Infants, Down syndrome and the Alzheimer disease: A multidisciplinary approach

This post was contributed by Aline Lorandi, a visiting postdoctoral researcher under the supervision of Prof Annette Karmiloff-Smith, investigating the precursors of phonological awareness in Down Syndrome. She also is a collaborator in the infant stream of the London Down Syndrome Consortium (LonDownS), which investigates the links between Down syndrome and the Alzheimer disease

One of the premises of developmental neuroscience is based on the fact that, in order to understand certain phenotypes, it is crucial that we investigate their origins, that is, that we track the developmental trajectory that leads us to different sorts of behaviour, cognitive profiles, disorders, and diseases.

DNA StrandsWe must also acknowledge that the advances made by the field of developmental neuroscience allow us to take the debate between the contribution of genes and environment to another level: It is a fact that it is only possible to understand such contribution in a bilateral way, in which one modifies the other all the time.

With all that in mind, we can understand the curious title that Dr Esha Massand gave to her talk: ‘What can infants possibly tell us about Dementia?’ It seems a bit odd to think how studying babies can provide us any kind of relevant information about a condition typically related to ageing. Nevertheless, from the study of Down Syndrome arose the inspiration to establish the link between child development and Alzheimer’s disease.

The research described by Dr Massand is part of the LonDowS Research Consortium, involving different universities, which works in five sites: Genetics, mouse models, cells, adults, and infants.

The aim of the infant stream, according to Dr Massand, is to understand individual differences in infancy that may point to early signs of Alzheimer’s Disease. It is known that individuals with Down Syndrome have an extra copy of chromosome 21, and there is a gene in this chromosome, called APP gene, that produces a protein that, because of this extra chromosome, will be overexpressed in all individuals from the womb throughout development.

This APP gene produces plaques that are found in the brains of individuals with Alzheimer’s Disease. As the APP gene is overexpressed in Down Syndrome, it is very important to investigate its relationship with Alzheimer disease. One of the interesting facts is that, although all individuals with Down Syndrome will present, by the age of 30 onwards, the plaques in their brains, not all of them will develop signs of Alzheimer’s Disease.

Using a varied range of methodologies (eye tracking, sleep pattern measuring, EEG/ERP, behavioural tasks), Dr Massand and colleagues aim to understand how behaviour and neural responses may shed some light on whether it is possible to track some early biomarkers that can point to the onset of the disease in a developmental way. Among the cognitive and neural underpinnings, they are looking at several abilities, such as memory, attention, language, sleep fragmentation, mother/father/infant interactions, and many others. All those methodologies are very child-friendly.

Although preliminary, many interesting results already point to important individual differences, like the relationship between language and the gap-overlap/disengaging effect (the ability to disengage from one stimulus to look at another one, concomitantly or not).

Dr Massand’s team found that the fewer words a child understands and produces, the longer he or she takes to disengage from the stimulus presented in the task. Additionally, the disengaging effect was positively correlated to aggressive behaviour. That means that the higher the score that the child reached in the behaviour questionnaire (related, among other measures, to aggressive behaviour), the longer he or she took to disengage from the stimuli.

They also found a positive correlation between the ability to pay attention to novelties and detect them, to more sleep. Analysing several trials during a test to find the location of the objects, they also discovered that children with Down Syndrome may take longer to habituate to the objects and may take longer in the tasks: While typically developing children can detect a change of location of the objects in a first trial, observable by the duration of them looking at the screen in the eye tracking, children with Down syndrome do better – or more ‘typically’ – in a second trial, presenting more variability in the first trial than typically developing children. All these findings are related to individual differences that may be correlated to those who will be at risk of developing Alzheimer disease.

Exciting trends and lots more to do for Dr Esha Massand’s team! There are more data to collect, especially from controls, findings from EEG/ERP to analyse, which may point to underlying neural differences related to Alzheimer’s Disease, and the exciting combination with the data from the other streams (cells, mouse models, genetics, and adults) to explore.

As the questions from the audience show, this is the kind of research that makes us excited and curious about! Should the participants be followed longitudinally? How long do children take to get familiarised to the cap in the EEG tests? These and other questions about the relationships between the different cognitive abilities were answered by Dr. Massand, who also highlighted that the hope is to find those individual differences in adults as well, in order to seek a better understanding of the factors that might indicate early clinical signs of the Alzheimer’s Disease.

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Protein machines in the molecular arms race

This post was contributed by Clare Sansom, Senior Associate Lecturer at the Department of Biological Sciences

Birkbeck’s Science Week 2015 was held from Monday 23 to Thursday 26 March and included three evenings of public talks by senior researchers. The first two lectures, on the Tuesday, were given by two of the college’s most distinguished women scientists: Helen Saibil from the Department of Biological Sciences and Karen Hudson-Edwards from Earth and Planetary Sciences; they were billed together as a ‘Women in Science Evening’.

Pathways of pore formation – illustration by Adrian HodelThe lectures were all introduced by the Dean of the Faculty of Science, Nicholas Keep who described Saibil, a close colleague, as “our most eminent female scientist”. She came to Birkbeck from Canada via a PhD at King’s College London under the supervision of Nobel laureate Maurice Wilkins and post-doctoral work at Oxford.

Since arriving here in the 1980s she has built up an internationally renowned structural biology lab, focusing in particular on the technique of electron microscopy. She has been a Fellow of the Royal Society since 2006 and of the Academy of Medical Sciences since 2009.

Saibil began her lecture by explaining that proteins can act as little machines, performing mechanical tasks that are essential for the maintenance of life. Her group has been interested for some time in proteins that can punch holes in the walls of cells. This allows the cell contents to leak out in a damaging process known as lysis, and it also allows toxins to enter the cells. These proteins can therefore be thought of as powerful weapons, and they are deployed on both sides of a ‘molecular arms race’: by pathogens and by the immune systems of humans and other animals.

Most soluble proteins fold into a single stable structure that tries, as far as possible, to keep their hydrophobic (“water-hating”) parts – the side chains of certain amino acids – in the interior of the protein, with the hydrophilic (“water-loving”) side chains on the outside, in contact with the watery environment inside or outside cells.

Pore-forming proteins, however, have a ‘Jekyll and Hyde’ like identity: they can form two distinctly different shapes, one as individual, soluble molecules and the other when they associate with each other into membrane-bound rings to form cylindrical pores. These structures, and the conformational change between them, are remarkably similar in proteins from bacteria and from the immune system.

Pore-forming toxins have been found in types of bacteria that are responsible for some deadly human diseases, including meningitis and pneumonia. The structure of a monomeric form of these proteins in solution was first solved in 1998, using X-ray crystallography. However, large complexes of many protein molecules are more readily solved by electron microscopy, particularly when those complexes are embedded in membranes.

In 2005 Saibil and her group described structures of the pore-forming toxin pneumolysin, from Streptococcus pneumoniae, in complex with a model cell membrane. They found that the proteins formed two distinctly different ring-shaped structures. Initially, they formed into a ring sitting on top of the membrane, which was termed the pre-pore; then they changed shape to burrow part of each protein deep into the membrane and form the pore itself. Each monomer in the pre-pore had a structure that was similar to that of the molecule in solution, but they underwent large structural changes to form the pore.

Most structures solved by electron microscopy are at lower resolution than those solved by X-ray crystallography, and it is not possible to trace the positions of individual atoms at lower resolutions (eg worse than 3 A). Saibil and her colleagues were able to interpret the structure of the proteins making up the pore by fitting pieces of the X-ray structure of the isolated molecule into their electron density.

They found a dramatic change in structure, with the tall, thin protein structure collapsing into an arch and a helical region stretching out to form a long, extended beta hairpin. It is these hairpins that join together to form the walls of the pore. The process of pore forming therefore has three stages: firstly the toxin molecules bind to the surface of their target cells, then they associate into the circular pre-pores and finally they change shape in a concerted manner, punching holes in the cell membranes by ejecting a disc of membrane, letting other toxins in and cell contents out.

Saibil then turned the focus of her talk from attack by bacteria to the human immune system’s defence. Natural killer (NK) cells are specialised lymphocytes (white blood cells) that kill virally-infected and cancerous cells in the bloodstream. They kill on contact with their target cells by releasing a toxic protein into those cells that stimulates those target cells to commit suicide in a process known as programmed cell death or apoptosis. We have only recently learned that the mechanism through which the NK cells work is very similar to the mechanism of the bacterial pore-forming toxins.

Natural killer cells express a protein called perforin that has a similar structure in solution to the bacterial pneumolysin. Although there is very little sequence similarity between these proteins – there is only one amino acid conserved throughout all the known bacterial and vertebrate proteins of this family, a glycine at a critical position for the conformational change – the structures are similar enough to suggest that the proteins all once had a common ancestor.

Saibil and her colleagues used electron microscopy to discover that this protein forms a pore through a similar mechanism to pneumolysin: the helical region that unfolds into the beta hairpin to form the pore forms the core of the molecular machine and is largely unchanged between the structures. There are some differences between the structures, however; in particular, there is no need for the perforin structure to ‘collapse’ as the molecule has ‘arms’ that are long enough to form the hairpin and punch the hole without bending into an arch.

The mechanism through which the NK cells kill their target cells is now quite well understood. When the two cells come into contact they form a temporary structure called an immune synapse that allows the pore to form and proteases called granzymes, which induce apoptosis, to enter the target cells. This YouTube video illustrates the natural killer cells’ mechanism of action, and this one shows a detailed view of the immune synapse. Other, similar proteins have been identified in oyster mushrooms; these form more rigid structures that are easier to work with. Saibil’s group and their collaborators have been able to solve the structure of this protein in intermediate stages of pore formation and are beginning to gain an understanding of exactly how it unfolds.

Mutations in perforin that prevent it from functioning cause a rare disease called haemophagocytic lymphohistiocytosis, which is almost invariably fatal in childhood. Understanding the mechanism of action of this important family of protein ‘weapons’ in both attack and defence may help find a cure for this devastating condition, as well as for some commoner disorders of the immune system and important infectious diseases.

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Image Caption: Pathways of pore formation – illustration by Adrian Hodel

Birkbeck hosts IAPSS World Congress 2015

This post was contributed by Odessa Primus, Chair of Organising Committee for the IAPSS World Congress

The International Association for Political Science Students (IAPSS) last week held its annual global international congress with Birkbeck College, University of London as its host and major partner.

(l-r) Tarek Osman and  Odessa PrimusIAPSS is the worldwide representation of students of political science and related studies. The association strives to deliver a sustainable academic contribution to the education of its members and to foster exchange among young political scientists across the globe.

This year’s World Congress welcomed more than 400 students from five continents, more than 60 speakers that are leaders in their field and more than 200 student paper presentations selected from over 800 applications.

Inspiring speakers included Professor Sir Adam Roberts from Oxford University; French-Czech political scientist Jacques Rupnik, who was an editor at the BBC in London between 1977 and 1982 and advisor to President Vaclav Havel from 1990 to 1992; and Eric Kaufmann, leading researcher of Nationalism and Ethno-Religious conflict.

Over four full congress days, students from all around the world witnessed expert sessions, panels and keynotes by a diverse field of academics, independent journalists and political leaders.

Among notable sessions was a keynote by Carne Ross, the founder and director of the Independent Diplomat, who was in the British Foreign Service from 1989 and his testimony in the Butler Review directly contradicted the British position on the justification behind the invasion of Iraq.

Carne Ross gave a talk on ‘Anarchist Diplomacy: New Approaches to International Relations’, which was filmed by the BBC and will be part of a documentary about him. Wednesday afternoon saw an invigorating expert panel titled ‘Political Dynamics in the Middle East: Four Years after the Middle East’ attended by:

  • E. Falah Mustafa Bakir, the Minister for Foreign Affairs of the Kurdistan Regional Government of Iraq
  • Tarek Osman, writer of the international best-seller Egypt on the Brink;

It was moderated by Dr Barbara Zollner, expert on the Middle East and lecturer at Birkbeck University.

His Excellency Ambassador Michael Žantovský gave a fascinating expert session on Europe and Russia and joined a charged panel with Hussein Shobokshi, independent journalist and businessman from Saudi Arabia; and Ellen Hume, former White House and political correspondent to the Wall Street Journal and now independent media analyst at the Central European University in Budapest; where they discussed ‘Media and Democracy: Limits, Contributions and Contradictions’.

A London Organising Committee and the IAPSS Executive Committee, consisting of members situated across the world in Nepal, Holland, the Czech Republic, Germany and Sweden, conducted the organisation of the entire event.

The three central organisers were Odessa Primus, the Head of Congress in London; Jannick Burggraaff, Head of Congress Management at IAPSS; and Philipp Aepler, the President of IAPSS.

The Congress was hosted by Birkbeck College, University of London, which was also the main partner, and contributed to much of the logistical organisation. Birkbeck greeted participants from diverse backgrounds and nationalities amongst which were East Timor, Botswana, Mongolia, the Philippines and Australia.

Many of these students were Paper Presenters that brought topics such as ‘On the Role of Non-State Actors’, ‘Sub-National Politics and Communalisation of Governance’, and the winner of the IAPSS Award for Academic Excellency 2015: Mr David Wong De-Wei, from Oxford University, with his outstanding paper on ‘Who is my Neighbour: Cultural Proximity and the Diffusion of Democracy’.

The IAPSS World Congress 2015 in London was the largest congress yet by the International Association for Political Science Students and students are invited to next year’s held in Berlin, Germany in April.

IAPSS holds conventions, study trips, and summer and winter schools, as well as publishes in their several online journals and research portfolios. This year’s World Congress was a success beyond any expectation and has been praised by participants on social media channels, where it continues to build its reputation and IAPSS membership.

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How the brain recognises faces

This post was contributed by Dr Clare Sansom, Senior Associate Lecturer, Department of Biological Sciences 

The first of two evening lectures on the Wednesday of Birkbeck Science Week 2015 was given by Martin Eimer of the college’s Department of Psychological Sciences.

He, like the other Science Week lecturers, was introduced by the Dean of the Faculty of Science, Nicholas Keep; Professor Keep explained that Eimer, a native of Germany and a recently elected Fellow of the German Academy of Sciences, had built up his research lab at Birkbeck over the last fifteen years.

Language

His internationally recognised research concerns the relationship between brain function and behaviour in health and disease. The topic he selected for his lecture was a fascinating one: how our brains recognise human faces and what happens when this automatic process goes wrong.

Eimer began by outlining some reasons why we find faces so interesting to look at. When we look at a face we may be able to recognise that individual, either immediately or with difficulty, but – if our brains are working correctly – we will be able to tell what the person is feeling, or what they are looking at.

It seems that the facial expressions that are associated with basic emotions such as happiness, surprise, fear and disgust are common between most if not all cultures. And we also use faces to lip-read. People with hearing impairments are dependent on this, and learn to do it very well, but we all have some intrinsic lip-reading ability that we use automatically in noisy environments.

Next, he used perceptual demonstrations to illustrate that we process faces rather differently to other objects. If we look at a photo of a familiar or famous person that has been turned upside down we automatically think it looks odd, and we find the face hard to identify. This so-called ‘inversion effect’ is also seen with other objects but is much more pronounced with faces.

A stranger effect occurs if the photo of a face is altered so that only the eyes and mouth are upside down. This looks grotesque, but turning the altered photo upside down so that the eyes and mouth only are the right way up makes it look surprisingly normal. This was named the ‘Thatcher illusion’ by the scientists who discovered it in 1980, perhaps as an imaginative way of taking revenge for an early round of education cuts.

It is likely that we instinctively respond so differently to faces out of the normal upright orientation because our brains have an inbuilt ‘face template’. Even young infants respond to ‘face-like’ stimuli with two eyes, a nose and a mouth in approximately the right proportions and positions.

Face recognition, too, depends on small differences in these parameters between individuals (e.g. the height of the eyes above the nose and the distance between them). Contrast polarity is also important, and we find it much harder to identify face images if their contrast is inverted (as in a photographic negative). Interestingly, however, the task becomes easier if the eye region only is reverted to normal contrast. This suggests that we attach a particular importance to that region. It is also difficult to determine gaze direction if the contrast polarity around the eyes are inverted.

Eimer introduced another optical illusion in which half of each of the faces of George Clooney and Harrison Ford had been combined into a composite. The audience found it almost impossible to distinguish the two actors until the half-faces were separated. We had all instinctively formed a new face from the components and failed, for obvious reasons, to match it to an individual. This trick, which is known as holistic face processing, is also specific to faces.

The second half of the lecture dealt with the neuroscience of face recognition, and what happens when it goes wrong. When we look at a face (or any object) information from the image focused on the retina is initially transferred to a part of the back of the brain known as the primary visual cortex. It is then transferred to other parts of the brain, including the inferior temporal cortex, where objects are recognised.

Several types of experiments have been developed for measuring exactly what goes on in the brain. These include functional magnetic resonance imaging (fMRI), which generates brightly coloured images associated with changes in blood flow to parts of the brain, and electroencephalography (EEG) which records electrical activity on the scalp.

These techniques are complementary; EEG is faster but can only record signals from the surface of the brain. Between them, they have allowed scientists to identify several areas in the brain that are activated when faces, but not other objects, are perceived and a rapid, strong electrical impulse that seems to be a unique response to faces.

It is much easier to recognise the face of a familiar individual – family member, friend or celebrity – than to distinguish between the faces of unknown people. This task, however, is required in many professions: most often and most obviously passport officers and detectives, but also, for example, teachers at the beginning of each new school year. Some people are much better at doing this than others, but even the most skilled make mistakes, and the UK immigration service (and, no doubt, the equivalent bodies in other countries) is looking into ways of doing it automatically.

People at the other end of the spectrum – who find it particularly difficult to recognise faces – are said to have a condition called prosopagnosia, or ‘face blindness’. These people have a severe but very specific defect in recognising faces: their intellect and their vision are normal, and they can recognise individuals easily enough from their voice, gait or other cues.

This condition is divided into two types: acquired prosopagnosia, which arises after brain damage, and developmental prosopagnosia, which can be apparent from early childhood, without any obvious brain damage. The acquired type is typically more severe; the eponymous Man who Mistook his Wife for a Hat described in Oliver Sacks’ fascinating book suffered from this condition. The rapid brain response to faces is missing from an EEG of a person with acquired prosopagnosia, and other tests will show that the brain regions that are specifically associated with face processing have been damaged.

About 2% of the population can be said to have some degree of developmental prosopagnosia. There is no association with intelligence and it affects many successful professionals. Eimer showed part of a TV programme featuring an interview with a woman who is particularly badly affected. She explained the problems she has encountered throughout her life, ranging from following characters in films to telling her own daughter from other little girls with bunches in the school playground. Her father had also suffered from the condition, and she had been very relieved to receive a formal diagnosis.

The EEG patterns of individuals with developmental prosopagnosia are less different from normal than those of people with brain damage, but they are recognisable. Interestingly, differences in brain responses to upright as compared to inverted faces are not seen in people with developmental prosopagnosia.

Face recognition abilities form a continuum and many people who think of themselves as being ‘terrible’ at recognising faces will find that they are in the normal range. Eimer’s group has a website that includes an online test, the Cambridge Face Memory Test. Participants are asked to memorise a face and then pick it out from a group of three; the tests start easy but become more challenging. People with very high and very low scores will be invited to be involved in further research in the Brain and Behaviour Lab at Birkbeck

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