Crystallography: From Chocolate to Drug Discovery

This post was contributed by Dr Clare Sansom, senior associate lecturer in the Department of Biological Sciences. Dr Sansom attended inaugural Rosalind Franklin Lecture during Birkbeck Science Week 2016.

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Birkbeck has already established lecture series in honour of some of its most distinguished alumni. Until 2016, however, Rosalind Franklin – co-discoverer of the DNA structure and perhaps the most widely recognisable of its ‘famous names’ – was missing from the list of honourees. This gap has now been filled; the annual Rosalind Franklin lecture forms part of the college’s Athena SWAN programme and will always be given by a distinguished woman scientist.

And fittingly, the inaugural lecture, which was part of Science Week 2016, was devoted to Rosalind Franklin’s own discipline, crystallography. Elspeth Garman, Professor of Molecular Biophysics at Oxford University, gave an entertaining and illuminating lecture to a large audience that included Rosalind’s sister, the author Jenifer Glynn.

Exploring crystals

Garman began her lecture by showing a short video that she had produced for OxfordSparks.net that used a ‘little green man’ to illustrate the method of X-ray crystallography that is used to obtain molecular structures from crystals. The rest of the lecture, she said, would simply go through that process more slowly. She started by showing some beautiful examples of crystals. All crystals are formed from ordered arrays of molecules. They can be enormous, such as crystals of the mineral selenite in a cave in Mexico that measure over 30’ long or too small to be visible with the naked eye.

In the early decades of crystallography, structures could only be obtained from crystals of the smallest, simplest molecules: the first structure of all, published in 1913 by the father-and-son team of W.H. and W.L. Bragg, was of table salt. When they were jointly awarded the Nobel Prize for Physics in 1915, the younger Bragg was a 25-year-old officer in the trenches on the Western Front. His record as the youngest Nobel Laureate was unbroken until Malala Yousafzai’s Peace Prize in 2014.

The Braggs’ discoveries paved the way for studies of the structures of many, many substances: including the chocolate of the lecture title. Few of the audience can have known that chocolate exists in six different crystal forms, or that only one of these (Form V) is good to eat. The process of ‘tempering’ – a series of heating and cooling steps – is used to ensure that it solidifies in the correct form.

Professor Nick Keep and Professor Elspeth Garman at the inaugural Rosalind Franklin lecture

Professor Nick Keep and Professor Elspeth Garman at the inaugural Rosalind Franklin lecture

Protein crystallography

Garman then moved on to talk about her own field of protein crystallography. Proteins are the ‘active’ molecules in physiology, and they are formed from long, linear strings of 20 different ‘beads’ (actually, small organic molecules known as amino acids). Chemists can quite easily find out the sequence of these beads in a protein, but it is impossible to work out from this the way that the string will fold up into a definite structure ‘like a piece of wet spaghetti’. And it is this structure that places different units with different chemical properties on the surface or in the interior of the protein, or near each other, and that therefore determines what the protein will do.

Protein crystallography only became technically possible in the mid-twentieth century, and even then it was a painfully slow and complex process that could only be used to study the smallest, simplest proteins. Dorothy Hodgkin, also a professor at Oxford, won her Nobel Prize in Chemistry in 1964 for the structures of two biologically important but fairly small molecules: penicillin, with 25 non-hydrogen atoms and vitamin B12, with 80. She is perhaps better known for solving the structure of insulin, the protein that is missing or malfunctioning in diabetics. This has 829 non-hydrogen atoms; in contrast, the 2009 Chemistry Nobel Prize was awarded for the structure of the ribosome, the large (by molecular standards) ‘molecular machine’ that synthesises proteins from a nucleic acid template. The bacterial ribosome used for the Nobel-winning structural studies is well over 300 times larger than insulin, with over a quarter of a million atoms.

Real world applications

Dr Rosalind Franklin

Dr Rosalind Franklin

Protein structures are not only beautiful to look at and fascinating to study, but they can be useful, particularly for drug discovery. Many useful drugs have already been designed at least partly by looking at a protein structure and working out the kinds of molecule that would bind tightly to it, perhaps blocking its activity. Some viral proteins have been particularly amenable to this approach.

Rosalind Franklin did some of the first research into virus structure when she was based at Birkbeck, towards the end of her tragically short life, and her student Aaron Klug cited her inspiration in his own Nobel lecture in 1982. X-ray crystal structures were used in the design of the anti-flu drugs Relenza™ and Tamiflu™ and of HIV protease inhibitors, and more recently still structures of the foot and mouth virus are helping scientists develop new vaccines for tackling this potentially devastating animal disease. The foot-and-mouth virus structure even made the front page of the Daily Express.

The equipment that Dorothy Hodgkin and her contemporaries used to solve protein structures in the 1960s and 1970s looks primitive today. Now, almost every step of protein crystallography has been automated. Powerful beams of X-rays generated by synchrotron radiation sources, such as the UK’s Diamond Light Source in Oxfordshire, allow structures to be determined quickly from the smallest crystals. It is even possible to control some of these machines remotely; Garman has operated the one at Grenoble from her sitting room. Yet there is one step that has changed remarkably little. It is still almost as difficult to get proteins to crystallise as it was in the early decades. Researchers have to select which of a large number of combinations of conditions (temperature, pH and many others) will persuade a protein to form viable crystals. Guesswork still plays a large part and some researchers seem to be ‘better’ at this than others: Garman adds the acronym ‘GMN’ or ‘Grandmother’s maiden name’ to her list of conditions to reflect this.

Yet, with every step other than crystallisation speeded up and automated beyond recognition, the trickle of new structures in the 70s and even 80s has become a torrent. Publicly available structures are stored online in the Protein Data Bank, which started in 1976 with about a dozen structures: it now (May 2016) holds over 118,000. Protein crystallography as a discipline is thriving, but there are many challenges ahead. We are only now beginning to tackle the 70% or so of human proteins that are only stable when embedded in fatty cell membranes and are therefore insoluble in water. It is possible to imagine a time when it is possible to solve the structure of a single molecule, with no more need for time-consuming crystallisation. And, hopefully, women scientists will play at least as important a role in the second century of crystallography as they – from Quaker Kathleen Lonsdale, who developed important equations while jailed for conscientious objection during World War II, through Franklin and Hodgkin to Garman and her contemporaries – have in the first.

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Cognitive Training in Psychological Wellbeing

This post was contributed by Jessica Swainston, a PhD researcher under the supervision of Professor Nazanin Derakshan, investigating the effects of adaptive cognitive training on building resilience in breast cancer survivors. Jessica attended Professor Derakshan’s Birkbeck Science Week event on Thursday 14 April, titled ‘How can adaptive cognitive training improve resilience and mental well-being?’

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A Crisis in Psychological Health

Emotional disorders such as anxiety and depression are of increasing prevalence. The world health organisation has recently estimated that 50 million years of work, an annual global loss of £651bn, will be lost to anxious and depressive disorders between now and 2030. This figure is not only critical for the state of the economy, but more importantly is concerning for the future psychological wellbeing of individuals, their families, and the society we live in.

As it stands, current pharmacological and therapeutic treatments have been shown to be only modestly effective in both the treatment and prevention of such disorders. It is imperative then that more research is carried out in order to better understand the underlying mechanisms involved in these conditions. By achieving this, there is hope that we can develop effective interventions to not only treat psychopathology, but further to build resilience against its onset and recurrence.

Building Resilience

So, how do we become more resilient? How do we continue to cope with the ever demanding stresses that society and life place upon us?

Professor Nazanin Derakshan and her team are currently attempting to address this very issue, and was discussed in her captivating talk during the Birkbeck Science week.

Derakshan is of the mind that our ability to flexibly direct where we place our attention, is the key mechanism in regulating our emotions and boosting our psychological resilience. In other words, the better we are at paying attention to our current goal (e.g. Writing this blog post), the less cognitive resources we have available to attend to irrelevant intruding and ruminative thoughts (e.g. ‘What if I fail my PhD?!’). Accordingly, there has been a wealth of research to support this claim.

A multitude of behavioural studies have indicated that individuals with high levels of Anxiety and Depression have inefficient levels of attentional control, which is a critical component of our working memory, a system that monitors the incoming and temporary storage of information. In addition, anxious individuals have been shown to require recruitment of additional cognitive resources, in a compensatory manner, to reach the same performance levels as non-anxious individuals, thus indicating poor processing efficiency and filtering of irrelevant information. That is, anxious individuals must invest more effort in reaching required goals than non-anxious individuals, a factor that will more quickly lead to cognitive and emotional fatigue.

Of further importance, neuroimaging studies have indicated that anxiety and depression are associated with irregular connections between the limbic (emotional) and prefrontal (cognitive) systems of control in the brain. More explicitly, increased activity in the limbic areas have been linked to decreased activity in the prefrontal areas of the cortex, further highlighting the association between inefficient pre-frontal cognition and increased emotional activity.

How can we improve our Attentional Control?

If then attentional control is the key mechanism by which emotional vulnerability can be moderated, how then can this process be targeted?

In a new and exciting line of research, it transpires that there is potential to improve our levels of attentional control through adaptive cognitive techniques that train working memory. For example, a series of studies have shown that improvements in working memory on an adaptive n-back task, in which participants are required to remember the position of a visual or auditory target n-trials back, have been shown at both the behavioural and neural levels. Importantly, gains in working memory abilities have been shown to transfer to other tasks requiring attentional processes, indicating that the training may help to improve cognitive control across varying tasks, not just on the task itself.

Benefits of Cognitive Training in Psychological Health and Sports Performance

So, considering that the well documented link between emotion and cognitive function, can attentional control training decrease anxious and depressive symptomatology? Further, is the training applicable to other circumstances, such as improving anxious states that can interrupt sports performance? Professor Derakshan presented some preliminary findings that show great promise.

As yet, compared to control groups, a course of adaptive attentional control training has shown to result in:

  • Reduced levels of state anxiety
  • Reduced levels of depressive and ruminative symptomatology ( at behavioural and neural levels)
  • A decrease in cancer related thoughts in Breast Cancer survivors
  • Improved tennis performance in a high pressure environment

Cognitive Training as an aid to current therapies

Professor Nazanin Derakhshan

Professor Nazanin Derakhshan

Professor Derakshan raised an interesting point in relation to the future directions and clinical relevance of cognitive training in psychological health. A number of current psychological therapies such as mindfulness and cognitive behavioural therapy are of varied success. This may in part be due to the lack of attentional resources that severely depressed and anxious individuals possess. If one’s attention is poor, how can one easily engage in a 10 week course of psychological therapy which requires focus and concentration?

It can often be problematic. Thus if, as a complimentary treatment, attentional control processes are improved through training, patients will be better enabled to pay attention and gain the most value from their psychological therapy. In fact, one recent study by Course-Choi et al., (2016) showed just this. Results indicated that a combined course of mindfulness and attentional control training showed greater reductions in trait worry, compared to a course of mindfulness by itself.

In sum, Professor Derakshan presented a compelling theoretical framework for improving our cognitive flexibility as a means to build resilience and protect against emotional vulnerability. With this in mind, there is promise for improving psychological health in the coming years. As poignantly remarked by Derakshan,

‘It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change’. – Charles Darwin, 1809.

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The Speech/Song Illusion

This post was contributed by Rosy Edey, PhD student and graduate teaching assistant in the Department of Psychological Sciences. Rosy attended a Birkbeck Science Week 2016 event on Thursday 14  April – ‘Talk: The Speech/Song Illusion’ (led by Dr Adam Tierney)

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Sadly all good things must come to an end, and the finale of Birkbeck’s 2016 Science Week was a compelling musical one, by one of Birkbeck’s newest members of the Psychology Department, Dr Adam Tierney. In a humorous and engaging way Adam took the audience through the scientific story of the “evolution of music”. Music seems almost completely purposeless, and let’s face it a little bit strange, so why do we love it so much?

What is music?

Adam placed the first known musical instrument (an intricate bone flute) back 40,000 years, which was way before the first record of written word (5000 years ago), but much later than (a good estimate of) when we first evolved to make vocalisations (400,000 years ago). The absolute origin of music is obviously very difficult to pinpoint – as it is possible (and probable) that way before we built tools – like the bone flute – to make music, we were signing our hearts out in the moonlight.

This questionable timing of the birth of music raises the question: what came first, speech or music? Whichever one came first, if one evolved from the other we would expect music and language to share similar characteristics. Indeed, Adam presented evidence that both the huge varieties of globally spoken languages and music from around the world share common universalities (which at first seemed very unlikely based on the diversity of music that was perfectly demonstrated through a bizarre example of washing machine “music” and also a collection of songs from the playlist from the Voyager I and II spacecraft gold plates).

These shared acoustic qualities included alternating beat patterns, descending melodic contours, and increases in final phrase duration. Using the very complicated sounding “Normalised Pairwise Variability Index” (i.e. jargon for a measure of rhythmic alteration, or a measure of paired stress in phrases) Adam showed there were also commonalities between languages and music within and between specific countries (basically English music sounds English, and French sounds French, but English music/ language does not sound like French music/language). All of these beautiful subtleties hidden in the acoustics of spoken word and music provide vast amounts of data, which signal meaning to the listener. These underlying similarities do hint that music and speech are distant cousins.

Music as Speech with added extras

Playing music with speech can change it into a song; The Jazzy Sarah Palin Interview was a good example of this:

 

And it seems even without music our brains can transform speech into music. Diana Deutsch discovered this phenomenon in 1995, while looping some spoken data.

After several iterations the phrase “sometimes behave so strangely” no longer sounded like speech, and had converted into song (I now cannot even read this phrase without hearing the tune). All the phrases in Adam’s Corpus of Illusion Stimuli turned into singing, but interestingly, the “control” sentences didn’t have the same effect. This illusion appears to be a useful tool to test further the idea of music evolution and ask more detailed questions, such as: “what is required for speech to become song?” and “what mechanisms are going on in our brains when we change speech into song?”

Testing the Science

Dr Adam Tierney

Dr Adam Tierney

Adam has pulled out the acoustic elements that predict what speech phrases are heard as song. He suggests there are two main factors which induce the illusion; increased beat variability and increased pitch intervals. Remarkably, there is large variability between people’s experience, and being a trained musician doesn’t improve your ability to detect the illusion.

So what is going on in the brain? Adam’s hunch was that these ‘musical’ phrases are processed in the same way as when listening to speech, but with a little added extra. And this does in fact seem to be the case, we activate a similar network to when we hear normal speech, but extra activation in regions that are highly pitch sensitive (e.g. Heschl’s Gyrus – a very early part of the auditory system), and also motor regions (e.g. precentral gyrus – which hosts a map of the body, but specifically the mouth region) when we listen to the ‘song’. Interestingly, there were no regions that were more active for just speech over the song phrases. Adam suggested participants were imagining singing and tapping along to the beat, and processing the pitch more deeply in these ‘song’ phrases. This evidence neatly fits the behavioural data, showing that phrases that have a strong rhythm and more of a melody are processed differently by the brain, which results in them being distorted from speech into song.

Although it is virtually impossible to know the true origin of music, Adam managed to make quite a convincing case that song is just speech with some ribbons on, and quite possibly did evolve from speech.

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Investigating the moon and meteorites

This post was contributed by Dr Jennifer Harris, postdoctoral researcher in Birkbeck’s Department of Earth and Planetary Sciences. Dr Harris attended two Birkbeck Science Week 2016 events on Tuesday 12 April: Analysing the Moon (led by Dr Louise Alexander); and Looking Inside (led by Natasha Almeida)

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What small fragments of rocks can tell us about the moon, the formation of the Solar System and even the early Milky Way was the subject of the second half of Birkbeck Science Week 2016’s Planetary Science evening on Tuesday 12th April.

Dr Louise Alexander, a postdoctoral researcher and Birkbeck student alumna based in the UCL/Birkbeck Centre for Planetary Sciences, and Natasha Almeida, a Birkbeck PhD student and Meteorite Curation Assistant at the Natural History Museum spent an entertaining and informative hour detailing just how much could be gleaned from tiny fragments of extra-terrestrial rocks, and how exactly they go about doing this in their own research.

Apollo Moon samples

Dr Louise Alexander

Dr Louise Alexander

The first half of the session was dedicated to the Moon with Louise Alexander giving us an introduction to the lunar samples brought back by the Apollo astronauts that she uses in her research.

As anyone who’s ever spent any time looking at the full moon can tell you, the moon can be divided into two rough units, one bright and one dark. Lunar samples also fall into these two categories representing the dark Mare basalts and the brighter highland rocks together with a third category of pyroclastic samples. Information from these samples can be used to provide evidence to support the Giant Impact Formation theory of the moon, tell us about the moons internal structure and help to validate surface age estimates from crater counting techniques.

The particular samples that Louise’s work has focused on are all Mare Basalts and are fragments only millimetres in size. Key instruments for extracting data from such small samples are Electron Microprobes, like the one housed by Birkbeck Department of Earth and Planetary Sciences, and Gas Mass Spectrometers.

These instruments enable scientists to peer inside tiny fragments of rock and identify the different mineral crystals that comprise it. Despite the size of each sample, by looking at a large number of them Louise and her collaborators are able to build up a picture of the petrological variety that exists within the Apollo 12 site.

It’s now been over 40 years since the last samples were brought back from the moon and so it’s in the interests of those scientists lucky enough to be in possession of any of them to squeeze as much data out of them as possible. Having used them to gain an understanding of the history of the moon Louise and her colleagues are now investigating the possibility that these samples could have recorded evidence of high energy galactic events over the past few billions of years as the moon has moved through the Milky Way.

This research is still in its infancy and Dr Alexander was keen to point out that the best samples for doing this would be ones from several metres beneath the lunar surface. Sadly for this research no such samples have ever been collected, but if we were to send people back to the moon they could be!

Mapping inside meteorites

Natasha Almeida

Natasha Almeida

An important consideration of the analysis that was described in the first half of the session was that many of the techniques resulted in the destruction of the sample. However not all analysis has to be destructive as we would find out from Natasha Almeida. As a curator Natasha has a professional bias towards preserving her unique and precious samples, whilst as a researcher, still wanting to exploit them as much as possible.

The Natural History Museum in London is home to the oldest collection of meteorites in the world and makes crucial loans of their 4870 samples to researchers across the globe. These meteorites are fragments of the surfaces of Mars and the Moon, and surfaces and interiors of numerous asteroids, some of which have been identified and some of which have not. In order to analyse these rare rocks Natasha uses equipment most of us will have some experience of, an X-Ray scanner, more specifically a micro-CT scanner. Just like a medical CT the NHM’s micro-CT makes use of X-rays to scan through the rock and build up a 3D picture of its interior.

There are some clear differences however; primarily the strength of the beam and the duration of the scan. Rock is more impervious to X-Rays than flesh and bone requiring a much stronger beam and a longer scan time. Each scan results in a 3D image with a resolution of down to 5mm/voxel (a voxel is a 3D pixel) and around 20 – 30Gb of data.

With these images Natasha has extracted a variety of information from numerous meteorites including spotting internal structures and features that would otherwise only be found by cutting into the sample, tracing cracks to establish the possibility of internal contamination by the atmosphere of the Earth and mapping out internal fractures and pores. This final result is especially key for meteorites as the historical methods for working out the porosity of a rock sample involve dunking it in a bucket of water. This method is a purely quantitative one that tells you how much space is in the rock but not how it is distributed unlike micro-CT.

In addition submerging your sample in a tank of water definitely counts as a high contamination risk, something meteoriticists and curators try and avoid like the plague! Unlike the electron microprobe analysis discussed in the first half of this session micro-CT for meteorite analysis is a technique that is still in its infancy but it certainly holds a lot of promise, especially if we have to wait another 40 years for people to bring us back more samples from another planetary body.

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