Author Archives: Guy Collender

From structural biology of neglected diseases to Brazilian science

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This post was contributed by Dr Clare Sansom, of Birkbeck’s Department of Biological Sciences.

The prestigious Bernal Lecture is given annually at Birkbeck to honour the legacy of Professor J.D. Bernal, the first head of the Department of Crystallography (now part of Biological Sciences). In 2013 this lecture was given by a distinguished alumnus of the College, Professor Glaucius Oliva of the Institute of Physics of São Carlos, University of São Paulo, Brazil.  Introducing Professor Oliva, the Master of the College, Professor David Latchman, said that in the over forty years since the lecture series started, there had rarely been a better fit between Bernal’s interests in science and society and the chosen topic.

Professor Oliva spent four years at Birkbeck in the 1980s, studying for a PhD under Professor (now Sir) Tom Blundell. He started his lecture with a tribute to his colleagues from those days – many of whom were in the audience – mentioning in particular their passionate interest in their subject, hard work and desire that the knowledge they were gaining would be exploited for the good of society as a whole. His time in the Blundell lab at Birkbeck had, he said, changed his life. The main part of his lecture focused on two linked topics: the development of science in his native Brazil, and his research there into the structures of proteins that are linked to some of the world’s least studied infectious diseases.

There was very little science in Latin America until the early years of the twentieth century. Bernal described something of a “scientific renaissance” in the Spanish-speaking parts of the continent in his book The Social Function of Science (1939), but said very little there about Brazil. That country did, however, make its first serious investment in science and technology at about the same time, and continued to make slow progress throughout most of the last century, admittedly from a very low base. This growth has accelerated in the last decade, and the country now has a respectable place in the international tables: about 3% of all publications in peer reviewed journals include at least one Brazilian co-author. Even more encouragingly, there has been an enormous increase in enrolments into higher education since 2000. Significant challenges remain, however, particularly in encouraging private industry to invest in research and technology.  Brazil is a member of the increasingly influential BRIC group of large rapidly developing countries along with Russia, India and China, which, with other East Asian countries, is well ahead of the others in the group in patent numbers and similar metrics.

Links between the Department of Crystallography at Birkbeck and Brazil go back to the late 1970s and have made a significant contribution to the development of structural biology there. Professor Oliva was one of several young scientists to study here during the 1970s and 1980s. He returned to São Paulo in 1988 to set up his own crystallography lab. And he had to start small; his first major piece of equipment, an X-ray detector, arrived two years later.

Tackling infectious diseases
Since then, the research in Professor Oliva’s laboratory has focused on a group of infectious diseases that are common in tropical countries. Infectious diseases are still responsible for about a quarter of all deaths worldwide, and that proportion is far higher in low- and middle-income countries and in children. The effect of disease is often measured as a loss of “Disability Adjusted Life Years” (or DALYs) and these diseases, which are generally grouped together under the title of “neglected tropical diseases”, are estimated to cause about 90 million lost DALYs each year.

Professor Oliva described his group’s efforts to obtain information about the structures of proteins from the parasitic organisms that cause several of these diseases. Chagas’ disease is caused by a protozoan, Trypanosomacruzi, and is endemic in Central and South America. It is rarely fatal but chronic infection can cause debilitating and long-lasting disability. Professor Oliva’s group was the first to solve the structure of the enzyme glyceraldehyde-3-phosphatase from T. cruzi. This enzyme is essential for the parasite’s metabolism and its structure is distinctly different enough from that of the human enzyme for its inhibitors to show promise as anti-parasitic drugs. Developing such a drug, however, was always going to be difficult in a country with essentially no research pharmaceutical industry. The strategy pursued by Professor Oliva and his co-workers has been to exploit Brazil’s natural biodiversity, screening plant extracts against the structure to extract and purify compounds that are potent inhibitors of the enzyme. Some variants of the compounds originally identified in these screens are now undergoing pre-clinical testing as candidate drugs for Chagas’ disease. The group has also solved structures of an enzyme, purine nucleoside phosphorylase, from the parasitic flatworm Schistosomamansoni. This is one of the causative agents of schistosomiasis, a chronic, debilitating disease that can take a variety of forms; S. mansoni mainly causes hepatomegaly (enlarged liver) and other immune reactions.

Science without Borders
Professor Oliva returned to science policy towards the end of the lecture, in discussing the new Brazilian Science without Borders initiative, which he directs. This ambitious scheme aims to place at least 100,000 students and young scientists from Brazil in laboratories outside the country within four years.  Thanks to generous sponsorship – not least from the banking sector – 101,000 fellowships had been agreed and 41,000 awarded by May 2013.  So far, the UK is proving the second most popular destination country among Fellows appointed through this scheme. One of the first three to come to the UK, Dr.Jose Luiz Lopes from the University of São Paulo, spent a year working in Professor Bonnie Wallace’s lab in Biological Sciences. He is now back in Brazil as a postdoc, working in a collaborative project involving Birkbeck and the University of São Paulo that has joint financial support from BBSRC and Brazil’s CNPq. Birkbeck’s scientific links with Brazil are at least as strong as they were when Professor Oliva arrived here as a raw PhD student almost thirty years ago.

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Science Week: Structures of sodium channels

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This post was contributed by Dr Clare Sansom, of Birkbeck’s Department of Biological Sciences.

The structures of sodium channels and what they can teach us about human health, particularly rare neurological diseases, were explained during Science Week.

Professor Bonnie Wallace, of Birkbeck’s Department of Biological Sciences, delivered the fascinating and accessible lecture on 18 April. She has been at Birkbeck for about twenty years and now directs the department’s impressive research work on the structural biology of membrane ion channels.  Membrane proteins are ubiquitous, are responsible for the transport of both chemicals and signals into and out of cells, and form some of the most important drug targets. They are also, as Professor Wallace made very clear in her talk, some of the most challenging of all proteins for structural biologists to examine.

All cell membranes are semi-permeable, which means that some substances can pass across them easily while others are excluded. Ions, which are charged, are generally excluded by the hydrophobic (“water hating”) membranes. This could be something of a problem, as ion transport into and out of cells is an essential physiological process. Ion channels are evolution’s solution to this problem: proteins embedded in membranes that allow ions to selectively enter and leave cells.

Much of Professor Wallace’s work over the last 10 years has focused on the structures of voltage gated sodium channels. These open to allow sodium ions to enter cells, and close to prevent them from doing so, in response to changes in potential across the membrane, and they are found throughout nature. Small molecules can bind to these channels, holding them either open or closed; some of these are severely toxic, but others are important drugs for cardiac arrhythmias, epilepsy, and pain.

It took over ten years for Professor Wallace and her group to isolate the gene, clone and purify the protein, obtain crystals and finally solve the structure of the channel pore. The structure was finally solved using the powerful X-rays generated at Diamond, the UK’s only synchrotron radiation source located near Harwell in Oxfordshire.

Different structural forms
These channels exist in three different structural forms: “open”, “closed” and “inactivated”. Many years before the detailed structures were solved Professor Wallace and her group had used a biophysical technique, circular dichroism (CD) spectroscopy, to examine the conformational changes that occurred when mammalian and bacterial channels switched from one state to the other. As always, however, the full atomic-crystal structures yielded very much more information.

Professor Wallace and her group were the first to solve the structure of an open form of the channel which showed the “top” part of this structure, towards the extracellular membrane surface, has a hydrophobic surface, and an internal selectivity filter which allows sodium ions in while keeping others, including potassium and calcium ions, out.  The lower part, on the extracellular surface, is where the ions exit. This open structure could be compared with the published structure of closed form of the channel, and showed that the upper portion containing the selectivity filter was virtually unchanged The conformational change associated with opening and closing the channel occurs at the internal or cytoplasmic side of the protein. When the pore closes, a small turning motion of the “bottom” part of the helical bundle causes the bottom ends of the pore to come together and the diameter of the pore to shrink; the resulting channel is too small for sodium ions to pass through, so any inside the pore become trapped there.

Two subunits of the bacterial sodium channel pore in the “open” conformation, shown as a ribbon structure

Two subunits of the bacterial sodium channel pore in the “open” conformation, shown as a ribbon structure

Bacterial  voltage gated sodium channels have a domain at the C-terminal end of the molecule that is necessary for channel activity but that was not visible in any of the crystal structures. Professor Wallace and her group looked at this part of the molecule using a particularly powerful form of CD spectroscopy called synchrotron radiation CD spectroscopy that she had pioneered, and showed that each subunit had an extremely flexible protein chain separating the pore from a C-terminal helix. Using this information, the group have proposed a novel mechanism for channel opening in which the conformational change in the pore is enabled by these helices oscillating up and down.

Two subunits of the bacterial sodium channel pore in the “open” conformation, shown as a ribbon structure

Two subunits of the bacterial sodium channel pore in the “open” conformation, shown as a ribbon structure

Implications for health
The final part of Professor Wallace’s talk was devoted to the role of sodium channels in health and disease, and as a drug target. A few unfortunate individuals have mutations in a type of channel that is involved in the response to painful stimuli. If this channel is jammed open, patients experience a constant, burning pain termed erythromelalgia, most commonly in their hands and feet. Professor Wallace showed that an equivalent mutation from phenylalanine to valine at the base of one of the protein subunits could cause the channel to open just enough for ions to pass through. There are also people in whom these channels are jammed in the closed position or are missing altogether, and they feel no pain, even if they walk on hot coals. It may one day be possible for drugs based on our knowledge of these structures to be designed to ease both these conditions.

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Science Week: Making sense of medical genetics

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This post was contributed by Dr Clare Sansom, of Birkbeck’s Department of Biological Sciences.

Professor Nick Keep (left) and Professor Jonathan Smith (right)

Professor Nick Keep (left) and Professor Jonathan Smith (right). Photo: Harish Patel

Genomics is still quite a young science. It is scarcely a decade since the first human genome sequence was decoded, at a cost of $3 billion, and we are already discussing the implications of the $1,000 or even $100 genome. Accurate genetic testing is now available for a wide range of diseases and conditions. And it is perhaps not surprising that we find it difficult to deal with this barrage of information, particularly when it comes to how it affects our own health.In the last of the 2013 Science Week lectures, Professor Jonathan A Smith, from Birkbeck’s Department of Psychological Sciences, described how people at risk of genetic disorders made decisions about testing, and how they responded to test results: thus, how they made sense of the personal implications of the complex discipline of medical genetics. His approach to his discipline is qualitative rather than quantitative: the case studies he reported involved in-depth discussions with a small number of participants rather than questionnaire evidence from large cohorts. Using this, he has been able to gain considerable insights into the thought processes involved in complex, personal and ethical decision making. Furthermore, he stressed, his is a two-way approach: he as the researcher is in some sense in a similar position to his participants in attempting to make sense of their genetic stories. At the same time, he is also in a different position from the participants as his sense-making is always of an account that they provide.

Genetic testing
In his lecture on 18 April, Professor Smith began by explaining the process that is involved in clinical genetic testing. Generally, an individual with a family history that indicates that he or she may be at risk for a condition will approach a clinic directly to be tested. There, the specialist will take a complete family history and explain the genetics of the condition, the possible spectrum of risks involved and what the results may mean. Whether the test goes ahead will be the client’s (or patient’s) own decision and that decision is very rarely a straightforward one. Test results will move the individual tested from a broad risk category into a narrower one and, in a few cases, that narrow risk category will be a 0 per cent  or 100 per cent risk of the disease. That individual risk, however, may not be the only result; very often, a test result for one individual will mean changes in risk category for some of his or her blood relatives. These relatives may not want to take the test, or they may lack the capacity to decide for themselves (if, for example, they are children). And once a test is taken, the knowledge obtained cannot be un-learned: there is no way to put the genie back in the bottle. 

Huntington’s disease
Huntington’s disease is one of the most devastating of all genetic conditions. It is a fatal, progressive neurological disorder with an onset at any age between the 30s and the 60s, so many  patients will already have children before they are diagnosed. All people who inherit one copy of the faulty gene will eventually develop the condition, although it is impossible to tell when, and a child with one parent with the disease is at 50 per cent risk of developing it. A genetic test is available that will either reduce that risk to zero or increase it to 100 per cent.

Professor Smith presented the results of a study of decision-making in people at risk of Huntington’s disease using a technique known, in the jargon, as interpretative phenomenological analysis. The investigators spoke in depth to a small number of participants, used no fixed questions, and aimed to let the participants tell their own stories. In this particular case, all these had one parent diagnosed with Huntington’s disease and so were at 50 per cent risk of the disease before testing; and each of them already had children of their own. He described the very different thought processes and reasons that three of these individuals brought to their decisions – two were in favour of taking the test, and one was inclined to not take the test.

One thing united these three individuals (and by implication the other participants whom they in some sense represented): the desire to “do the right thing by their children”. Professor Smith presented this as a case of a classic moral dilemma, where no one strategy should be seen as right or wrong, and suggested that the case studies would help genetic counsellors to understand the range of emotions and responses that is likely to be experienced by their clients.

 

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Science Week: Earthquakes in Italy

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This post was contributed by Bryony Stewart-Seume, of Birkbeck’s Department of Biological Sciences.

Professor Gerald Roberts

Professor Gerald Roberts. Photo: Harish Patel

Science Week continued with a popular lecture about the widespread damage and complicated scientific questions arising from earthquakes.

Professor Gerald Roberts, of Birkbeck’s Department of Earth and Planetary Sciences, delivered a talk, entitled Earthquakes in Italy: the role of the historical record of earthquakes and geology, on 18 April. He began with a little history. The 1915 Avezzano earthquake killed a reported 30,000 people, and destroyed all but one building.

On  6 April 2009 an earthquake with its epicentre close to the town of L’Aquila in central Italy killed “only” 309 people. However, 30-50 per cent of the buildings in the town were badly damaged or razed to the ground, including a halls of residence in which eight students lost their lives. To better get an idea of the extent of the damage to the town (the centre of which has still not been repopulated), Prof. Roberts asked us to imagine half of the city of Bath being damaged beyond repair.

In an unfortunate twist the Town Hall of L’Aquila, which contained plans for dealing with such situations, was also badly damaged. Several 13-15th century cathedrals and churches were damaged and part of the modern hospital fell into the underground car park below it. The older masonry buildings proved especially vulnerable.

The financial cost of the 2009 earthquake has been estimated at €16 billion .

Scientists in the dock
There is, however, more to the story of the L’Aquila earthquake of 2009 than damage and a number of deaths. Prior to the earthquake citizens concerned by a number of tremors that had been rocking the city called upon the National Commission for the Forecast and Prevention of Major Risks to give an idea of the potential danger. What followed was unfortunate, in that initially the answer was along the lines of “it is not possible to predict earthquakes but this area has a long history of earthquakes and you should be vigilant”; a correct statement, but subsequently one of the members said in a TV broadcast that there was “no danger” which was not correct. 

When the earthquake did hit, police had reportedly told people that as there was “no danger” they should return to their houses. Seven members of the National Commission were subsequently tried, and convicted, for involuntary manslaughter. Their conviction was met with disgust by parts of the scientific community, although it was stated by the judge that it was not science that was judged, or the inability to predict an earthquake, but the failure to communicate consistently. This highly controversial conviction has led to concern amongst scientists about the future for those studying and communicating earthquake science.

So what can be done about this? Earthquakes will not stop happening. The African plate will not stop pushing into the plate containing Italy. And Italy will not stop being pulled apart. So how can we better communicate what we do know, and what we can do?

Asking the right questions
The question “when will there be an earthquake here?” is not one that can be answered. When an earthquake happens along any given fault is unpredictable. That an earthquake will happen along any given fault is inevitable. Earthquakes are caused by the movement of the plates of the Earth’s crust. Professor Roberts demonstrated through use of a model with springs and metal blocks moving on a sandpaper surface just how chaotic the movement is. The elastic crust pulls apart (or pushes together), tension builds up and the ‘elastic’ releases. This is what causes the earthquake itself. 

Professor Roberts took us through a more useful series of questions that populations should be educated to ask rather than the standard “when” question, the first being; does my area have a history of earthquakes. If you happen to live in central Italy the answer is obviously and demonstrably “yes”.

The next question that should be asked is; do I live in an earthquake zone? If you live near to an active fault, the short answer is “yes, you do.” But how active is it? How can that be measured? The question to ask here is “how much has the fault shifted, and how quickly?” This is measurable, believe it or not, with the help of supernovae – burnt out and blown up stars that send out high energy particles that react when they hit calcium, for example in limestone around L’Aquila to produce new 36Cl atoms. 

Professor Roberts stressed that although earthquakes cannot be predicted, in areas containing active faults they are inevitable and this needs to be communicated to populations.

The more time that elapses between each earthquake the more tension builds up and therefore the bigger the quake will be when it does happen. Which it will. They are inevitable, but not predictable.

Given that it is the building that kills you, not the earthquake itself, the best way to prepare for a quake is to make sure your buildings will take the strain. Buildings made out of cubes are weak and no match for the ferocity of  nature. But if you reinforce the buildings with struts to make triangles in corners, you will improve the integrity straight away.

There is, therefore, a need to educate populations about the right questions to ask and about the significance of small tremors. These questions should be asked many years in advance to ascertain whether earthquakes are inevitable in the area they inhabit and how they can undertake actions to prepare buildings to withstand the seismic shaking.

Just because there has not been an earthquake for a long time does not mean that you are safe. In fact, quite the opposite. All this needs to be conveyed, but without being alarmist.

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