environment is fluid. Chopin’s variants emerge from his experience of performing his music. The integration into these digital editions of material arising in performances, and of actual recordings of performances, is now being explored at Cambridge, along with the use of tools such as time-based mapping and visualisation.

“The edition itself will become a living entity,” said Young – reflecting what Rink described as “the notion of contingency and re-creation at the heart of any work.”

“What we’re really talking about here,” Rink continued, “is a parallel between the way the mind seeks and forms connections between ideas – some straightforward, some subtle – and the way the internet works by facilitating connections. In these emerging new editions a perpetual, kaleidoscopic process is enacted and opened out by virtue of new technologies. This is about nothing less than releasing and then harnessing the human imagination in ways that exploit its infinite creative potential.”

Forests are essential for life on earth. They provide a habitat for a myriad of different plant and animal species – too numerous to count but certainly running into millions. Forests are also home to some 5–17 per cent of the global human population, a fact easily overlooked from the urban perspective. How worldwide forests are changing, and the serious threats they face, is the focus of Cambridge University’s Forest Ecology and Conservation Group (FECG), Department of Plant Sciences.

“Whether we live among trees or not, we all depend on forests. They are the lungs of the biosphere, and in providing oxygen function as important sinks of atmospheric carbon dioxide, helping to reduce and offset the build-up of this climate-changing ‘greenhouse’ gas. Forests also have important roles in soil-building and conservation, flood control, and fluxes of chemical elements between the bedrock, soil and atmosphere,” said Dr David Coomes, head of FECG.

Our timber comes from forests – and so too do many foods, medicines and other products. Forests represent the provisioning, regulating, supporting ‘ecosystem services’, upon which economists now attempt to put monetary value in efforts to recognise their importance in the market economy, and further incentivise their protection. Intrinsic, inspirational and spiritual values of forests cannot be costed in the same way, but lend further weight to the imperative of their conservation.

Although forests are so valuable, they are all-too-frequently threatened. The world’s largest rainforest, in Amazonia, is home to over half of the world’s terrestrial fauna and flora, but this has not stopped a massive encroachment of cattle ranching. In Sumatra, over 95 per cent of the lowland forests have been logged and planted with oil palms for the commercial food industry and biodiesel. Current rates of loss of tropical humid forests equate to a 100 m wide strip of land being devoured at 66 km per hour.

Forests also face less obvious threats. Introduced ‘alien’ plants can invade forests and compromise their integrity and functioning. Droughts and fires can impact on the make-up of tree mixtures, and turn forests from carbon sinks to carbon sources, exacerbating the cause of climate change.

FECG aims to understand these challenges better. Dr Coomes explained: “We look at change from a bottom-up approach, working from the first principles of how trees establish, grow, compete with one another for resources, reproduce and die. Repeat measurements from permanent forest plots, sometime as part of national forest inventories, can make an important contribution to knowledge of forest dynamics. Such information provides the critical numbers to plug into computer models, which take a mixed stand of trees and simulate what happens to them under stable or changing environmental conditions.”

While accurate forest plot data are vital, their collection can be laborious and time-consuming. Conventional methods of data gathering – involving individual measurements of tree diameters and heights – provide useful snapshots of what is happening in forests.  But what about the bigger picture – scales of measurement which match the concerns of the millions whose livelihoods depend on it? The gathering of detailed information on a large scale is where remote sensing technologies have a growing role.

Satellite- or aircraft-borne instruments are able to take images of forests and other land covers, and do so across whole landscapes and regions. The resulting images are more than just photographs: they contain layers of detail about different properties of the forest canopy, for example how foliage reflects different wave-bands of light. These properties, cross-referenced with data gathered on the ground, tell us different aspects about what is going on – and how forests change in space as well as time.

“We’ve been increasingly using this ‘top-down’ approach to the study of forests. In particular, we have been developing uses of a new kind of remote sensor – a type of laser scanning known as lidar – in forest science,” explained Dr Simonson, Research Associate in FECG. “For lidar, think radar, though the technology uses laser light rather than radio waves. Lidar involves the firing of laser pulses at very high frequency (many thousands per second) and detecting the backscatter off different objects. In the context of forests, these objects are tree leaves, branches, under-storey plants and the ground surface. These reflectance signals can be timed to minute precision and, based on the speed of light, the relative heights of these objects can be determined.”

Further processing steps, using on-board flight data, transform these clouds of data points into a virtual landscape showing the profile of the terrain and presence of different layers in the forest. Various statistical descriptors of this modelled forest can be extracted and compared to field and other environmental data to help pick up trends. Individual tree crowns can be isolated in the dataset using algorithms that locate their conical or spherical shapes from the canopy surface model. Plans are also afoot in FECG to develop methods for making much fuller use of LiDAR information: using plot data to calibrate leaf-location models linking the distribution of LiDAR-measured  heights to the size and number of trees on the ground.

Dr Simonson described how FECG has been applying lidar in one particular setting. “In Portugal and Spain, cork oak woodlands are not only the source of the cork wine stoppers, but contain important assemblages of plants and animals. We’ve been using lidar to distinguish different types of plant community and associated diversity within these forests, and have demonstrated how this technology can be used not only to map these important habitats, but also to track their change over time. Cork oak forests are one of the habitats being targeted by European environmental protection legislation, and the group hopes to contribute towards developing stringent systems for enforcement and monitoring.” 

Scientists at FECG are using lidar to help answer a range of research questions elsewhere in the world: mixed boreal forests in Canada, tropical moist forests in Sierra Leone, swamp forests of Borneo, and closer to home, lowland deciduous woodlands across southern England. In each case, lidar is employed to model the structures of tree crowns and forest patches. A particular focus is the study of the biomass of forests and tonnage of carbon that trees can lock up in their trunks, branches and root systems. Forest carbon stores represent a highly significant component of the global carbon cycle, and this is recognised by climate change mitigation schemes such as REDD (Reducing Emissions from Deforestation and Degradation).

Lidar provides a potential tool for making the calculations on carbon saved by avoided deforestation, and channelling funds for this purpose. Another strand of research combines two remote sensing data types: lidar and hyperspectral imagery. “Hyperspectral images hold information on the reflectance properties of tree foliage in narrow bandwidths of the electromagnetic spectrum, and these properties relate to chemical characteristics (traits) to do with light capture and growth, longevity and defence, and maintenance and metabolism. Lidar allows us to delineate tree crowns within the hyperspectral imagery, look at the spectral properties and traits of individual trees, and see what factors influence them,” said Dr Coomes.

"Forests will always keep many secrets, but they are so important to us that we need to understand better how they function, how they are changing, and how we can manage that change. Lidar is becoming an important part of the modern toolkit for building that better understanding.”
 

Researchers have pinpointed a catalytic trigger for the onset of Alzheimer’s disease – when the fundamental structure of a protein molecule changes to cause a chain reaction that leads to the death of neurons in the brain.

For the first time, scientists at Cambridge’s Department of Chemistry, led by Dr Tuomas Knowles, Professor Michele Vendruscolo and Professor Chris Dobson working with Professor Sara Linse and colleagues at Lund University in Sweden have been able to map in detail the pathway that generates “aberrant” forms of proteins which are at the root of neurodegenerative conditions such as Alzheimer’s.

They believe the breakthrough is a vital step closer to increased capabilities for earlier diagnosis of neurological disorders such as Alzheimer’s and Parkinson’s, and opens up possibilities for a new generation of targeted drugs, as scientists say they have uncovered the earliest stages of the development of Alzheimer’s that drugs could possibly target. 

The study, published today in the Proceedings of the US National Academy of Sciences, is a milestone in the long-term research established in Cambridge by Professor Christopher Dobson and his colleagues, following the realisation by Dobson of the underlying nature of protein ‘misfolding’ and its connection with disease over 15 years ago.

The research is likely to have a central role to play in diagnostic and drug development for dementia-related diseases, which are increasingly prevalent and damaging as populations live longer.

In 2010, the Alzheimer’s Research UK showed that dementia costs the UK economy over £23 billion, more than cancer and heart disease combined. Just last week, PM David Cameron urged scientists and clinicians to work together to “improve treatments and find scientific breakthroughs” to address “one of the biggest social and healthcare challenges we face.”

The neurodegenerative process giving rise to diseases such as Alzheimer’s is triggered when the normal structures of protein molecules within cells become corrupted.

Protein molecules are made in cellular ‘assembly lines’ that join together chemical building blocks called amino acids in an order encoded in our DNA. New proteins emerge as long, thin chains that normally need to be folded into compact and intricate structures to carry out their biological function.

Under some conditions, however, proteins can ‘misfold’ and snag surrounding normal proteins, which then tangle and stick together in clumps which build to masses, frequently millions, of malfunctioning molecules that shape themselves into unwieldy protein tendrils.

The abnormal tendril structures, called ‘amyloid fibrils’, grow outwards around the location where the focal point, or 'nucleation' of these abnormal “species” occurs.

Amyloid fibrils can form the foundations of huge protein deposits – or plaques – long-seen in the brains of Alzheimer’s sufferers, and once believed to be the cause of the disease, before the discovery of ‘toxic oligomers’ by Dobson and others a decade or so ago.

A plaque’s size and density renders it insoluble, and consequently unable to move. Whereas the oligomers, which give rise to Alzheimer's disease, are small enough to spread easily around the brain - killing neurons and interacting harmfully with other molecules - but how they were formed was until now a mystery.

The new work, in large part carried out by researcher Samuel Cohen, shows that once a small but critical level of malfunctioning protein ‘clumps’ have formed, a runaway chain reaction is triggered that multiplies exponentially the number of these protein composites, activating new focal points through ‘nucleation’.

It is this secondary nucleation process that forges juvenile tendrils, initially consisting of clusters that contain just a few protein molecules. Small and highly diffusible, these are the ‘toxic oligomers’ that careen dangerously around the brain cells, killing neurons and ultimately causing loss of memory and other symptoms of dementia.

“There are no disease modifying therapies for Alzheimer’s and dementia at the moment, only limited treatment for symptoms. We have to solve what happens at the molecular level before we can progress and have real impact,” said Dr Tuomas Knowles from Cambridge’s Department of Chemistry, lead author of the study and long-time collaborator of Professor Dobson and Professor Michele Vendruscolo.

“We’ve now established the pathway that shows how the toxic species that cause cell death, the oligomers, are formed. This is the key pathway to detect, target and intervene – the molecular catalyst that underlies the pathology.”

The researchers brought together kinetic experiments with a theoretical framework based on master equations, tools commonly used in other areas of chemistry and physics but had not been exploited to their full potential in the study of protein malfunction before.

The latest research follows hard on the heels of another ground breaking study, published in April of this year again in PNAS, in which the Cambridge group, in Collaboration with Colleagues in London and at MIT, worked out the first atomic structure of one of the damaging amyloid fibril protein tendrils. They say the years spent developing research techniques are really paying off now, and they are starting to solve “some of the key mysteries” of these neurodegenerative diseases.

“We are essentially using a physical and chemical methods to address a biomolecular problem, mapping out the networks of processes and dominant mechanisms to ‘recreate the crime scene’ at the molecular root of Alzheimer’s disease,” explained Knowles.

“Increasingly, using quantitative experimental tools and rigorous theoretical analysis to understand complex biological processes are leading to exciting and game-changing results. With a disease like Alzheimer’s, you have to intervene in a highly specific manner to prevent the formation of the toxic agents. Now we’ve found how the oligomers are created, we know what process we need to turn off.”

Inset image: L-R, Professor Christopher Dobson, Dr Tuomas Knowles and Professor Michele Vendruscolo

For more information, please contact fred.lewsey@admin.cam.ac.uk

Paper reference: "Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism"

Samuel I. A. Cohen, Sara Linse, Leila M. Luheshi, Erik Hellstrand, Duncan A. White, Luke Rajah, Daniel E. Otzen, Michele Vendruscolo, Christopher M. Dobson, and Tuomas P. J. Knowles,

Proceedings of the National Academy of Sciences, May 2013
pnas/cgi/doi/10.1073/pnas.1218402110

Denmark has Sarah Lund, Sweden has Wallander, Norway has the alcoholic Harry Hole. Now, the South African fictional detective is coming into its own – and coming to Cambridge.

On Tuesday 21 May at the Faculty of English, Margie Orford, author of a bestselling series of novels featuring journalist-turned-psychological profiler Dr Clare Hart, will be discussing the South African crime-fiction wave and what it tells us about South Africa today.

Attention has been focused on crime and policing in South Africa through recent high-profile events. For some South Africans, however, a deep fear of crime is the stuff of daily life – even though the victims of violent crimes are, disproportionately, the vulnerable and the disaffected, despite the perceived extent of the spread of crime into the suburb.

Dr Christopher Warnes, Senior Lecturer in Postcolonial Literature at the University of Cambridge, believes that the phenomenal popularity of crime fiction in South Africa demands serious scholarly critical attention. In an article published in the latest issue of the influential Journal of Southern African Studies, he writes that “the number of crime novels written in and about post-apartheid South Africa is assuming the ‘epidemic proportions’ some believe characterise actual crime rates in that country.”

In the wake of the “false certainties of apartheid”, and as South Africans lose faith in the post-apartheid institutions and policies designed to protect them, “the detective,” writes Warnes, “returns to South African literature with a vengeance.”

The crime fiction that has been produced in such volume by mainly white South African writers since the country’s first free election in 1994 has been regarded by critics as escapist and apolitical, where previously, as exemplified by Nobel Prize-winners J. M. Coetzee and Nadine Gordimer, the novel was charged with a sense of political mission.

But for a society so disturbed by violent crime, “what kind of escapism is it,” asks Warnes, “that takes you so close to your greatest fears, your horrors? If these novels are ‘escapist’, then escapism is clearly not a simple phenomenon. I think that these books are providing some kind of benefit to their millions of readers.”

Through the figure of the detective, the seemingly intractable issue of crime in general is distilled into one shocking case. “The detective then deciphers clues, signs, which open out onto a reading of society at large.” Through this ‘reading’ of fraught situations, the case is solved, order is restored – and larger issues, by extension, are resolved, if only for the duration of the after-glow of a work of fiction.

Yet an explanation of this phenomenon purely in terms of the levels of crime in South Africa does not stand up: crime fiction flourishes in Scandinavia and Japan, which have relatively low crime levels. “These books are ultimately a response to a sense of threat rather than to danger,” says Warnes. “If you were in actual danger, you probably wouldn’t reach for a crime novel to protect you!” Threat is something more subjective, the product of beliefs and preconceptions, and this is where the politics come in, because these novels are about much more than just crime.

This paints a bleak picture of South Africa today, and there is bleakness in these books. Orford prefaces her second novel, Blood Rose, with a line from The Four Quartets by T S Eliot: ‘Here is a place of disaffection’. Although it refers to the setting for the crimes – Walvis Bay in Namibia, it hangs over the novel like the desert dust that pervades the desolate port town.

But redemption and even catharsis are to be found from these books – which are, says Warnes, the product of “an essentially liberal society, seeking to come to terms with transition and flux.” There are signs in these novels, as in post-apartheid fiction at large, that South African society hasn’t yet given up on the sense of possibility and promise that was so much a feature of the Mandela years.

Warnes is struck by the ways in which, through their detective heroes, crime writers like Orford and Deon Meyer are increasingly addressing larger post-apartheid themes. Orford provides Dr Clare Hart with a PhD dissertation based on the hypothesis that ‘because we averted a civil war in South Africa … [the] unspent violence was sublimated into a war against women’. And of Deon Meyer, he says: “in a genre that often embraces banal revenge fantasies, it is surprising to find a critique of the notion of vengeance. Meyer’s damaged detectives find personal rehabilitation through protecting others.”

South Africa’s serious crime-writing squad is blurring some of the boundaries between the politically-conscious apartheid-era novel and the formulaic, popular crime book, as well as playing out the tension between a liberal approach to crime, and embattlement and revenge.

“There is no shortage of serious analysis of change in South Africa,” according to Warnes. “But what is it like to live through it? How does it feel? How do you negotiate its tensions, contradictions and uncertainties, and deal with the sense of threat and indeed the sense of promise? It’s all there, in the novel.”

‘Writing Crime’ with Margie Orford and Dr Christopher Warnes Room GR-05, Faculty of English, West Road, Cambridge 5.00pm on Tuesday 21 May. Free event.

As the fungus responsible for ash dieback continues to devastate ash tree populations throughout the UK and other threats to the countryside continue to emerge, experts convened by Defra are advocating for stronger measures to protect the UK’s trees and plants.

The independent Tree Health and Plant Biosecurity Expert Taskforce was established by Defra’s Chief Scientific Adviser, Professor Ian Boyd, late last year to address the current and emerging threats to the UK’s trees and plants. Working with an advisory group made up of various stakeholder organisations, to include industry, Defra, and the Forestry Commission as well as Border Force, the taskforce is proposing a number of initiatives aimed at minimising the risk of plant pests and diseases.

Professor Chris Gilligan, chair of the taskforce and Professor of Mathematical Biology and Head of the School of Biological Sciences at the University of Cambridge, said: “The UK needs to be better prepared for threats to plant health. In the last few years alone, several previously unknown pests and pathogens have emerged, posing significant risks to the UK’s crops as well as trees in woodlands, commercial forests and in urban environments.

“By increasing our understanding of what pests and diseases are the biggest threats and how best to mitigate their impact, we can minimise potentially devastating outbreaks.”

The scientists believe that the threats have increased because of globalisation in trade and travel and the subsequent escalation in volume and diversity of plants and plant products entering the UK, all of which potentially harbour plant pests and pathogens. Once established, pests and pathogens can wreak havoc on biodiversity, timber and crop production, the landscape and, in certain circumstances, human health. (In addition to Chalara, recent examples include horse chestnut leaf mining moth, oak processionary moth, bleeding canker of horse chestnut and Dothistroma needle blight on pines.)

Professor Charles Godfray, a member of the taskforce from the University of Oxford’s Zoology Department & Oxford Martin School said: “Globalisation poses many challenges including to the health of our trees and other plants; the taskforce has tried to suggest proportionate measures that will materially lessen the risks to the nation’s trees and forests without adding unnecessary barriers to trade and commerce.”

Although the remit was to focus on trees and related woody species, the taskforce noted that many of the principles addressed in recommendations for tree health are applicable to pests and diseases that affect other plants (including agricultural, horticultural and biomass crops, indigenous vegetation and ornamental plants).

Taskforce recommendations

Currently, there are numerous risk assessments for individual pests and pathogens at both the national and European level. The taskforce recommends a single national Risk Register for plant health. This new UK Plant Health Risk Register would serve to identify and prioritise pests and pathogens that pose a threat to the UK and to identify what actions must be taken should the threat materialise. 

The taskforce is also advocating an individual at a senior level who is responsible for overseeing the UK Plant Health Risk Register and providing leadership for managing those risks. The Chief Plant Health Officer would work in a similar fashion as the Chief Veterinary Officer, who oversees animal-related emergencies.

The appointee would also be responsible for developing and implementing procedures for preparedness and contingency planning to predict, monitor and control the spread of pests and pathogens. There was also a recommendation that current governance and legislation needed to be reviewed, simplified and strengthened.

Because of globalisation, more and more people and goods are travelling greater distances at an increasingly greater rate. As a result, there is a significant increase in the risk of introducing non-native pests and pathogens. In order to minimise the risks of introduction at the border, the taskforce has made several recommendations regarding the import of trees and other plants. They propose that no plant material for personal use be imported from outside the EU.

The import of live plants, foliage, branches and other plant parts has seen a 71 per cent increase since 1999, dramatically increasing the risk a pathogen or pest might be introduced.  Therefore they also propose the Plant Passport scheme, which currently only applies to some plants associated with pests and pathogens, be strengthened and also applied to seeds as a means of ensuring traceability (showing all ports of calls within the EU and last port before entry to the EU).

Dr Jens-Georg Unger, taskforce member and Head of the Institute for National and International Plant Health in Germany, said: “There have been too many introductions of serious new pests in recent years into EU countries - improvements are needed urgently. Efficient protection can only be achieved by more complete and faster exchange of information between countries and more focussed and better coordinated action in all EU countries. The UK taskforce is an extremely important step for the initiation of such improvements on the national and the EU level.”

Additional recommendations include improving the use of epidemiological intelligence from EU/other regions and work to improve the EU regulations concerned with tree health and plant biosecurity, developing a modern, user-friendly, system to provide quick and intelligent access to information about tree health and plant biosecurity, and addressing key skills shortages.

For more information about this story, please contact: Genevieve Maul, Office of Communications, University of Cambridge. Email: Genevieve.Maul@admin.cam.ac.uk; Tel: 01223 765542.