Category Archives: Science

World TB Day: Exploring new ways to fight a deadly menace

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This post was contributed by Arundhati Maitra, an associate research fellow, Department of Biological Sciences

World TB Day on 24 March marks the day in 1882 when Robert Koch discovered Mycobacterium tuberculosis, the causative agent of one of the most dreadful infectious diseases known to man – tuberculosis (TB). This year, on 21 March, Dr Sanjib Bhakta (Academic Head and Director of the Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Birkbeck) chaired a conference organised by EuroSciCon which raised the question – ‘Mycobacterium tuberculosis…Can we beat it?’ The event at The Royal College of Pathologists brought together several great minds in the field of TB research in the UK and from around the world.

The conference began with an introduction to the raging issues in TB management. Dr Bhakta emphasised the fact that an integrative approach is essential to target the various physiological states the germ can exist in inside an infected patient: active state, causing full blown infection, and the latent state, also called persisters, lying dormant within the patient.  

In 1993, WHO reported TB as a global health emergency. The disease continues to remain a serious threat to mankind 20 years on.  Though the TB incidence rates remain constant in the Eurozone, rates in the cosmopolitan cities in the UK such as London, Manchester, etc. speak of a different story. In 2011 the number of TB cases reported in London was higher than that of reported AIDS cases.

In a hard-hitting presentation, Professor Graham Bothamley of Homerton University Hospital, UK, remarked that the failure to contain the disease is largely due to the lack of political commitment and roadblocks in health care delivery. A survey across Europe showed that not only are drugs unavailable in some regions, but the regimens followed in various countries do not follow the tested, WHO approved guidelines, putting many lives at risk.

The essential requirements to lessen the burden of TB are twofold – speedy and accurate diagnostics and development of novel drugs and treatment regimens.  

Diagnosis by sputum microscopy and culture tests are the predominant methods of TB detection. Professor Mike Barer from the University of Leicester reported an interesting finding which could have far reaching effects in latent TB detection. His group has recently discovered that sputum analysis, usually used to detect active infection could also give an insight to the level of persister population in the patient by detecting presence of lipid bodies in the bacteria.

Though remarkable, this still doesn’t answer the need for a rapid and accurate means of TB detection. That is what Christopher Granger, Director of Oxford Immunotech Ltd claimed to have achieved. He described the T Spot TB test, a simple test based on ELISpot assay, which is more specific than the regular tuberculin skin test, detects latent infection and is time as well as cost-effective. However, Dr Jayne Sutherland from the MRC Unit in Gambia mentions that a simple dip-stick test that can be available at the point-of-care is essential in the areas with highest incidences of TB. She described how many of the clinics are in remote areas and can only be referred to as ‘bush clinics’, lacking necessary infrastructure for TB detection. Her team is engaged in developing lateral flow based tests, something similar to the pregnancy test kits available today.

New diagnostic equipment to detect TB is being developed at the University of Amsterdam by Ngoc Dang. It detects biomarkers of lipid origins by thermally assisted hydrolysis and methylation followed by gas chromatography and mass spectroscopy. This equipment, when available, would have positive implications in areas where a large number of samples need to be tested.

Moving on to drug development and treatment strategies, Professor Stephen Gillespie of the University of St Andrews discussed several new anti-tubercular drugs and shorter treatment regimens in various phases of clinical trials. He also emphasised the need to develop predictive models for regimens as newer drugs are being discovered.

Detection of targets specific to the infectious agent is essential for the development of novel drugs. A couple of these targets were discussed by Dr Luke Alderwick from Birmingham University and Professor Edith Sim from Kingston University. While Dr Alderwick focussed on a cell wall synthesising enzyme, DprE1 and its inhibitor benzothiazinone (BTZ), Dr Sim focussed on enzymes essential for the bacteria’s survival within host cells, N-acteyl transferase and HsaD. Dr Brian Henderson from UCL described the role of proteins that have more than one specific function (moonlighting proteins) in virulence of these bacteria and suggested that these could be potential targets.

A common theme was observed in presentations by Dr Anthony R.M. and Professor Tim Mc Hugh. Both were strong proponents for the need to monitor the progress of treatment in the earlier stages rather than the current practice of 18 months on. The former explained a ‘treat to test’ strategy following the belief that upon starting of treatment an initial burst of dead cells makes for easy detection of the kinetics of the response of the host to treatment. The latter suggested the use of various biomarkers obtained from the bacteria and the host such as colony counts to assess bacterial load, bacterial RNA and small RNA from the host, to indicate the effectiveness of the treatment and likelihood of a relapse.

An interesting Q&A session began with a question regarding the importance of point-of-care diagnostics and was led by Dr Bhakta to touch on the other issues plaguing TB management today. Dr Juan D Guzman from ISMB, Birkbeck was asked to comment on the scaffolds found in natural and synthetic compounds that are especially effective as anti-tubercular drugs.

Poster presentations were invited and the top prizes went to Ngoc Dang, University of Amsterdam for her work on TB diagnostics and Dr Tulika Munshi from ISMB, Birkbeck, for her poster on ATP-dependant Mur ligases as novel therapeutic targets for TB drug development (http://dx.plos.org/10.1371/journal.pone.0060143).

On the whole, the conference was one step towards defeating TB as interdisciplinary research, collaborations and alliances are urgently required to fight this menace.

Face blindness – an artist’s perspective

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This post was contributed by Bernice Wilson, an artist living and working in East London, who gave a talk at Birkbeck’s Department of Psychological Sciences‘s Prosopagnosia Open Day on 5 October.

I am an artist interested in exploring identity and the sense of self. By scrutinizing portraiture in various forms, from CCTV through photography and sculpture, to voyeuristic photographs and paintings of acquaintances or complete strangers, I attempt to stimulate my audience to think and look at identity in a different way.

My new body of work is drawing inspiration from what it is like to be face blind. A condition that is almost inconceivable as we take for granted this primeval and instinctive form of communication – knowing ourselves and knowing and recognizing our kin/family/tribe.

Through my research into the condition I have met with several people who have face blindness – better known as prosopagnosia in the medical profession – and as a result of these meetings I was invited along to the 2nd Annual Symposium on 5 October, 2012 to talk about my work and how it relates to face blindness. I have to say I was flattered and excited to be asked and talk to the audience whom I took as direct inspiration for my work. 

I spoke about how and when I came across face blindness and emphasised that my work is an interpretation, my best guess, that it in no way claims to know what face blindness actually feels like. I spoke about the findings in my research: that I have become aware that people who are faceblind are very good detectives. They adapt, often subconsciously, by looking for triggers, telltales, specific features such as moles, glasses, voices etc… that they can then recall on future encounters with each face they meet to help them identify the individual. These are the notions that I used to inform the concepts in my work, together with some of the research methods – for example, the eye tracking tests that are conducted, that I too took part in as a control subject earlier this year.

The audience were intrigued, I think. It would have been great to get some direct feedback but lack of time on the day meant this wasn’t possible although I am hoping to gain some very soon via the “London Faceblind Group” who meet regularly to discuss common ground and offer mutual support.

Bernice will be exhibiting some more face blind inspired works at a group show: Matt Roberts Arts, 25b Vyner St, London E2 9DG from 8-24th November 2012. All images copyright the artist.

BabyLab Showcase 2012

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This post was contributed by Denise Breitenbach and Yvonne Whelan 

Introduced by Prof. Mark Johnson, this year’s Birkbeck BabyLab Showcase highlighted the importance of researching aspects of infant cognition over time. Between birth and adolescence, our grey ‘jelly-like’ brains expand three times in size and undergo an astounding amount of structural adaptation. These changes aren’t solely reliant on our genes: genetic information unfolds over time by interacting with our external world experiences. For example, social skills related to the processing of facial cues such as smiling, develop early on as children experience seeing others’ faces. Early life contextual factors can also impact negatively upon development: poverty has been linked to effects on the brain which can result in a range of mental health difficulties.

So how are BabyLab scientists linking structural brain changes to the development of perceptual, cognitive, motor and language abilities? As babies often lurch rapidly between contented gurgling, gutsy wailing and gentle snoozing, novel experimental techniques are required. These include: 1) Behavioural testing such as eye tracking (e.g. used for testing preferential looking at faces versus complex objects) 2) Electromagnetic recording methods (EEG/ERPs) using a damp hat to record tiny voltage changes on the scalp as groups of neurons synchronously fire together on exposure to a task 3) Optical imaging (NIRS), where weak light beams are used to track blood flow in the brain as babies are thinking/perceiving stimuli 4) MRI scanning – used for sleeping babies to discover more about brain structure and functioning.

Changing their mind

In the first showcase talk, Dr Natasha Kirkham explained how good working memory (WM) and inhibitory control (IC) in children contribute to the development of decision-making, remembering of rules and the production of contextually appropriate behaviour  (e.g. speaking loudly in assembly, but not at the cinema). Childhood development of WM and IC has been tested using the Dimensional Change Card Sort Task where firstly, children were asked to match a target card with reference stimuli according to shape, and then to only match according to colour. Although 3 year olds performed worse than 5 year olds where there was a category conflict according to the prior rule (e.g. a red truck had to be matched with a red star), scaffolding a 3 year old child’s learning experience helped to improve their performance. For instance, instructing them to repeat a new rule, rather than solely providing ‘yes/no’ feedback to card choices delivered the greatest improvement. Next, Natasha provided us with an additional experimental example testing WM and IC – the ‘Delay of Gratification Task’ where in order to earn many more Oreo cookies, children were asked to refrain from eating those already placed before them until an adult re-entered the room. Amusing strategies employed included children sitting on their hands or putting cookies in drawers!

Shining Light on the Infant Brain

In the second showcase talk Dr Sarah Lloyd-Fox informed us how an exciting and novel way to shine light on the functioning of an infant’s brain is to do it literally by using a technique called NIRS. This works by shining a weak light into the infant’s head which passes through the infant’s skull and reaches underlying brain tissue.

NIRS comes with many benefits to researchers: it can be used on babies who are awake (so they can be tested with visual imagery rather than sounds only) and has better spatial resolution than MRI. At Birkbeck, NIRS has been used to investigate when infants start to see and interpret actions, alongside questions such as ‘is our ability to use our hands to interact with our environment related to how we respond when we see other people performing similar actions?’. As emphasized by Dr. Natasha Kirkham earlier, the experimental value of play should never have been underestimated and this question was examined using games testing infants’ manual expertise. Intriguingly enough, evidence suggests that there may be a relationship between the way our developing brain responds to the sight of human motion and the motion we learn to form ourselves.

Infant time perception – ‘Escaping the Eternal Now’

In the third talk Dr Caspar Addyman highlighted how babies are often absorbed in something in the ‘now’: “in one moment babies can be in howls of tears and the next, in peals of laughter”.

How is it that humans gauge how quickly an event ‘feels’? Caspar described how for adults the longer ago something occurred, the fuzzier a memory exists of it. Judging the ‘fuzziness’ gives us a measure of how long ago in time it occurred. Since infants’ memories are not very well developed, it is difficult for them to judge the continuity of events. Thus, in order to learn more about the development of infants’ perception of time, BabyLab researchers are testing the long and short term memories of 6, 10 and 14 month olds using habituation (the classic technique of making babies bored!) with heart rate measures and eye movements being monitored. In addition, movement is thought to be very important to an infant’s developing understanding and judgement of time and events – at 6 months the world has to come to you, by 14 months exploration increases as crawling and walking ensue, expanding an infant’s sphere of the world. Such interaction may link to changes in the judgement of time. This is ongoing research and we look forward to hearing the results of Caspar’s study in the future.

Autism in infancy

The final talk, given by Dr Teodora Gliga, described the progress developmental science is making towards understanding autism spectrum disorders (ASD). ASD are presently diagnosed from 24 months onwards when children fail to meet social communicative developmental milestones. Researchers at Birkbeck are investigating how ASD can be detected and diagnosed earlier, for example by trying to decipher the pre-requisites for language development. As ASD is a genetic disorder (there is a 10% chance of developing ASD if one has a sibling with it vs a 1% chance for the general population), a prospective longitudinal study has been used to investigate infants who have siblings with autism over a 3 year clinical assessment period. 

Evidence indicates that although there are no differences in paying attention to faces between ASD and typically developing infants at 6 months and 12 months, there are early differences with gaze direction and a failure to follow gaze from 6 months – a precursor of social ability. In order to inform intervention strategies, future studies will need to focus on testing children at multiple time points and using measures such as attention (looking away from irrelevant objects), the ability to discriminate gaze direction, follow gaze, to acquire words,  maternal input (words child hears), the social and biological environment, a child’s genes, and risk factors during pregnancy.

Read more about BabyLab research in the news.

Birkbeck Commemorates World TB Day by Discussing Drugs from Plants

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This post was contributed by Clare Sansom, a part-time lecturer in Birkbeck’s Department of Biological Sciences, and a freelance consultant and science journalist.

World TB Day is held on 24 March every year, to mark the day in 1882 when Robert Koch, one of the fathers of microbiology, first announced that he had discovered the cause of tuberculosis (TB) – the bacterium now known as Mycobacterium tuberculosis. Over 125 years since its discovery, and despite billions of dollars of investment in drug discovery, this bacterium is still a killer. The World Health Organisation estimates that about two billion people are infected with latent tuberculosis; in 2010, the last year for which full figures are available, over eight million people became ill with active tuberculosis, and 1.4 million people died from the disease. Two factors help make TB particularly deadly: it often occurs in people infected with the HIV virus, where it is one of the major causes of death, and drug resistant forms are becoming more common. In January 2012, Nature reported the identification in India of so-called “totally drug resistant” (TDR) tuberculosis, resistant to all anti-TB drugs in general use.

In 2012 at Birkbeck, World TB Day coincided with the start of the College’s annual Science Week. Dr Sanjib Bhakta, head of the Mycobacteria Research Laboratory in the Department of Biological Sciences, organised a well-attended symposium on tuberculosis and its treatment. Besides two scientific presentations, the symposium featured a short video, Tuberculosis: The Real Story, highlighting the views of people affected by TB in the UK, and a panel discussion led by the grassroots volunteer organisation Results UK on some of the political challenges raised by tuberculosis. 

Both science lectures focused on plants as a source of potential new drugs for tuberculosis. Professor Franz Bucar from the University of Graz in Austria highlighted the extreme chemical diversity of compounds that could be extracted from plants, particularly as compared to those found in the average synthetic compound library. Plants have always existed alongside their own microbial pathogens and have evolved natural antibiotics to protect themselves. Our ancestors, before the dawn of scientific medicine, used plant extracts to treat infectious disease, often quite successfully. The sub-discipline of ethnomedicine involves “mining” these traditional or historical remedies for pure chemicals that can be developed as, or modified into, drugs.

Bucar described a European herb, elecampane or Inula helenium, which is known to have been used to treat lung disease in the sixteenth century. He explained how a complex mixture of natural products derived from this plant had been tested against mycobacteria. Compounds found to have anti-mycobacterial activity were extracted and purified. Other plants have also yielded useful lead compounds; extracts of bark from a small tree with the Latin name of Berchemia discolor have even been shown to inhibit multi-drug resistant strains of Mycobacterium tuberculosis at useful concentrations.

Discovering antibacterial products in plant extracts, however, is only a first step towards drug discovery. Even when natural products like these compounds are found to be selective for bacterial over human cells, it is necessary to discover their mechanism of action; to modify them to optimize their activity; and, since plant sources are often scarce and extraction processes costly, to determine methods of synthesizing them in the laboratory.

The second scientific presentation was given by Dr. Bhakta himself and described current work in Birkbeck’s Mycobacteria Research Laboratory in searching for potential drugs for TB. These are needed not only to combat resistant forms of the bacteria but to improve current treatment regimens for “standard”, drug-sensitive TB. This requires a combination of four drugs to be taken for two months followed by two drugs for another four months, and many patients, particularly poorer and less well educated ones, fail to complete such a long and complex regimen. This in turn can lead to the development of further resistant strains.

Ideally, new drugs are required that target proteins not targeted by existing drugs, as resistance will be harder to develop. Mycobacteria have extremely complex cell walls, unlike those of other types of bacteria; they are essential for the bacteria to survive, and the enzymes used to synthesise them have no equivalents in mammalian genomes. These enzymes, therefore, have many of the characteristics of excellent drug targets.  Bhakta and his group have been exploring ways to inhibit the synthesis of the peptidoglycan that is one of the most important constituents of that cell wall. This molecule has been described as the bacterium’s “Achilles heel”, but no drugs targeting its synthesis have yet entered the clinic.

Mycobacteria synthesise peptidoglycan via a series of enzymes known as ligases, each of which adds a new link to the growing peptidoglycan chain. Bhaka’s group has focused on one of these ligases, termed MurE. This enzyme is essential for the bacterium to survive and it is conserved in all Mycobacterium tuberculosis strains. Working in collaboration with Professor Nick Keep, also in the Department of Biology, Bhakta solved the structure of MurE and showed it to have an active site that could in theory, at least, be occupied, and blocked, by a relatively small, “drug-like” molecule. He and his co-workers are now searching libraries of natural products for compounds that might inhibit this enzyme. They have identified promising MurE inhibitors from plants endemic to both Colombia and China, and are synthesizing analogues of these compounds for further testing.

It is unlikely that the next generation of anti-tuberculosis drugs will include any unchanged natural products. It is extremely likely, however, that natural products will yield the “scaffolds” on which these desperately needed drugs may be built, and perhaps one of these will be generated from within Bucar’s or Bhakta’s groups.