Features

Problems related to pregnancy claim the lives of hundreds of thousands of women every year. Almost all of these deaths are in developing countries – the countries least able to provide effective medical care.

Pre-eclampsia is a serious problem of pregnancy and causes the deaths of more than 60,000 women annually, and many of their babies. There is huge potential to reduce these fatalities in developing nations.

The ambition of Dr Stephen Kennedy, head of Oxford’s Nuffield Department of Obstetrics & Gynaecology, is to help achieve this by educating health professionals globally on all aspects of maternal health. His vision is being backed by The John D & Catherine T MacArthur Foundation, which is funding the development of web-based materials to improve pre-eclampsia care.

Pre-eclampsia is characterised by high blood pressure and protein in the urine and, if left untreated, can cause strokes, kidney and liver damage, and death. The condition usually develops after the 20th week of pregnancy with early delivery of the baby the usual treatment. It is much rarer in developed countries where the drug magnesium sulphate, the most effective treatment, has been available at low cost for 20 years.

There are three obstacles preventing improvements in pre-eclampsia care in poorer countries: the absence of national guidelines based on effective treatments, too few specialists, and scarce supplies of magnesium sulphate, also known as Epsom salts.

To tackle the first of these problems, Oxford University is joining forces with eXact learning solutions, a provider of online distance learning material.

With the Nuffield Department of Obstetrics & Gynaecology and the Oxford Maternal & Perinatal Health Institute the company is developing a web-based training pilot for midwives, nurses and doctors. The material will be used initially in hospitals in India, Mexico and Nigeria, where pre-eclampsia is most common.

The initiative is being funded by The John D & Catherine T MacArthur Foundation which stepped in after a conference in 2007 hosted jointly by Oxford University and EngenderHealth. Delegates called for magnesium sulphate to be readily available in developing world hospitals together with training and protocols in its use.

The partners’ long-term objective is to offer the training course worldwide. Dr José Villar, who is leading Oxford University’s work with eXact learning solutions, said: ‘Treatment for pre-eclampsia should be equally available in developing countries and the developed world.

‘Our work with eXact learning solutions will make significant inroads into improving global healthcare for those suffering pre-eclampsia. The aim now is to win additional funding to develop this pilot initiative into a far larger programme of education and treatment.’

Bacteria have a canny way of protecting themselves from attack by toxic chemicals, aiding their survival and development. They have small channels in their cell wall, some of which can shut if there is no threat or open to help fight the toxins.

These tiny channels act as molecular ‘gatekeepers’. They control the flow of ions into and out of the cell and in that way safeguard bacteria, including the superbugs, E.coli, Salmonella and Legionella. If the channels could be kept open artificially, bacteria could be killed or their growth hindered.

Stuart Conway from Oxford University’s Department of Chemistry is part of a team studying the survival mechanisms of bacteria. The group’s latest research used synthetic chemicals to open and close the protective channels.

The new study, published in this week's PNAS, reveals that the channels work like molecular switches, sensing the presence of toxic chemicals. Some chemicals keep the channels shut but other chemicals can open them up, helping the bacteria to survive.

When a toxin is detected, the channels open, increasing the acidity, or pH, of the cell, which prevents damage. When the threat has passed, the channels close, allowing the cell to revert back to its normal pH.

Stuart, and colleagues from the University of Aberdeen and University of St Andrews, see the channels as targets for new antibiotic drugs. They hope further research will facilitate the development of alternative treatments to tackle bacteria that are resistant to existing antibiotics.

'We are very excited about applying our chemical tools to the study of fundamental biological problems, which may ultimately allow us to develop new leads for novel antibiotic drugs,' Stuart told us.

Dr Stuart Conway is based at Oxford University's Department of Chemistry.

It's 30 years since research by Oxford University scientists led to the development of one of the world’s most popular rechargeable batteries.

The lithium-ion battery is used in electric cars, mobile phones, laptops and even hearing aids, and by the military and NASA in surveillance and communications equipment.

Despite fires and explosions during development, its relatively light weight and slow loss of charge has allowed manufacturers to significantly reduce the size of portable devices, and cut greenhouse gas emissions.

Today the Royal Society of Chemistry is marking the academics’ work with the award of a special plaque to be mounted at the entrance to Oxford University’s Inorganic Chemistry Laboratory where the four scientists made their discovery.

‘The idea just came out of the woodwork,’ one of the academics, Dr Phil Wiseman says. ‘When you see children in Vietnam using mobile phones it’s odd to think their devices use the compound we investigated three decades ago. Lithium-ion batteries in cars are also based on the same concept. Our paper was the starting point.’

In 1976, Professor John Goodenough, newly appointed head of Inorganic Chemistry, formed a research group to look again at the potential for creating rechargeable batteries.

Soaring oil prices had encouraged multinational Exxon to seek alternative forms of vehicle power but battery short circuiting and explosions, coupled with a subsequent fall in oil costs, deterred the company from continuing.

The Oxford group took on the task ‘kicking around ideas on a blackboard,’ recalls Dr Wiseman, then Professor Goodenough’s research assistant.

‘We looked at it in a different way using lithium cobalt oxide at the positive terminal and pulling the lithium out; this produced a huge cell voltage, twice that of the Exxon battery. It was this spare voltage that allowed alternatives at the other terminal where Exxon had been forced to use lithium metal which was fraught with problems.

‘Instead lithium-ion material could compose both electrodes. Mind you, I always thought the cobalt oxide would be too reactive; we also had a fire in the lab and had to call the fire brigade.’

It took a year of painstaking work before they could publish their research in the Materials Research Bulletin in the summer of 1980.

The potential of the scientists’ findings was seized by electronics giant Sony which, after further research, manufactured the first lithium-ion battery ten years later. More recently, concerns about climate change have increased the demand for green power supplies and sparked further developments.

No more than four blue Chemical Landmark plaques are awarded annually. They are the RSC’s official recognition of historical sites where important chemical breakthroughs have been made. The third and fourth members of the team, Dr Koichi Mizushima and Dr Phil Jones are flying from Tokyo and France respectively to attend the unveiling today.

‘Everyone involved is named on it,’ Dr Wiseman says. ‘Koichi did most of the work but has never received much recognition. It will also be good for students to see. You never know; in one or two years’ time something similarly groundbreaking could come out of their research as well.’

Professor Peter Edwards, Head of Inorganic Chemistry at Oxford University, said: ‘It is tremendous for the University that such an important contribution to both science and technology is being recognised in this way. This plaque is a fitting tribute to Professor Goodenough and the team for making such a landmark discovery 30 years ago. It is also remarkable that as we celebrate today, Professor Goodenough will also be formally admitted as a Foreign Member of the Royal Society.’

During his career in tropical medicine Professor David Warrell has milked snakes, studied malaria and rabies and helped thousands of medical students learn about the deadliest diseases.

Now Professor Warrell has received the Osler Memorial Medal, which is given once every five years to the Oxford medical graduate who has made the most valuable contribution to the science, art or literature of medicine. He was presented with the bronze medal at a ceremony on Saturday.

David Warrell, emeritus professor of tropical medicine and an Honorary Fellow of St Cross College, Oxford, has played a key role in global health research at Oxford. This has been not only through the research he carried out, but in setting up a series of clinical research units in South-East Asia and Africa.

It is the success of this network of centres that has established Oxford’s global reputation for research on infectious diseases that are some of the world’s biggest killers. Currently recommended treatments for malaria, dengue shock syndrome, typhoid, and many others are all based on work conducted by tropical medicine researchers at Oxford.

As the first director of the Centre for Tropical Medicine at Oxford University, Professor Warrell set up the first of Oxford’s overseas research units in 1979 with funding from the Wellcome Trust. The success of that unit in Bangkok, Thailand, has served as a model for later units in Kenya, Vietnam and elsewhere.

Importantly, the work of these clinical research units isn’t solely about finding practical solutions that will save lives in combating infectious diseases, it’s about fostering partnerships with local researchers and doctors, and training the next generation of health leaders in the developing world.

‘There was no real tradition of tropical medicine at Oxford when I arrived,’ says Professor Warrell. But there was a readiness among those already in Oxford in the 1970s to make things happen, and ‘everything ignited from there’. Tropical medicine at Oxford is now world-renowned. ‘It won a Queen’s Anniversary Prize in 2000 and is now one of the best funded parts of biomedical science at Oxford,’ Professor Warrell adds.

Another important strand of Professor Warrell’s work since 1983 has been as a senior editor of the Oxford Textbook of Medicine, the accepted reference work for general medicine across the English-speaking world. Countless medical students in India, Australia and South Africa, as well as the UK, will have made use of this standard work during their education and once in practice.

David Warrell’s career has involved working as physician, teacher and researcher in many African, Asian and South American countries. His research interests have largely focussed on malaria, rabies and snakebites. These efforts have ranged from defining the symptoms of conditions such as cerebral malaria, to understanding the paths that diseases take, and improving treatments in the clinic. With his wife Mary Warrell, he developed less expensive ways of using high quality vaccines against rabies – very important in areas of the developing world where rabies is a problem and money is scarce.

Since he retired in 2006, he has devoted his energies to redress the neglect of snakebites. Snakebites often occur among poor rural farmers in the developing world and – although only 2% of bites result in death – he says the number of bites mean than there are estimated to be around 46,000 deaths per year in India and 6,000 deaths in Bangladesh. He published a significant review of snakebites, their prevention and treatment in the Lancet medical journal at the beginning of the year, raising it as a neglected area of medicine.

All of this is a good example of David Warrell’s drive not just to leave research at the result stage, but push it through to implementation. He has been active in helping draw up guidelines for the World Health Organisation on malaria, rabies, snakebites, and anti-venom production.

‘I was extremely surprised, and enormously moved, to be awarded the Osler Memorial Medal,’ says Professor Warrell. He says the example of William Osler, who the award is named after, means a lot. (Osler was the Regius Professor of Medicine at Oxford at the very beginning of the 20th century.) ‘Osler is a supreme example of a meticulous clinician, and a very special example for people who work in the developing world where resources are not enough for modern medicine.’

Patterns are everywhere in the animal kingdom but understanding the mechanisms that produce them is a real challenge.

In this week's Physical Review E Thomas Woolley and Ruth Baker of Oxford University's Mathematical Institute report on mathematical simulations that may explain how stingrays generate their distinctive spots.

I asked Thomas about this work and the relationship between maths and nature's spots and stripes:

OxSciBlog: What are the challenges in reproducing these patterns?
Thomas Woolley: The biology! Mathematically, we have a number of models that produce qualitatively the same patterns as animal skins. However, there are currently no specific biological examples which can be unequivocally linked to the maths.

The specific difficulty with stingrays, which is why they have not been considered before, is that their spots have a dark halo around the central spot. The BVAM model is one of the first biological pattern formation systems that is able to produce this dark halo.

The Barrio-Aragon-Varea-Maini (BVAM) model is a set of mathematical equations that models two chemicals which are able to diffuse and react in a domain. They are generalisations of all other such pattern forming systems and therefore very complex. They are used as a way explore a wide variety of chemical dynamics from two simple equations.

OSB: How did you set out to reproduce stingray patterns?
TW: It was in fact the other way around. We were able to produce the patterns and thus wanted to find a biological example that exemplified them.

As mentioned above, there are a great number of mathematical models which can produce animal pigmentation patterns. A particularly large group of such models are called Turing systems (named after Alan Turing who originally considered them).

Normally, these models give only a single particular type of pattern; either spots or stripes. The BVAM model, we considered, is a generalisation of all of these. This means that it can give many different types patterns (see below). It was noticed that the spots that the model produces were not of the normal Turing type (Turing type spots do not have the dark halo).

In a precursor paper it was shown that these are very similar to a stingray’s skin pattern. We generalised the results that appeared in the previous paper and showed that the spots can exist for a larger range of parameters than previously thought.

OSB: How could your results be tested?
TW: The analysis we have done on the model connects the parameters of the equations and the size of the spots. An initial test would simply be to measure the spots on a large number of stingrays. By varying the model parameters we can vary the size of the simulated spots, however, if we are unable to produce the correct size, which correspond to reality we immediately show that the BVAM is not the system behind stingray patterning.

The best way would be to try and discover the stingrays’ chemical signals which produce the spots and, either, show it corresponds to, or differs from, the BVAM equations. This is currently a difficult problem for biologists, which is why there are currently no clear biological examples. In the end, biologists will probably never be able to “prove” a model is correct only that it fits current data and is thus not incorrect.

Hence, if biologists are able to alter the system to produce a pattern that the BVAM system cannot reproduce we must conclude that the BVAM system is not biologically accurate and return to the drawing board. However, a disproved model is still important as it implies what adaptations are needed in order to generate a more refined system.

OSB: What do these results tell us about biological mechanisms?
TW: The patterning systems we use tend to rely on diffusion as the key mechanism. In terms of evolution this is important as it suggests that no energy from the animal is needed to produce the pattern; only to create the chemicals which will naturally diffuse.

Another important aspect is that it suggests many types of fish depend on the exact same model to produce their individual patterns. This supports the idea that evolution has simply picked the simplest mechanism, whilst mutations and various types of selection will specify how the model behaves.

OSB: How could what you learned be applied to other problems?
TW: The BVAM system, because of its general nature, not only has applications in animal skin patterning, but it has also been linked to a model of cardiac regulation and, further, it has the potential to be used in encoding digital information (the spots can act like binary digits).

The particular use of my work will be the analytical methods that we have produced, which can be used on many similar problems in various fields. Further, it broadens the number of patterns which can be treated mathematically. For a long time we have been able to consider spots and stripes, but we are the first to consider the biological applications of the dark-ringed spot. 

 Thomas Woolley is based at Oxford University's Mathematical Institute.