Features

An astonishing and shocking story from the time of the Japanese occupation of Indonesia has been unearthed, thanks to the efforts of J Kevin Baird, who directs the Oxford University Clinical Research Unit based in Jakarta, and his Indonesian colleague, Professor Sangkot Marzuki, Director of the Eijkman Institute for Molecular Biology.

Reported in The Observer at the weekend, the events include hundreds of deaths of forced labourers, accounts of the torture of local doctors and researchers, and the beheading of a leading Indonesian scientist who is likely to have been innocent of any crime. A full account also appeared earlier this month in Science.

In July 1944, during the Japanese occupation of Indonesia, around 900 Indonesians in a forced labour camp outside Jakarta were injected with a vaccine. All of them died within a week.

The Japanese military police arrested local researchers, doctors and staff at a scientific institute in Jakarta, accusing them of sabotaging the vaccine. The Indonesian head of the Eijkman Institute and a leading light in clinical research at the time, Professor Achmad Mochtar, was executed for this crime by the Japanese military police in July 1945 as the War in the Pacific drew to an end.

Kevin Baird teamed up with Sangot Marzuki, who heads the present-day Eijkman Institute of Molecular Biology where the Oxford University Clinical Research Unit is based, to investigate what really happened.

They sought out documents from the time, written accounts, and interviewed former institute staff and family members of those who survived Japanese captivity and torture.

They are convinced their research exonerates the executed Mochtar, who appears to have confessed to the crimes to save his colleagues. They also suggest that the 900 deaths occurred not through contaminated vaccines, but may have occurred during the course of a Japanese medical experiment. Baird and Marzuki believe that the forced labourers were likely to have been given an experimental tetanus vaccine developed by the Japanese and intended for their troops, then given tetanus toxin to see if it worked.

Thanks to their work, some light has been shed on the causes behind hundreds of deaths in a forced labour camp some 65 years ago. And the standing of a remarkable scientist – and a remarkable man – Achmad Mochtar is on its way to restoration.

In mammals, many birds, and some invertebrates young offspring are totally dependent on their parents for food and protection.

But why is such helplessness a good strategy? And how has evolution resulted in 'lazy' youngsters trying to out-beg their siblings for a feed?

New research led by Andy Gardner of Oxford University's Department of Zoology, published in Proceedings of the Royal Society B, uses mathematical models to examine how some of these traits are related. I asked Andy about the costs and benefits of intensive parenting:

OxSciBlog: What are the advantages of having young that are more dependent on their parents for food/care?
Andy Gardner: In the animal world, the most basic form of parental care is when the parent guards their offspring from predators while the young forage for their own food. This can evolve as a simple extension of egg guarding, for example.

However, innovations in parental care that lead to parents actually feeding their own offspring can be favoured, because this allows parents to make their nests in safer - but food-scarce - environments.

An extreme example is when birds nest in trees. The safety of the canopy means that parents can leave the nest in search of food, without needing to guard their young. But, apart from the odd insect hovering around the nest, there isn't much scope for the offspring to feed for themselves - which makes them fully dependent upon their parents for survival.

OSB: How might ecological conditions drive species to have more dependent young?
AG: Whether the initial innovation of parental feeding is favoured depends upon a number of factors, for example the relative efficiency of parents feeding their offspring versus offspring feeding themselves. If food items are difficult for the young to process - they may not have very strong jaws - then it may be more efficient for parents to chew up the food for them.

OSB: What links have you found between this dependency and traits such as nest choice/sibling competition?
AG: The parents' choice of nest site can play a huge role in deciding how dependent the young will be on their parents for survival. Obviously, if the nest is situated far from sources of food, this leaves the young totally dependent upon their parents.

But, more subtly, parental feeding can lead to offspring being even more helpless, as natural selection will favour those offspring that give up even trying to feed themselves and instead compete with their siblings for the food that their parents bring to the nest.

OSB: Why do we think evolution of dependency is 'one way' - with species unlikely to reverse to evolve more independent young?
AG: Sibling competition for parentally-derived food puts parents in a cruel bind. The more food they offer to their offspring, to supplement that which the offspring have foraged for themselves, the less interested the offspring are in their own foraging, and the more effort they put into begging their parents for food.

Parents are then forced to increase the amount of food they give to their offspring, just to make up for their offspring's laziness. This reinforcement between parental feeding and sibling competition means that, once parental feeding is established as the norm, it is difficult to return the species to its ancestral state - even if environmental conditions change to make parental feeding less efficient.

This just emphasises that evolution progresses for the good of individuals, in this case lazy offspring, and will not generally find the most efficient solutions for the family unit.

Dr Andy Gardner is a Royal Society Research Fellow based at Oxford University's Department of Zoology. The research was carried out by Dr Gardner and Per Smiseth of Edinburgh University.

When Howard Florey came to Oxford in 1935 as the newly appointed Professor of Pathology, he arrived to state of the art but largely empty labs in the new Sir William Dunn School.

He soon set about recruiting a research team and – by the early war years – Florey, Ernst Chain and others had turned over the department to making penicillin and demonstrating how effective it could be against bacterial infections. Penicillin then seemed nothing short of miraculous, banishing many infectious diseases that were some of the leading killers of the time. Indeed the work of the Oxford team ushered in the modern age of antibiotics.

It is 70 years since Florey – together with Norman Heatley and Jim Kent – carried out a crucial experiment which showed the clear potential of penicillin for the first time. On the 25th May 1940, eight mice were infected with lethal doses of streptococci bacteria. Four of the mice were then given injections of penicillin. In the morning, the untreated mice were dead while those that had received penicillin survived for days to weeks.

70 years on, the Dunn School of Pathology in Oxford is once again building new laboratories and looking to recruit top researchers for three vacant professorships.

The new £30m building next to the original Dunn School buildings – the Oxford Molecular Pathology Institute (OMPI) – offers an opportunity for top scientists to come to a leading Oxford biomedical research department and set up fresh research investigating the biology underlying disease processes.

Whether or not there’s a parallel with Howard Florey’s first arrival in Oxford all that time ago, OxSciBlog can take this opportunity to look back at some of the historical successes of the Dunn School with Eric Sidebottom, who has become the unofficial historian of the department.

The Dunn School is established
Teaching of pathology began in Oxford in 1896, but a full Department of Pathology wasn’t established until the new century in 1901 with James Ritchie as head of department. On Ritchie’s departure to Edinburgh in 1907, the first professor of pathology was appointed: Georges Dreyer.

A windfall of £100,000 in 1922 changed things significantly. The money, given by trustees of funds left by a Scottish trader called Sir William Dunn, enabled a brand new building to be constructed. The newly built Dunn School with its stylish red brick frontage was one of the best equipped labs in the country, says Eric Sidebottom.

Dreyer made a number of advances during his time as professor of pathology. During WW1, he set up a standards lab for growing bacterial cultures which were used to immunise the troops against typhoid. Also during the war, he developed the first oxygen masks for pilots and in the 1920s he thought he’d developed a new TB vaccine. ‘But by the end he’d run out of steam,’ says Eric. ‘Howard Florey came to take over the department in 1935 to find wonderful labs, but it was largely empty space with little research funding.’

It was a close-run thing that Howard Florey ended up with the chair, Eric recounts. An electoral board had to decide on the appointment, and it had two influential external members: Sir Edward Mellanby, secretary of the Medical Research Council, and Sir Robert Muir, a Scottish pathologist.

Sidebottom says: ‘Mellanby was for Florey but Muir had an older, safer candidate in mind. Mellanby’s train broke down on the way to the board meeting that was to decide on the position. In his absence, the board decided to go for the safe pair of hands. But before the meeting ended, Mellanby arrived and persuaded them differently.’

The story of penicillin
Florey in short time recruited the German émigré chemist Ernst Chain from Cambridge. ‘It was Chain who rediscovered Fleming’s earlier paper on the antibacterial qualities of penicillin,’ says Eric.

Everyone associates Alexander Fleming with penicillin. It was in September 1928 at St Mary’s Hospital Medical School that he noticed stray mould growing on a plate of bacteria, and around the Penicillium mould was a clear area where the bacteria had been killed. He recognised the significance of the observation and set about identifying the antibacterial substance responsible, calling it ‘penicillin’. But he never went on to purify the substance or test it against bacterial infections in animals or humans.

Those large and vitally important steps required the vision, graft and dedication of Florey’s team in Oxford.

Florey and Chain began work on penicillin in 1939, says Eric. ‘They quickly confirmed Fleming’s findings and began to purify the substance.’ Here the contributions of another member of the team, Norman Heatley, were crucial. ‘Heatley had the technical vision necessary to purify penicillin,’ says Sidebottom. He devised a successful method for extracting and purifying penicillin from the cultures of mould grown in hundreds of vessels throughout the Dunn School labs. The automated process he came up with made use of bedpans, milk churns and baths all rigged together, yet it worked very well.

By the height of the blitz in May 1940 the team was at a point where they could carry out that crucial experiment in mice mentioned earlier. It would really test for the first time whether penicillin could be an effective antibacterial drug.

The results of the experiment were clear and impressive. But as Florey pointed out: ‘Treating and curing infections in mice was one thing, but humans are roughly 3000 times bigger and would need 3000 times more penicillin.’ As a result, the Dunn School was turned into a penicillin factory, production running 24 hours a day...

From mice to men
By February 1941, when Florey felt he had enough to begin trials in humans, he enlisted the help of a young doctor at the Radcliffe Infirmary in Oxford, Charles Fletcher. The first patient Albert Alexander, a 43-year-old policeman, was treated with penicillin on 12 February 1941.

The stories normally have it that Albert Alexander had scratched his face on a rose bush, the wound had become infected and the infection had spread. But Eric offers an alternative. He has an old police pamphlet of stories about individual officers which suggests Alexander was injured during a bombing raid while he was on secondment from Abingdon to Southampton. He was transferred to the Radcliffe Infirmary when his infection became severe. Frustratingly his hospital notes don’t reveal the cause of his infections.

Charles Fletcher injected Alexander with penicillin regularly over four days, and within 24 hours he was greatly improved. But even though the team went as far as extracting the precious penicillin from his urine and re-injecting it, supplies ran out before his cure was complete. He relapsed at the beginning of March, and died a month later.

Of the next seriously ill patients, four made recoveries thanks to penicillin. A child of four was also cured of his infection, but died of an unrelated brain haemorrhage.

Penicillin truly looked like a miracle drug: infections that had been killing people previously were cured. As companies in the US and UK began to take up manufacture of penicillin, enough was being produced to treat some of the military. Supplies accompanied the troops in the D-day landings and the death toll from infected wounds during the campaign was dramatically reduced.

Still, Eric Sidebottom suggests some sensitive decisions had to be made about how best to use what penicillin supplies there were: ‘In 1943, Florey and Chain travelled out to North Africa to oversee the use of penicillin to treat infected injuries. Penicillin was also found to be extremely effective in treating the clap (gonorrhoea). This presented the military with a problem: with limited supplies, which soldiers should receive the drug – those with clap or those with horrific injuries? Churchill reportedly decided to use it to “best military advantage” (give it those with the clap to get them back onto the front lines more quickly).’

So how did the greatest medical advance of the 20th century come to be solely linked to the name of Alexander Fleming in most people’s minds? After all, Fleming shared the Nobel Prize with Florey and Chain. And it was the Oxford team’s dedicated work that turned Fleming’s chance observations into a safe, effective drug capable of being manufactured on a large scale.

Eric has the answer: ‘When the potential of penicillin became clear in 1941 and 1942, St Mary’s Hospital realised what a coup it was going to be. The dean of St Mary’s, Charles Wilson (soon to be ennobled as Lord Moran), was also Churchill’s physician and president of the Royal College of Physicians. When he said, “We [St Mary’s] discovered it,” people listened. More than that, Lord Beaverbrook – the powerful press baron – was a patron of the hospital and was instrumental in setting the agenda in the press. In contrast to all the media attention Fleming was getting, Florey refused to speak to the press at all.’

Other advances
The history of the Dunn School of Pathology didn’t begin and end with penicillin, of course.

Penicillin inspired worldwide efforts to discover new drugs that could conquer the many diseases still threatening the world. Further antibiotics soon followed, including streptomycin, chloramphenicol, the tetracyclines, and erythromycin. The Oxford team continued to work on this area and another important family of antibiotics, the cephalosporins, were developed from research by Edward Abraham and Guy Newton at the Dunn School. Proceeds from these patents continue to fund research around the University, and are paying for most of the cost of the new OMPI building at the Dunn School.

‘Florey’s other legacy was a world-class research programme in Oxford,’ says Eric. ‘For example, Sir Henry Harris and Sir James Gowans were two of Florey’s students.’ Together they did a lot of the foundation work that allowed the discovery of monoclonal antibodies by others later on, Eric says.

Gowans worked out the life cycle of lymphocytes – a type of white blood cell that is central to our immune responses and fighting off disease – and their recirculation, while Harris developed the experimental technique of artificial cell fusion. In addition to leading to the discovery of monoclonal antibodies, this led to new theories about how cancers become malignant and how the body suppresses tumours from forming.

This historical research focus on immunity, cell biology, and fighting infections is reflected in the research interests of the department today. Current research strengths include cancer cell biology, influenza and HIV, gene transcription and RNA processing, Alzheimer’s disease, stem cell biology, and regulation of immune responses.

Into the future
The new institute OMPI is being built next to the original 1920s Dunn School building and will house over 200 researchers.

With new appointees to three vacant professorial chairs to add to the department’s existing strengths, who knows where research in the state-of-the-art labs will lead? Let’s hope it will add to Eric Sidebottom’s repertoire of stories of research successes from the Dunn School.

It isn’t everyone who has a set of holes named after them but then John Aubrey was one of the most intriguing characters to surface at Oxford University in the 17th Century.

I’ve blogged before about the role Oxonians played in the founding of the Royal Society 350 years ago. And, whilst he is most famous for his rediscovery of the prehistoric monument at Avebury (and Stonehenge’s Aubrey holes), Aubrey was also a founding fellow of the RS.

Aubrey was a friend to many of the great early scientists, an amateur who was fascinated by their ideas and often joined in their experiments, as well as recording their work for posterity.

William Poole of New College is the curator of an exhibition now on at the Bodleian Library about Aubrey (‘My wit was always working’), he tells me:

‘Aubrey attended Trinity College in the 1640s where there was a little experimental community, particularly keen on learning practical mathematics and doing chemical experiments. He later took personal mathematical tutors. But most of his learning came through his own reading - there was almost no formal instruction in anything we would recognise as a science in his day.’

It was here that he was bitten by the experimental bug at that time spreading like a fever through the city - which would erupt in the 1650s with Wadham’s ‘Experimental philosophy club’.

William reveals that at Oxford Aubrey indulged his - often dangerous - chemical passions: ‘His Trinity friends and he, for instance, were extremely taken with aurum fulminans, exploding gold.’

After entering Trinity in 1642 his studies were interrupted by the English Civil War. According to the DNB’s Adam Fox, it was on a trip from Oxford to Wiltshire in 1649 that Aubrey rediscovered the Avebury megaliths. It would spark a lifelong interest in ancient monuments that would later see him (re)discover the ring of ‘Aubrey’ holes at Stonehenge in 1663.

It was also in 1663 that Aubrey was elected to the Royal Society, William comments: ‘The early Royal Society was rather like a gentleman's club, replete with its own internal factions, and we can associate Aubrey with what we might call the 'Hooke faction', those who worked, drank coffee, and gossiped with the great experimentalist of the early Royal Society, Robert Hooke and also his colleague and friend Christopher Wren.’

He clearly felt at home in this club-like atmosphere: in the 1660s he would present papers on Wiltshire springs, a ‘cloudy star’ and winds, before submitting his ‘Natural History of Wiltshire’ to the RS in 1675.

But it was in his drive to record both the evolution of science and prehistory that Aubrey excelled.

William highlights the short biographies Aubrey wrote of many of his contemporaries, including his friends in the scientific community:

'He believed Hooke that Newton had failed to acknowledge that the inverse square law was suggested to him by Hooke, and Aubrey urged the Oxford biographer Anthony Wood to record the theft for posterity. Wood did not do so, but the letter from Aubrey to Wood, partially written by Hooke, survives, and an image of it is displayed in the exhibition.’

‘As we saw with Hooke and Newton, Aubrey also used his biographical work to guard rights of priority - English authors did not own their own copyrights until 1710, so who actually owned a scientific idea was a murky territory.’

Aubrey brought his interests in practical mathematics to the study of megaliths:

‘He was the first man to visit Stonehenge and Avebury with surveying equipment and draw accurate representations of the positions of the stones. He also correctly reasoned that they were far older structures than was commonly believed. For this work he is regarded as one of the fathers of English archaeology.’

So what might a survey of Aubrey’s life, with all its varied interests and passions, teach us about the evolution of science?

William comments: ‘Scientists could learn that the history of science is about what disparate activities came together to make the modern institutional idea of science possible, what new activities science has subsequently taken under its wing, and what old ones it has shed - and why.’

The exhibition ‘My wit was always working: John Aubrey and the Development of Experimental Science’ is on display at the Bodleian Library until 31 October 2010.

The accompanying book ‘John Aubrey and the Advancement of Learning’ by William Poole is available at the exhibition.

The Sun could be the best place to look for dark matter – the invisible ‘stuff’ that is thought to make up about 83% of the matter in the Universe.

That’s what new Oxford University research reported in a recent Physical Review Letters suggests.

The work looks at the possibility that dark matter is much lighter than the WIMP particles most dark matter hunters are looking for. Such ‘heavy’ particles are also their own antiparticles, so that when a WIMP meets a WIMP they annihilate each other, making it puzzling that there’s still so much dark matter around.

The Oxford team ask: what if, instead of being 100 times the mass of a proton, dark matter particles were only 5 times heavier than a proton but had the same asymmetry - excess of particles over antiparticles?

‘If it were five times heavier, it would get five times the abundance. That’s what dark matter is,’ Subir Sarkar of Oxford University’s Rudolf Peierls Centre for Theoretical Physics, who led the work with Mads Frandsen, told Wired.com’s Lisa Grossman. ‘That’s the simplest explanation for dark matter in my view.’

Because these ‘light’ dark matter particles don’t annihilate each other, Subir and Mads explain, they could be hoovered up by the gravity of a star like our Sun and trapped there.

Subir comments: ‘The sun has been whizzing around the galaxy for 5 billion years, sweeping up all the dark matter as it goes.’

The idea that the Sun acts as a cage for a large amount of dark matter could help to solve a long-standing mystery of solar physics – how the Sun transports heat from its core to the surface so fast when photons and ordinary particles should be colliding with each other, slowing the process down.

Dark matter particles inside the Sun interact very weakly with ordinary matter (but more strongly with each other) and can transport heat to the surface in a novel manner.

‘When we do the calculation, it turns out that this effect may help to solve the solar composition problem,’ Subir reveals.

Even better, calculations of what this component of dark matter would do to neutrinos given off by the Sun indicate that its effect would be detectable by two upcoming experiments: Borexino and SNO+.

‘We know protons make up most of the luminous matter in the universe and, as opposed to many other particles, we know the origin of the proton mass and why it is stable,’ Mads tells me. ‘So it really is a simple and intuitive idea that dark matter would share properties with the proton. Instead the WIMP type candidates in fact are nothing like the proton.’

Subir adds: ‘It’s a speculative idea, but it’s testable. And the tools to test it are coming on line pretty fast. We don’t have to wait 20 years.’

Professor Subir Sarkar and Dr Mads Frandsen are based at Oxford University’s Rudolf Peierls Centre for Theoretical Physics, part of the Department of Physics.