“By doubting, we come to inquiry, and through inquiry we perceive truth.”

- Peter Abelard, 1079–1142, French theologian and philosopher

Our latest edition of Perspectives on Education asked stakeholders from across the education sector what role inquiry-based learning has in an inspiring science education. We chose this topic because, despite widespread support for inquiry-based learning, there is the need for more robust research and critical debate to consider what it means in practice, with many questions still to address: What does the science education sector want to achieve through inquiry-based learning? What are the boundaries and limitations of inquiry? How can periods of inquiry be best supported by other pedagogies?

Now is an important time to consider these questions. The National Curriculum for England is currently under review and ministers of parliament are clear that the revised version will focus on ‘what’ to teach rather than ‘how’ to teach it. (1) Discussions about teaching and learning approaches are therefore needed to ensure that we retain the essence, as well as the knowledge, of science.

The views presented across the four individual essays led us to make some observations about inquiry-based learning – described in the introduction to the issue. These were further developed at a discussion meeting at the 2012 Association for Science Education conference, leaving us with several thoughts:

1) A definition of inquiry-based learning should be agreed and consistently used to facilitate research and discussion. We suggested the following wording in the publication:

“Inquiry-based science learning sees students learning through inquiry, using skills employed by scientists such as raising questions, collecting data, reasoning, reviewing evidence, drawing conclusions and discussing results. When students learn through inquiry they can develop scientific knowledge and they can also learn about inquiry, including the processes of science and how to construct reliable, valid and accurate investigations.” (2)

This definition requires that for science learning to be described as inquiry-based, pedagogies that allow students to learn through inquiry must always be present. Importantly, these are not limited to practical work or ‘investigations’ but also include discussion and the use of secondary sources.

At the ASE conference session, some delegates questioned the idea that students were “using skills employed by scientists” – although it was agreed that learning through inquiry did involve the activities listed. In fact, the study of many other subjects would recruit these questioning and analysis skills. Delegates highlighted the need to express what is different about scientific inquiry-based learning, if indeed it is distinct.

We also discussed what we actually want students to learn about inquiry. This is currently addressed through the ‘How Science Works’ element of the National Curriculum. However, what is contained within this element needs careful elaboration to ensure that students understand how to construct investigations – including different types of studies (e.g., randomised controlled trials); how to develop theories and models; and how to evaluate what their work. Some at the conference session felt that the proposed definition may not go far enough in detailing these different elements.

2) Despite widespread support, there is a shortage of robust research evidence demonstrating the positive impacts of learning through inquiry. Further research should consider the benefits of inquiry, how to most effectively structure learning through inquiry (including combining it with other pedagogies), and how student understanding about inquiry progresses.

3) Teacher preparation is key to ensuring the successful implementation of inquiry, and must cover understanding about inquiry as well as the necessary pedagogical content knowledge to teach through inquiry. Both aspects should be taught during initial teacher training and supported through good-quality continuing professional development courses. See also: Wellcome Trust report on Initiatial Teacher Training.

4) Learning through inquiry is closely linked to high-quality practical work. Science departments, therefore, need to be appropriately resourced with the necessary laboratories, consumables and staff.

5) A student’s understanding about inquiry is more difficult to assess than other areas of the curriculum, due to both its practical nature and the importance of thinking and reasoning. More effort needs to be put into developing appropriate assessments and, critically, to encourage their uptake by teachers and schools.

During the conference session, attendees highlighted assessments that have been developed with the aim of reliably testing inquiry skills. However it was noted that these more open and student-led assessments are more time-consuming for teachers, as well as often being optional parts of a qualification specification, with other alternative routes available. Courses that have more rigorous assessments are therefore often not chosen by schools at all and, even when they are, teachers may not opt for these particular assessments. Thus awarding bodies – who are in competition with each other for market-share – are not encouraged to invest in developing these complex assessments.

Taking account of these observations in practice requires input and collaboration from researchers, policy makers and educational practitioners. Only through such a joint approach will we be able to successfully develop inquiry-based learning that supports an inspiring science education for all.

Emily Yeomans, Project Manager, Education, Wellcome Trust

References

1. Michael Gove, Secretary of State for Education, to the National College for School Leadership Annual Conference, Birmingham, 16 June 2010.

2. Adapted from the definition in the IAP Conference Report on Inquiry Based Science Education held in York, October 2010.

A screengrab from one of the videos

We’re closer than ever to harnessing whole genome sequencing for everyday medical use. But what would you want to know – and what would you not? Anna Middleton invites you to take part in a new study looking to understand the ethical implications. 

Public engagement about genomics is de rigour at the moment. A whole genome test on a single saliva sample can tell a person about their genetic risks for hundreds of conditions all in one go, ranging from whether they are predisposed to developing Alzheimer’s disease or diabetes through to whether they are sensitive to certain antibiotics or whether their children might be at risk from inheriting something specific.

The anticipation is that genomics will soon become integrated into our lives in ways we have never experienced before. We therefore need to know what is possible and what we have to gain.

The Human Genomics Strategy Group reported recently on what the NHS needs to do to embrace genomic technologies. Meanwhile, genomic researchers, used to working with anonymous samples, are facing increasing pressure to share their findings with the volunteers who provided their samples.

There is now an urgent need to understand what the public and professionals want in terms of feedback of genome data. With this in mind, we at the Wellcome Trust Sanger Institute are asking people: what would you want to know?

We’re conducting an international study to explore some of the ethical implications of whole genome evaluation, in what we hope will be the largest survey of its kind. The aim is to provide robust empirical data to support policy decisions about the sharing of data from genomic studies. We hope that this will be useful in both clinical and research settings.

Example survey questions

We use an online questionnaire containing 10 short films describing the ethical issues surrounding feedback of genomic information. Participants then tick boxes in a series of brief questions. It takes about 20 minutes and anyone can participate, be they research participants, genomic researchers, health professionals or a member of the general public. You need have no prior knowledge about genomics, so if you’re interested, you can find out more and take part at: www.genomethics.org

Anna Middleton

Dr Anna Middleton is an ethics researcher and a registered genetic counsellor at the Wellcome Trust Sanger Institute.

At an event called Uniting to combat NTDs, the World Health Organization (WHO) launched a new roadmap for reducing the burden of NTDs between now and 2020, while 13 pharmaceutical companies announced donations of billions of tablets each year to treat the most common NTDs in endemic countries.

The UK’s Minister for International Development, Stephen O’Brien, said: “The world has come together to end the neglect of these horrific diseases which needlessly disable, blind and kill millions of the world’s poorest…. [We will] provide critical treatments to millions of people, which allow children to attend school and parents to provide for their families so that they can help themselves out of poverty and eventually no longer rely on aid.”

Tough targets

The companies and organisations represented at the event endorsed the London Declaration on NTDs, committing to take advantage of a “tremendous opportunity to control or eliminate at least ten of these devastating diseases by the end of the decade.” This statement reflects the targets in the WHO roadmap, which are to eradicate dracunculiasis (Guinea worm disease) by 2015 and endemic treponematoses (yaws) by 2020; the global elimination of trachoma, leprosy, human African trypanosomiasis (sleeping sickness) and lymphatic filariasis (elephantiasis) by 2020; and to bring under control by 2020 schistosomiasis, onchocerciasis (river blindness), soil-transmitted helminthiases (hookworm, roundworm and whipworm infections), Chagas’ disease and visceral leishmaniasis.

The next post in our NTDs series will be looking at the differences between control, elimination and eradication in more detail next week but, briefly, eradication means no more cases of a disease: this has been achieved only once before in human history when smallpox was eradicated last century – dracunculiasis could be the next to disappear (although polio is also getting close to extinction).

Elimination can be achieved regionally, which means that the transmission of a disease no longer takes place. Global elimination is when a disease has been eliminated from all regions. Control reduces the transmission of a disease to such an extent that it is no longer a major public health issue.

Other NTDs are included in the roadmap but without specific targets. These include dengue fever, Buruli ulcer, cutaneous leishmaniasis, trematode infections, cysticercosis and echinococcosis.

All of the NTDs in the WHO’s official list of 17 are accounted for in the roadmap. There are several other diseases that could also claim to be neglected and what happens to tackle these remains to be seen, but controlling or eliminating at least ten NTDs in the next eight years would be a historic achievement.

Not the only solution

Opening the event, Dr Margaret Chan, director of the WHO, said that in the past we may have relied too much on drug donation alone. “It is one solution,” she said, “but it is not the only solution.”

This point was echoed throughout the day as participants discussed the roadmap and the undeniably impressive drug donation commitments from the world’s pharmaceutical sector. A common issue was the urgent need for clean water and sanitation in the communities at risk from NTDs. And, of course, while treatments have been made available for numerous diseases, there is still the considerable challenge of delivering the pills to the people who need them and ensuring they produce the desired effect – better health and reduced burden of these diseases.

But as Haruo Naito, the president and CEO of Eisai, indicated, having these commitments from the pharma companies removes one obstacle from finding long-term solutions to NTDs. “Supply of drugs will not be the bottleneck,” he said.

Building the future of NTDs together

In the afternoon, a second event examined in more detail the WHO targets and what will be needed to achieve them. Many participants spoke of their emotional response to the news of the morning – Professor Alan Fenwick, director of the Schistosomiasis Control Initiative described it as a “transformational commitment” – but we were also reminded of the need to be cautious and not to forget all the other parts of the equation that need to be in place to achieve the WHO’s “stretching” goals.

Dr Lorenzo Savioli of the WHO explained that the roadmap was designed to provide guidance and technical insight to encourage countries and communities to act against NTDs. The drug companies’ donations had changed the situation: “Business is not as usual,” he said.

The World Bank is a major supporter of improving countries’ healthcare infrastructure and has funded NTD control programmes since the first such programme to control onchocerciasis in Africa launched in 1974. Dr Caroline Anstey, a Managing Director of the World Bank, said: “Part of the reason NTDs are neglected is because the people are neglected. They don’t have a voice so this is about shining a light. We have to create a lobby group for the voiceless.”

Professor Chris Witty from the UK Department for International Development, which announced a significant increase in funding for treating four NTDs last week, said that elimination and eradication get harder the closer you get to achieving them because you are left with territories in which it is more difficult to monitor and coordinate the effort. “A very difficult endgame will be a sign of success,” he concluded.

We also heard more from the pharmaceutical companies about their commitments beyond drug donation. Dr Jutta Reinhard-Rupp from Merck KGaA – which donates praziquantel for schistosomiasis – explained that her company is working on a formulation of praziquantel suitable for children. The current tablets are large and taste bitter if broken up.

Several pharmaceutical companies are now working together, or at least sharing libraries of compounds, to speed up development of better drugs for certain NTDs. Several industry people spoke of new drugs that needed to be reformulated so they could be given orally rather than by injection, which is impractical in poor rural areas. Many participants also described the need for more operational research – to understand the best ways to deliver drugs in the communities where they are needed.

Professor Sir Roy Anderson of Imperial College London set out several areas where scientific tools are available but not currently being sufficiently used. These covered treatment strategies, electronic monitoring of diseases, and the need for demographic analysis as well as epidemiology.

Sir Roy also said we will have to monitor very carefully any evolutionary changes in the parasites given they will be subjected to the most intense selective pressures in their long histories. Mass drug administration could potentially drive the development of resistance mechanisms and as we are currently reliant on just one or two drugs for so many NTDs, that could be disastrous.

Still neglected?

The global health community – including governments, public and private partnerships – has taken a huge step forwards in the task of reducing the burden of disease among the world’s poorest people. However, even if we have the resources and capacity to deliver the donated drugs and implement effective disease control strategies, the tools we currently have will not be enough to combat all NTDs in the next eight years. Looking beyond 2020, the tools of the future will come from basic and applied research being done today – research such as that funded by the Wellcome Trust, the Gates Foundation and others.

As reported in the Guardian yesterday, Bill Gates – who played a major role in bringing together the pharmaceutical companies in yesterday’s announcement – said: “Maybe as the decade goes on, people will wonder if these should be called neglected diseases. Maybe as the milestones go on, we will call them just tropical diseases.”

Of course, the name ‘neglected tropical diseases’ has not been around that long. It is a testament to the strength of the campaigners and advocates who have been extolling the need for action that people are already talking – albeit tentatively – about the term becoming obsolete.

Professor Fiona Powrie

Professor Fiona Powrie, who will be awarded the 2012 Louis-Jeantet Prize for Medicine later this year, has made significant contributions to our understanding of the immune system in the gut and what happens when it goes wrong in inflammatory bowel disease. Michael Regnier spoke to Fiona, a Wellcome Trust Senior Investigator, about her research and career to date.

There are more immune cells in the intestine than anywhere else in the human body. Their job is to identify and destroy invaders such as viruses, bacteria or parasites that could make us ill; however, unlike in other parts of the body, where any unfamiliar cell is likely to be potentially harmful, our guts play host to hundreds of species of bacteria.

Most of these bacteria are harmless or even help us – by aiding digestion, for example. The intestinal immune system, therefore, has to be more discriminating in its response to foreign bodies, which might explain why it needs so many immune cells.

When the immune system detects an invader, its response usually involves inflammation. This is caused by an influx of specialist cells and molecules that are equipped to deal with an intruder by neutralising, killing or consuming it – sometimes all three.

Inflammation can damage the body, but usually the short-term pain and swelling are worth it to snuff out the danger of serious disease. However, if the immune system triggers inappropriate inflammation in the gut, this can drive chronic, often devastating conditions called inflammatory bowel diseases, which include ulcerative colitis and Crohn’s disease.

Controlling the body’s response to the harmless bacteria in the gut while keeping it alert to dangerous microbes is a difficult balancing trick. In most of us, our immune systems pull it off, so what makes some people’s immune systems overreact? That question is at the heart of research led by Professor Fiona Powrie, a Wellcome Trust Senior Investigator at the University of Oxford.

Fiona probes the workings of the intestinal immune system and the inflammatory response, teasing out the molecular signalling pathways that determine how our bodies respond to the bacteria in our gut. We often talk about the immune system as if it were the same throughout the body, a consistent defence mechanism against invasion. Fiona explains that this is not quite true.

The immune system’s cells and signals do different things according to where they are. The immune system in a specific tissue – such as the gut – does not behave in the same way as it does in the blood, which is where it has most commonly been studied.

Pathway to success

Bacteria on the surface of intestinal cells

Fiona has been studying the intestinal immune system since her days as a postgraduate student in Oxford, when she made her first discovery about how the balance between our immune system and bacteria is maintained in the gut. Even in healthy people, there is a constant low level of intestinal inflammation that is kept in check by a group of immune cells called ‘regulatory T cells’. Fiona and her mentor Don Mason were among the first to describe the role of regulatory T cells in suppressing inflammation.

“I did my PhD in Don Mason’s lab in the William Dunn School of Pathology,” says Fiona. “There were only four of us in the team – you wouldn’t find many labs like that now.” The discovery that regulatory T cells had a suppressive role ran against the tide of thought in immunology at the time.

“Suppression had been floated as an idea before but then fell out of favour,” she explains. “New technology allowed us to identify a controlling mechanism for regulatory T cells and to demonstrate that negative regulation was important in the immune system.”

It meant that, rather than being switched off until it was needed, the immune response was always ticking over in a carefully controlled way. This might make it quicker to respond when genuine threats arise, at which point the regulatory T cells take off the shackles until the inflammatory response has removed the danger.

Fiona left Oxford to do more work on regulatory T cells with Bob Coffman at the DNAX Research Institute in California. There, she found that modifying regulatory T cells in mice led to intestinal inflammation similar to that seen in human inflammatory bowel diseases. Mice with these specific modifications could be used as research models to understand the human disease better.

“It was very exciting,” she says. “These were among the first models of inflammatory bowel disease to be developed. It opened up my eyes to the clinical importance of the area and led me to focus my work on intestinal immunology.”

Her research focus set, Fiona returned to Oxford with a succession of Wellcome Trust Senior Fellowships from 1996 to 2009. Then, she accepted the inaugural Sidney Truelove chair in Gastroenterology along with roles as Head of both the Experimental Medicine Division and a new Translational Gastroenterology Unit at Oxford’s John Radcliffe Hospital.

In 2011, she was among the first cadre of researchers to receive Wellcome Trust Investigator Awards. The new funding model provides a firm footing for research alongside her administrative roles: “The Senior Investigator Award is perfect for me in this setting,” says Fiona. “The length and flexibility of the award is very important as the programme of research moves forward. We’re able to expand our horizons from mouse models to understanding the pathways at work in humans, to understanding human disease.”

Location, location, location

The Translational Gastroenterology Unit is the ideal place for this research. Basic researchers work alongside clinical researchers, who are also doctors in the hospital treating the patients suffering from inflammatory bowel diseases.

Fiona says such collaboration brings much added value: “How we think about the animal models is influenced by thinking about patients and talking with clinicians about the challenges they face.

“The clinicians come to meetings where we are talking about research into the drugs and agents they are actually giving to their patients. It is inspiring, and there is huge benefit in having postdoc scientists with a better awareness of the interactions between these different disciplines.”

The aim is to apply that scientific understanding and develop new treatments for inflammatory bowel diseases. There are some promising candidates in development, and Fiona and her team have been working with pharmaceutical companies to run proof-of-principle trials in their patients.

It is equally important to develop better ways of diagnosing inflammatory diseases. As well as knowing which specific condition a patient has, their care could be improved if doctors knew accurately how far the disease had progressed and even how likely the patient was to respond to a particular treatment. Eventually, it may be possible to categorise groups of patients by their genes – genetics undoubtedly has an important role in determining our likelihood of getting inflammatory bowel disease.

“It’s a very exciting time in this area,” says Fiona. “We’re part of a global effort, revealing regulatory pathways from human genetics and mouse models, which leads to understanding the operation of these pathways in humans. In turn, that leads to an understanding of what goes wrong in the specific set of patients with inflammatory bowel disease.”

Image credits: Wellcome Images (Prof Powrie); Dr Paul Dean, Newcastle University / Wellcome Images (bacteria)

A relatively new term, neglected tropical diseases (NTDs), is raising awareness of the numerous infectious diseases it encompasses, the burden they place on the world’s poorest people, and the need to do more to control them. While each NTD will require specific research, treatment and prevention strategies, common to all is the need for a variety of approaches. In his latest post in our NTDs series, Michael Regnier investigates how multiple strategies are being pursued to combat dengue fever.

Dengue is a mosquito-borne viral infection that causes fluid to leak out of the blood vessels into the abdomen and other cavities, in some cases causing severe shock. While less than 1 per cent of people infected with dengue virus will die from the disease, it is endemic in many countries where it is a constant problem.

On top of this ‘background’ level of infection, there are peaks of infectious outbreaks – epidemics – that can produce three to five times the normal number of cases. Professor Gavin Screaton, a Wellcome Trust Senior Investigator and Head of the Department of Medicine at Imperial College London, says dengue has the potential to spread through communities like wildfire.

“Dengue is predominantly a disease of urbanisation,” he says. “It poses major challenges to healthcare systems in developing countries because of its epidemic potential causing explosive outbreaks in some major cities. In endemic countries they’re good at treating it with excellent support management – which consists of giving patients large quantities of replacement fluid – but you don’t know who will get severe disease, so many cases will require hospitalisation.”

No drugs, no vaccines

Because the majority of patients recover, dengue doesn’t receive the same attention as infections such as HIV, malaria and tuberculosis, or even some other neglected tropical diseases (NTDs). But there are currently no drugs or vaccines at all for dengue. A drug that could be used in the early stages of dengue would help to prevent severe disease, while a vaccine would prevent many infections and reduce hospital admissions.

Screaton studies the immunopathology of dengue – how it causes disease through its interactions with the immune system – in order to help the development of effective vaccines. He started his research into dengue when Juthathip Mongkolsapaya, then a PhD student in his lab, told him about her work in Thailand. “Ju told me it was fascinating epidemiologically and immunologically,” Screaton recalls. “And, of course, it was a very important pathogen with no vaccine.

Dengue virus seen under an electron microscope

“It’s actually four viruses, or serotypes, which differ from each other by about 30 per cent. You can be infected more than once and the majority of cases that get very sick are secondary infections.”

This is because the body generates specific antibodies against the dengue virus during the first infection. If the same serotype comes back, these antibodies quickly bind to it and neutralise it.

If a different dengue serotype enters the body, however, the previously generated antibodies bind to it less strongly because of the variation between serotypes. Weak binding means they are unable to neutralise the second serotype. The functioning virus is then able to infect more cells in the body, triggering serious disease.

The challenge in developing a vaccine, therefore, is to work against all four serotypes at the same time. “It’s extremely difficult to get vaccines that are not too hot that they cause febrile illness themselves and not too cold, that is, ineffective,” explains Screaton. In true Goldilocks fashion, the vaccine has to be just right: “The aim is a balanced immune response against four targets that are in some aspects very different but at the same time rather similar.”

Approaching the problem from all angles

Trials of dengue vaccines are in progress, as are antiviral drug trials, including one sponsored by Roche. Professor Cameron Simmons, a Wellcome Trust Senior Fellow at the University of Oxford, has been working on this trial and says much has been learned as a result: “It’s different running trials in acute disease interventions,” he explains. “The timing of intervention is crucial, and needs careful follow-up. It’s a different sort of approach to trials in hepatitis or HIV.” The results of the trial will be published soon but whatever the results, says Simmons, the experience will help to provide a toolbox of how and what should be done in future trials.

Simmons is also involved in the development of new diagnostic and prognostic tests for dengue. “We’d like to give clinicians a tool to predict who’s at risk of getting severe disease,” he explains. “Then the doctor may make a different triage decision.” Identifying which patients are at most risk would help to ease the burden on healthcare systems during an outbreak of dengue. With the right tests, doctors could make a more accurate assessment of patients when they come to the hospital and admit only those people at high risk of severe disease.

The mosquito vector for dengue fever

Another approach is vector control: preventing the transmission of the virus from mosquitoes to people. For example, Simmons is working on a project, in collaboration with researchers in Australia, to infect mosquitoes with a bacterium called Wolbachia. This makes them partially resistant to dengue, which could help reduce the number of infections in humans.

“The science has developed quickly and gone into the field very quickly,” says Simmons. “Vector control really struggled for a good research base for a long while but now we’re seeing scientifically robust work coming in. These approaches have emerged in the last five years or so, whereas vaccine research has been grinding away in the background for the last 20.

“The important point,” he adds, “is that all these approaches can be complementary. We’re not going to eradicate the virus any time soon, so we need a swag of tools to control dengue.”

This is true for most NTDs. Drug development and vaccine research take a long time; in the meantime, other approaches can be pursued to reduce the burden of disease. Ultimately, a combination of approaches will be the most successful.

Good partners

Simmons is based in Vietnam, where he and his team work closely with local partners who have first-hand experience of the disease. He believes this contributes to the strength of their research: “There are very few research groups based in countries where dengue is endemic. At the Wellcome Trust Major Overseas Programme in Vietnam, we can take a long-term view and tackle the research on the ground, taking into account the priorities of the local community.

“A lot of our work is hospital-based and, importantly, we do training at the hospital, building research capacity in the clinical setting. Hospital clinicians see dengue patients every day – they understand the strain in health systems during epidemics.”

Dengue was not included in the first list of NTDs but Simmons is clear that it fits the criteria: “Dengue is neglected in the sense that the true scale of the disease burden is poorly understood and certainly underestimated.

“The research community is pretty small but in the last five years it has been growing. We could well have a vaccine in the next ten years, there are novel approaches in vector control, and there is interest from both academics and industry in developing antiviral drugs. We’re building momentum.”

This is one of a series of blog posts accompanying a Wellcome News feature on neglected tropical diseases. Next week: the different implementation strategies available for tackling NTDs.

Related resources:

The Wellcome Trust website has a number of scientific animations showing the life cycles of many parasites, bacteria and viruses that cause NTDs, including dengue.

Controlling dengue fever, improving lives: an alternative approach to dengue vector control in this Wellcome Trust video.

Image credits: Wellcome Images and Foto Gov/Ba on Flickr (main artwork); Sanofi Pasteur on Flickr (dengue virus); Wellcome Images (mosquito).

In the latest of our shortlisted entries to the 2011 

To the ancient Greeks, Olympic sprinters were heroes, immortalized in statue and verse. A couple of millennia of later, we still celebrate the winners. But in at many respects, the Games today have moved on dramatically. While the Greeks could only pick out the winner of a race, in modern competition we time the runners with unprecedented degrees of accuracy; we obsess in keeping records and delight in comparing times from different competitions, tracks or dates.

Come London 2012, we will reward the winners and worship the record-breakers – can Usain Bolt, seemingly blessed by Nike (the Greek Goddess of victory) herself, turn a faster time than he did in Beijing four years ago? Modern electronic timekeeping should answer that question. But suppose he completes the race in exactly the same time? How can we be sure he wasn’t a fraction faster or slower? For all the sophistication demanded by Olympic rules, the fact that one race was measured by a particular clock in Beijing and the other by a different clock in London poses some interesting dilemmas. There’s an old truth that says a man with one watch knows the time, but the man with two is never sure.

Our clocks may be highly accurate – they mark out time in precise increments – but they are physical devices that can never be set in absolutely precise synchronisation. What they measure are changes in their own physical condition, rather than any true, absolute, universal time. We don’t know what time is.

Isaac Newton’s solution to the conundrum of time reflects our human experience of events. In his concept of a mechanical universe, the motion of the stars, the planets and falling apples could all be calculated – provided there was an eternal, constantly ticking, clock. As Dr Phil Meeson, a lecturer in physics at Royal Holloway University of London, puts it: “He felt that the Universe had a perfect, underlying sense of time.” That notion of perfectly metronomic time ticking away in the background allowed Newton’s maths to work, underpinning the workings of the modern world. Unfortunately, Newton’s notion of time turns out to be wrong.

Einstein swept away Newton’s vision of absolute time with a startling insight: the speed of light is constant, so rather than providing a universal, stable backdrop to events, time is actually dependent on the relative motion of observers – and on gravity. A timekeeper aboard a fast-moving aircraft high above the Olympic stadium would record a slower time for the 100m than a timekeeper next to the track. This has been proved in numerous experiments – last year the National Physical Laboratory flew one atomic clock around the world and compared the time it read with an identical clock left in the lab. As expected, the traveling clock came back behind its stationary counterpart. The implications are unsettling – it turns out that the present moment is not the same for all of us. Dr Setnem Shemar, a senior research scientist at NPL, explains: “There is no such thing as a universal ‘now’. There are places in the universe, at the edge of a black hole, where if you looked out at the rest of the universe you’d see billions of years go by in the blink of an eyelid.”

For science, understanding time could be the key to closing the gap between the macroscopic world of stars, planets and falling apples described by Einstein or Newton and the quantum world of atoms and smaller particles described by Einstein’s contemporary, Max Planck. The same laws of physics should hold true in both worlds, but any theory unifying them has eluded the Herculean efforts of the greatest minds of modern science. That failure to unify the large and small has spawned a compelling – but hugely controversial – line of thought that the only way toward a comprehensive understanding will be to redefine time, or even excise it from theories of how the universe works.

A world without time is virtually unthinkable. When is the train? What’s the record for the 100m sprint? Fortunately for such practical matters, our clocks are plenty good enough to measures runners to a thousandth of a second, whatever that is.

This is an edited version of Bill’s original essay. Views expressed are the author’s own.

Find out more about the Wellcome Trust Science Writing Prize in association with the Guardian and the Observer and read our ‘How I write about science‘ series of tips for aspiring science writers.

Over the coming months, we’re publishing the shortlisted essays in this year’s inaugural competition.

Image Credit: Wellcome Images

The earliest film, Onwards to Victory, 1953, most closely resembles government war propaganda from the Ministry of Information and the newsreels shown during the Second World War. The film exploits the viewers’ patriotism and builds on the metaphor of science and technology’s contribution to Britain’s victory. The public are asked to give generously in support of the campaign to defeat the peacetime ‘menace’ of cancer.

The second film, The Modern Crusaders, 1958, celebrates the heroic struggle of the white-coated ‘mid-twentieth century crusaders’ against cancer. The voice-over, by an unseen male narrator, explains how much money is needed to cover the cost of the high-tech equipment shown. Despite the reassurance of scientific progress, the film communicates an urgent and ‘anxious’ appeal for funds. It was shot at the British Empire Cancer Campaign’s Chester Beatty Research Institute at the Royal Cancer Hospital (aka Royal Marsden Hospital), Surrey.

The Fight against Cancer: An appeal by Margaret Leighton, 1959, is an appeal by the British celebrity Margaret Leighton, who would have been familiar to cinema audiences during the 1940s and was critically acclaimed for her theatrical performances in the 1950s. Complete with her clipped accent, pearls and fur stole, she gives a very personal appeal to the public to contribute to the funding effort. The endorsement of charitable causes by famous but more accessible actors became more prevalent around this time: Harry Secombe appears in Penny Parade, 1964, an appeal on behalf of the Spastics Society, which became later became Scope, a charity for those with cerebral palsy, which also campaigns for equality for disabled people.

A trend in health communication is to have a more patient-centred approach and use the testimony of the patients themselves. Television and the Internet are much more intimate spaces – the emotional impact of these real stories can be more powerful. A compilation of Cancer Research UK’s television commercials can be viewed on their YouTube channel. A selection of videos made for patients about cancer, including testimonies, can be viewed on the NHS Choices website.

Angela Saward, Wellcome Film

You can learn about the Wellcome Film project here. If you would like to make use of this archive footage in your own projects, please visit the Wellcome Library catalogue to download the original files, which are distributed under a Creative Commons Attribution-Non-Commercial 2.0 UK: England & Wales licence.

In the latest of our shortlisted entries to the 2011 

Its surface is white as snow and covered in ice. Large expanses are smooth and unblemished, belying a history of constant meteorite bombardment. In one site near this moon’s south pole there are cracks tens of miles long. Ice and water, from vast underground oceans, are constantly spewed out of these cracks into the blackness of space.

Sounds like something from Doctor Who, right? Well, this moon actually exists, and it’s closer than you might think.

Enceladus is the second smallest of Saturn’s major moons. Until the Voyager 2 satellite passed in 1981, we knew little about it. Now, with the Cassini-Huygens satellite performing having performed several close fly-bys, the story of Enceladus is beginning to become clear.

Enceladus has one of the most reflective surfaces of any object in the solar system. It is also one of the most geologically active solar system bodies. This may seem counterintuitive at first, but it is no surprise to the scientists that study Enceladus — geological activity is what makes the moon so pristine and reflective in the first place. Ice volcanoes are able to constantly replenish the surface, covering up the scars of meteorite bombardment.

As it orbits Saturn, the pull of the planet contorts Enceladus. Saturn inflicts so much force on the tiny moon that ‘hotspots’ are created near its south pole, creating four giant cracks. Each is around 80 miles long, a mile wide and 500 metres deep. These cracks, affectionately known as ‘tiger stripes’, are 100°C hotter than the rest of the moon.

Cassini took the first clear pictures of the tiger stripes in July 2005. Their signature however, had been seen a few months earlier. In February 2005, small changes in the magnetic-field data revealed Enceladus had an atmosphere containing water vapour. There was something a little out of the ordinary about it, as the atmosphere was concentrated around the moon’s south pole, right above the tiger stripes. Ultraviolet images later confirmed what scientists had suspected: the stripes were the source of the giant plumes of water vapour and ice being ejected into space.

In the 1980s, scientists had some idea that these plumes might exist. During its time around Saturn, Voyager 2 searched for them but found no conclusive evidence of their existence. Scientists working on the Cassini mission decided that they could not take any chances — a fly-by had its path altered, bring it closer to the surface of Enceladus. It flew through one of the gas clouds created by the plumes and confirmed the presence of water, dust and molecules containing carbon and hydrogen.

One of the few things that we knew about Enceladus before Voyager 2 and Cassini was that it was icy. Since the discovery of the tiger stripes and plumes, scientists have speculated that there is also liquid water beneath the surface.

Although the forces exerted by Saturn on Enceladus are insufficient to explain the heating occurring around the tiger stripes, combing their effect with that of a vast ocean beneath the surface, able to transport heat more efficiently, might explain the phenomenon.

Evidence of a hidden ocean was suggested in December 2008 when scientists noticed that the tiger stripes had moved. They think that something similar to the movement of Earth’s tectonic plates is occurring on Enceladus, with the surface of the moon splitting and material coming up from underneath to fill the gap. On Earth, the material that fills the gap is molten rock. On Enceladus, it could be water.

Yet more evidence came a few months later. Unusually high levels of salt were discovered in water from the plumes. Salt tends to come from large bodies of water; oceans are big enough to have significant amounts dissolved within them, while ponds are not.

Liquid water, combined with heat and the organic molecules seen in the plumes, increases the chance that life might develop on Enceladus. If water does exist on Enceladus, it will join Mars and Europa, a moon of Jupiter, at the top of the list of places to look for life in the solar system.

We are discovering more about this moon all the time. Earlier this year, for example, it was revealed that the ice volcanoes on Enceladus create an electrical circuit between the moon and its planet. This produces aurora, better known as the northern lights here on Earth, on Saturn.

If these recent discoveries are anything to go by, Enceladus is only going to get more interesting. The Cassini mission was originally meant to run for four years, until 2008. It has now been extended twice, and will keep exploring Saturn and its moons until at least 2017. Watch this space.

Kelly Oakes

This is an edited version of Kelly’s original essay. Views expressed are the author’s own.

Find out more about the Wellcome Trust Science Writing Prize in association with the Guardian and the Observer and read our ‘How I write about science‘ series of tips for aspiring science writers.

Over the coming months, we’re publishing the shortlisted essays in this year’s inaugural competition.

Image Credit: kokogiak on Flickr

Understanding these health impacts is a challenge for science. Communicating and acting upon that information is a challenge for all of us. Artists have been helping with this important process, for example the 2005 visit to the Arctic by a joint group of artists and scientists, which produced the novel Solar.

Video games have, in their own way, responded too. There are games that look specifically at the health issues (such as Climate Health Impact by the Wellcome Trust and Playgen) and games that put the player in the position of trying to persuade the world’s countries to act together (Fate of the World). But there are also games that use the changed world as a narrative setting.

Brink is a first-person shooter. Most such action games use aliens, World War II or terrorism as their setting. Brink uses climate change. I asked the game’s writer, Edward Stern, why. 

“We knew the narrative backdrop for Brink had to be visually distinctive and explain why people are fighting, what they’re fighting for, and why they don’t just leave. All of this seemed to require resource scarcity and isolation. Perhaps an island of some sort, but why would people be on an island?

“I’d read about the Sea Standing Institute and seen some other terraforming/engineering solutions to rising sea levels on Jeff Manaugh’s BLDG BLOG. So that lead to the Ark, Brink’s techno-visionary artificial island – built to combat climate change but cut off from the outside world and running out of spare parts… it wasn’t anything I’d seen in a game before… But it also plugged into current concerns.”

Given how much the science drives what you know (and don’t know) about climate change Stern looked for credible sources to inform his writing, but sorting what’s reliable in a controversial topic like climate change was a challenge for a non-expert.

“My training, such as it is, is as a Historian,” says Stern. “So my test for researching a topic is; have I read the primary sources, or am I relying on secondary sources, or have I just read one book, or have I read several web posts but they’re all misquoting each other?

“I used to follow the science and the culture/media brouhaha surrounding [climate change] as best I could, mainly starting with Science Blogs and Real Climate and following links from there. I couldn’t understand absolutely every detail of the Mann ‘Hockeystick’ and the stolen CRU emails, but I went through them as thoroughly as I could, keeping as open a mind as I could. If I couldn’t be an active combatant in the information wars, I could at least be a well-informed civilian.”

And how does the wealth of scientific information contribute to the creative aspects of the game?

“There’s the old statistics joke that the plural of anecdote is not data. But from a writer’s point of view, the singular of data is not anecdote – you can’t just invoke a scientific buzzword and hope that will make things seem credible or dramatic to a player/reader. It has to be something you can show or tell within the game.”

“I love it when a game connects to the non-gaming bits of the brain. I always cite Deus Ex as the first game I played where I genuinely didn’t know what to do. Not just what the game would reward me most for, or what would move the action along, but because I genuinely didn’t know how I felt about the real world choices and issues the designers had put in their game for my character to deal with.”

I’ve completed Brink and the setting of the game, and the characters’ responses to the world they’re in is credible and engaging. Given that climate change is a hot political issue, and will be for some time, its a bold decision to place the issue front-and-centre in a key part of popular culture – gaming. This is key as a growing number of people play games and see games as a primary source of understanding about the world around them. As Stern told me, “I was trying to make it as easy as possible for players to let the game stick in their minds, to plug into their existing concerns and prejudices about real world issues. And few people know or care absolutely nothing about climate change, whatever their outlook.”

Tomas Rawlings

Tomasis a Video Games Consultant for the Wellcome Trust. You can read the full version of Tomas’s interview with Edward Stern on his blog. See also his previous posts on games and science.

Find out more about the Wellcome Trust’s support for games.

Sue Horner

What is the role of inquiry-based learning in an inspiring science education? And what are its boundaries and limitations? In the last of our Perspectives essays, former Director of Curriculum Sue Horner outlines the difficulties in developing clear policy that can be easily interpreted and implemented.

A central challenge in writing a National Curriculum is one of definitions: what do we want the core content to be and how can this be best explained to a range of users? This is in addition to the challenge – common to all education policy – of offering a legislative framework that raises standards. For it to be respected, the framework needs to be intellectually cogent, realistic and practical to implement, and to attract sufficient support from the scientific and teaching communities.

One of the conventions of the National Curriculum is that it specifies the matter to be taught but not how it should be taught. The supposition that any subject can be ‘pedagogically blind’ is simplistic for two reasons. First, learning is constructed through pedagogy and the nature of a subject is conveyed by how it is taught. Second, the way the curriculum is written has implications for the classroom: the importance of scientific inquiry is inferred from how it is represented in the National Curriculum. The 2007 curriculum (1) emphasises ‘scientific thinking’, ‘practical and enquiry skills’ and ‘critical understanding’, and these rightly have clear implications for pedagogy. 

Scientific inquiry in the science curriculum

The National Curriculum seeks to capture the essence and scope of the study of science in school. Integral to that is the nature of inquiry and its relationship to scientific knowledge, derived through experimentation and observation. Students therefore need to understand not only scientific ideas but also how they are constructed.

Inquiry is essential to the development of scientific ideas and essential for understanding the world. This means that inquiry is more fundamental to real science than other pedagogies or classroom activities. It has always been hard to represent the integration of content and process in the curriculum.

The challenge for teachers is to select teaching methods that promote students’ understanding of how scientific knowledge is constructed. This gives greater significance to the pedagogies used in science, as they affect learning in more fundamental ways than those in other subjects may.

The curriculum is a framework that, before being implemented, needs interpretation by intermediaries – such as continuing professional development providers, awarding bodies, textbook writers and teachers. Of course, different intermediaries, with their own views of the subject, may emphasise the aspects they favour  There is a tendency for different groups to argue for content but not process.

What is defined in law is intended to provide a shared understanding of science. It also has to serve many purposes, for teaching and assessment, and a recent criticism of the science curriculum (2) is that lack of detail has led to inadequate guidance for these different purposes. Judgements, however, do have to be made about what is the irreducible core of science. This has been a constant struggle, especially because ‘new’ areas of knowledge will continue to appear, leading to a temptation to specify too much content. Alternatively, rigorous inquiry could be at the core – enabling students to tackle a subset of knowledge in depth and to develop skills that will enable them to understand science more broadly.

What is progression in science and how can it be assessed?

Progression in inquiry means, for example, students making more rigorous observations, taking account of more experimental variables, analysing more complex evidence and ensuring that conclusions are more scientifically valid. Poor articulation of this progression can lead to repetition rather then progress.

Assumptions about progress are most exposed in assessment. To support learning, assessments should recognize the complexity of a subject, but current qualifications mostly assess knowledge through written examinations and skills through set practical experiments. These methods of assessment do not therefore reflect the integration of knowledge and inquiry upon which science relies.

Recent critical events in assessment have exposed some of the problems:

• GCSEs have recently had to be rewritten as, according to Ofqual, there was too great a reliance on multiple-choice questions. (3) They seemed to focus on recall of information; by age 16 this was not considered sufficiently challenging since it reveals nothing about the thinking required to explain processes, ideas and the significance of evidence.

• Key Stage 2 science tests came under fire because it was thought that a reasonably knowledgeable pupil who had studied no science at all could answer some of the questions based on ‘common sense’. There were also concerns that tests were too susceptible to cramming information. Again, as with GCSE examinations, remembering the facts or making simple deductions was considered inadequate.

A completely different model of assessment underpinned the criteria in Assessing Pupils’ Progress (APP). (4) Instead of specifying knowledge separately and recognising process, the assessment criteria focus on effectiveness in aspects of inquiry, including ‘thinking scientifically’, ‘communicating and collaborating in science’, ‘using investigative approaches’ and ‘working critically with evidence’. This is the best attempt so far to describe progression in these skills. The apparent lack of content in APP initially caused anxiety, but it soon became evident that students could only progress if they used and developed their scientific knowledge. In fact, APP provided a framework within which knowledge was activated and teachers collected more varied and richer evidence of what their students actually knew. This, then, was a way of integrating knowledge and inquiry in assessment.

Techniques for assessment need to be sufficiently sophisticated to support a complex view of learning in science. If scientific inquiry is inextricably linked to knowledge and understanding, then assessment needs to find ways to test this. If not, inadequate assessments will continue to inhibit teaching and learning.

Inquiry and the whole curriculum

The processes of inquiry are not solely the purview of science, with common ground clearly evident in 11 of the 12 subjects in the 2007 National Curriculum (the exception being modern foreign languages). No skills or processes can be learned in a vacuum and, although the kinds of question and the methods of investigation may vary between subjects, students are being asked to undertake similar thinking. Students benefit when connections enable them to develop and apply skills across subjects, since they are not relearning but applying and adjusting their learning to a different context.

The importance of these skills is underlined in the QCA’s Personal, Learning and Thinking Skills (PLTS), (5) which see ‘independent enquirer’ skills as essential to success in life, learning and work. Even though these are non-statutory, many schools see them as important for their students, and employers are keen for applicants to demonstrate these skills. Pupils, too, have voiced their preference for active, participatory and collaborative learning, as evidence from NFER6 and CUREE7 shows. So, scientific inquiry not only animates learning in science but also contributes to the development of the wider skills needed by all learners.

The National Curriculum seeks to set out what we, the nation, want our young people to know, understand and be able to do. The 2007 version sought to include the necessary knowledge and skills for those who will become scientists or take up science-related work, as well as providing a basis for all students to make sense of the world. Integrating scientific ideas and knowledge with rigorous inquiry methods can promote this, and policy can support this approach. What policy can’t do is ensure that everyone agrees and that all the intermediaries interpret the curriculum in the same way.

With the National Curriculum now potentially moving into a new phase, it is the responsibility of all those with a stake in science teaching to use their judgement and autonomy to make sure inquiry is fully integrated into science learning.

Sue Horner

Dr Sue Horner is Former Director of Curriculum of the Qualifications and Curriculum Authority. She has worked in national policy roles on curriculum and assessment for 18 years, during which her priority was to find ways to take forward thinking and practice in teaching and learning. She also works in the arts and is on the Board of several national charities.

The original version of this essay appears in the newest issue of our Perspectives on Education series, in which four authors explore these questions from their perspectives as a teacher, an international education expert, a policy maker and a researcher. We’ll be publishing each essay here on the blog, but you can download the full publication for free on the Wellcome Trust website. 

References

1. The National Curriculum statutory requirements for key stages 3 and 4. QCA, DCSF; 2007.
2. Oates T. Could Do Better: Using international comparisons to refine the national curriculum in England. Cambridge Assessment; 2010.
3. The new GCSE science examinations: Findings from the monitoring of the new GCSE science specifications: 2007 to 2008. Ofqual; 2009.
4. Department for Children, Schools and Families. Assessing Pupils’ Progress. 2009 [accessed October 2011].
5. Qualifications and Curriculum Authority. Personal, Learning and Thinking Skills. 2008.
6. Lord P, Jones M. Pupils’ Experiences and Perspectives of the National Curriculum and Assessment. Final report for the research review. National Foundation for Educational Research; 2006.
7. Centre for the Use of Research and Evidence in Education. Building the Evidence Base. Qualifications and Curriculum Development Agency; 2010.

Professor Fiona Powrie

Professor Fiona Powrie, a Wellcome Trust Senior Investigator at the University of Oxford, is one of two scientists who will be awarded the 2012 Louis-Jeantet Prize for Medicine at a ceremony in Switzerland in April. She will receive CHF 625,000 (£430,000) for her research and CHF 75,000 (£50,000) as a personal award.

Fiona wins the prize for her work on “the interactions between the bacterial intestinal flora and the immune system”. Her research looks at why the immune system does not usually attack the numerous beneficial bacteria that live in the gut, and how we can improve treatment for conditions caused when the immune system gets it wrong. Inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease are caused by an inappropriate immune response in the gut.

I interviewed Fiona last year and will be posting a feature on her work in the next week or so. It is fascinating research, not least because the immune system in the intestines in not quite the same as it is in the blood, which is where it is more usually studied. Immune cells and signals do different things according to where they are. As Fiona said, it’s all about location, location, location!

Fiona was one of the first people to receive a Wellcome Trust Investigator Award and she has made important contributions to immunology throughout her career. As a DPhil student in Oxford, she discovered the role of regulatory T cells in suppressing inflammation, and later she developed some of the first mouse models for inflammatory bowel disease. Today, she is Head of the Experimental Medicine Division and the Translational Gastroenterology Unit at the John Radcliffe Hospital in Oxford, as well as being the inaugural Sidney Truelove Professor of Gastroenterology.

Many congratulations to Fiona, and to Professor Matthias Mann, a German researcher who also wins the Prize this year for his work on developing the use of mass spectrometry in proteomics.

Image credit: Wellcome Images

Alex Bateman

In a world in which anti-science appears to be on the increase, it is imperative that scientists improve how they engage with the general public about their research. A traditional way to do this is to give talks at science fairs and engage directly with schools. A problem with this ‘standard’ public engagement approach, however, is that the reach can be quite limited and is often a case of preaching to the converted.

Of course, if your research is ‘hot’ enough you can push stories through the mass media, such as TV and newspapers, hoping that the results don’t get too garbled in the telling. I believe that these limitations, combined with the fact that many of these activities are time-consuming, inhibit many scientists from communicating effectively with the public.

If you really want to let the public know about your science then the only way is Wikipedia. For better or worse, Wikipedia has become the central repository of knowledge on the internet. If you don’t believe me then try the following experiment. Pick a word and type it into Google. For most terms – e.g. ‘malaria’, ‘research’ or ‘opinion’ – Wikipedia is the top hit.

If you want to get a quick overview of a topic, it’s likely you’ll go straight to Wikipedia. Now think about the hundreds of millions of internet users out there who will, at some point, want to find out something about science, technology or medicine. I’m afraid that they will almost certainly not be heading to your latest research article to do so.

Editing Wikipedia can seem daunting at first. Some researchers might be put off because their first impulse is to tackle editing an article there the same way as they would write a research paper – perfect it and then let others review it before final publication. Wikipedia doesn’t work that way. You don’t need to rewrite the history of a science article, just add a sentence here, a reference there. You can make a useful contribution to Wikipedia without making a large investment of your time.

So if you are interested in helping the public understand what your research is all about then I urge you to learn how to edit and improve Wikipedia. Find the relevant article and make whatever changes you think are needed to ensure that the content is scientifically accurate and up to date. It doesn’t take a lot to make a big difference, and you get to fulfil some of your public engagement responsibilities in the process too.

Alex Bateman

Dr Alex Bateman is a research scientist at the Wellcome Trust Sanger Institute.

Neglected tropical diseases (NTDs) affect the world’s poorest people, causing death, disability and prolonged disadvantage. Many of these diseases lack effective treatments but the rising profile of NTDs means more resources are becoming available for research and development. However, the challenges of finding new drugs for NTDs go beyond funding, as Michael Regnier reports in the fourth post in our NTDs series.

A handful of NTDs – schistosomiasis, trachoma and hookworm, for example – have effective drugs available for treating them. For these diseases, the challenge lies in acquiring and distributing sufficient doses to treat the millions of people suffering with them. However for many, if not most, NTDs either there are no drugs or the drugs we do have are old, cause significant side-effects, are very expensive, or are losing their potency because the parasites, viruses and bacteria that cause the diseases are developing drug resistance.

Professor Alan Fairlamb

Professor Alan Fairlamb, Co-Director of the Wellcome Trust-funded Drug Discovery Unit (DDU) at the University of Dundee, says that only a handful of NTD drugs are truly fit for purpose: “Many compounds were originally developed with a different indication in mind, maybe from cancer research or anti-fungal drug discovery programs. The target product profile for these original indications does not take into account the association with poverty and the rural setting where most NTD drugs are needed.”

The cost of new drugs is another significant issue. “Expensive drugs are good for the odd safari but too costly for the local population,” he adds. “People often can’t afford the treatment, so they don’t complete the course and this drives resistance. The challenge is to develop cheaper and safer drugs.”

The Dundee Unit works with scientists who have discovered a promising target but perhaps don’t have the know-how or the infrastructure to do drug discovery. “Our vision is to take excellent basic science and turn it into useful medical products,” explains Fairlamb. They work directly with industry and through product development partnerships such as the Drugs for Neglected Diseases Initiative (DNDi).

“The product development partnership is a good model,” says Fairlamb. “It is starting to transform the situation with respect to new drugs [for NTDs]. But there is a five-year cycle of funding, they need to demonstrate success and, understandably, are therefore slightly risk-averse to early stage drug discovery. The DDU fills this gap.”

The Unit’s most successful project to date is based on an enzyme called N-myristoyltransferase (NMT), which was developed as a target for new drugs to treat leishmaniasis and other diseases at Imperial College London by Professor Deborah Smith, now at the University of York.

Journey of drug discovery

“We sequenced genes from Leishmania parasites transmitted by sand flies and screened for molecules produced exclusively in the infective stage of their life cycle,” Smith explains. “We found one molecule that had to undergo a specific modification in order to be presented on the surface of the parasite cells. That modification was catalysed by NMT, which we knew had been previously developed by Pfizer as a drug target for fungal pathogens.”

Although Pfizer had developed inhibitors of NMT, they were each specific to particular species of fungus. Doctors would have had to identify the type of fungus infecting their patient before treating them with the right NMT inhibitor. Because fungal infections can be difficult to distinguish, Pfizer had instead turned its attention to developing general antifungal drugs that would work against multiple species.

Knowing that Pfizer had already worked on NMT meant Smith and her colleagues could be confident that it was a strong candidate for development. The specificity of NMT inhibitors would be less of a problem because, while there are different species of parasite that cause leishmaniasis, they cause distinctly different symptoms in different parts of the world.

Smith persuaded Pfizer to share some of their compounds for her research to confirm that NMT is vital to Leishmania parasites. Then she discovered that the enzyme is also found in the parasites that cause human African trypanosomiasis (sleeping sickness) and may even be a target in Plasmodium, the parasite that causes malaria.

Professor Deborah Smith

“Will one key enzyme be a target for multiple parasites? There’s still a long way to go,” says Smith. Even if the work on NMT does not lead to a viable drug for all these diseases, however, it will be valuable research. “We’re doing the groundwork for future potential opportunities,” she concludes.

A large consortium is now working on drugs to target NMT in the various diseases. Work on human African trypanosomiasis is being led by the Dundee Drug Discovery Unit, while Smith is leading work on leishmaniasis and Plasmodium in York in collaboration with colleagues at Imperial College London, the Medical Research Council National Institute for Medical Research in London, and the University of Nottingham.

Safeguarding treatments

Professor Paul Kaye, Director of the Centre for Immunology and Infection at the University of York, has been doing research into leishmaniasis for many years and knows that new targets like NMT are rare and clinical trials even more so. “Poverty is a major driver both in the disease and in limiting investment,” he says. “We don’t have the money to do iterative testing as in other diseases. Malaria has seen 20 to 30 trials in recent years, whereas we’re seeing the first clinical trial in leishmaniasis to be funded in ten years.” As with all NTDs, it is crucial to keep pursuing other avenues of research.

Professor Paul Kaye

For example, Kaye and Smith are working together on developing a therapeutic vaccine for leishmaniasis, targeting a different arm of the immune system to that focused on by most previous research (CD8 rather than CD4 T cells) and using new vectors to deliver the vaccine. It is one of just two second-generation vaccines in development for leishmaniasis and they hope to start phase I trials this year.

“We need to protect the drugs we have,” says Kaye. “We only have three leishmaniasis drugs and there is already resistance to the commonest drug in parts of India where visceral leishmaniasis is endemic. Second-line drugs are being used but while these are very effective, they do have some side-effects and are costly. A therapeutic vaccine given in combination could help protect the drugs’ lifetimes. Also, we could use lower doses or a lower number of doses or expect greater compliance, which would all help to minimise resistance.”

Underpinning this work are years of basic research. Kaye himself has spent 25 years looking at the fundamental immunology of why chronic disease develops from some leishmaniasis infections and not others. “Most people are well-protected and don’t show any symptoms,” he says. “What makes others susceptible?”

Smith’s postdoctoral research was in molecular biology, looking at the control of gene expression in Drosophila (fruit flies). “I became interested in the potential for applying the tools I was using in fruit flies to sand flies and the parasites they carry,” she explains. “We are basic, fundamental biologists working on pathogenic organisms. Our long-term goal is to have an impact on human disease, work that is desperately needed. We’ve been to these countries and are aware of the constant and continuing challenge these diseases present.”

This is one of a series of blog posts accompanying a Wellcome News feature on neglected tropical diseases. Next week: Approaching the problem from all angles – why a number of approaches are needed to tackle any one NTD.

Related resources:

Frearson, J., Brand, S., McElroy, S., Cleghorn, L., Smid, O., Stojanovski, L., Price, H., Guther, M., Torrie, L., Robinson, D., Hallyburton, I., Mpamhanga, C., Brannigan, J., Wilkinson, A., Hodgkinson, M., Hui, R., Qiu, W., Raimi, O., van Aalten, D., Brenk, R., Gilbert, I., Read, K., Fairlamb, A., Ferguson, M., Smith, D., & Wyatt, P. (2010). N-myristoyltransferase inhibitors as new leads to treat sleeping sickness Nature, 464 (7289), 728-732 DOI: 10.1038/nature08893

The Wellcome Trust website has a number of scientific animations showing the life cycles of many parasites, bacteria and viruses that cause diseases including some NTDs. Eg:
Leishmaniasis – fly / human
Human African trypanosomiasis – fly / human
Malaria – mosquito / human

Prof. Elaine Fox

What causes mental illnesses such as anxiety disorder or depression? Are some people more likely to develop these conditions than others? What is the best way to treat them? These are just some of the challenging questions that Professor Elaine Fox, a psychologist at the University of Essex, is trying to answer. She and her colleagues have recently found that a variation in the gene that encodes a particular protein could make some people more sensitive to their emotional environment – and more susceptible to anxiety disorders – than others. I spoke to Professor Fox to find out more.

Which protein have you been studying?

We’ve been looking at the serotonin transporter, a protein that ‘recycles’ serotonin [a neurotransmitter] during nerve signalling. When a nerve signal is passed from one neuron [nerve cell] to the next, serotonin released by the first neuron carries the signal across the gap to the second neuron. Afterwards, serotonin transporters remove serotonin from the gap and return it to the initial neuron, ready to be released again when another nerve signal is transmitted.

Why were you interested in it?

We’ve known for a while that the gene that contains the instructions for making the serotonin transporter seems to play a role in increasing the risk of a person being emotionally vulnerable, particularly in relation to depression and anxiety.

This gene varies across the population. Some people have short versions that result in them having fewer copies of the serotonin transporter, and therefore higher concentrations of serotonin in the gaps between neurons. Others have long versions of the gene that lead to more copies of the serotonin transporter and lower serotonin levels.

About a year ago Arne Öhman, and his group from the Karolinska Institute in Sweden, published a paper that showed that people with short versions of the serotonin transporter gene learnt to fear [by exposure to a “highly annoying but not painful” electric shock] much more quickly than people with long versions.¹ Their findings suggested that these people have brains that are much more reactive to threat.

I thought it would be really interesting to look at this link between the serotonin transporter gene and how the brain learns in the context of the attention bias modification (ABM) procedures that I was already using.

What are attention bias modification (ABM) procedures?

They are techniques that can be used to change the amount of attention a person pays to something, known as an attention bias. ABM training typically involves using a computerised training programme to alter a participant’s attention bias.

It’s normal for healthy people to have low levels of ‘trace’ attention bias, which may focus their attention slightly more towards either positive information [if they have a positive trace attention bias] or negative information [if they have a negative trace attention bias].

People with anxiety disorders have a very strong bias in their attention towards threats [a negative attention bias that is much larger than the trace levels found in healthy people]. The interesting question is: do people with anxiety disorders have a strong negative attention bias because of their anxiety, which tunes them into things that are threatening, or are these biases part of the reason why people have developed anxiety in the first place? The evidence now indicates that the biases can indeed cause anxiety problems to develop.

We want to find out whether ABM techniques can be used as a treatment to reduce negative attention biases in patients with anxiety disorder, and therefore reduce their emotional vulnerability. It may be that they won’t be used as a stand-alone intervention, but might actually be very powerful if combined with other techniques, like cognitive behavioural therapy [a talking therapy] or drug therapy.

What did you do?

We combined ABM training with genetic testing for the first time, to investigate the relationship between the serotonin transporter gene and how quickly people can “learn” to develop a bias in attention².

Our experiment involved testing two groups, each of 57 healthy people. We used computer-based tasks to test whether the volunteers had an initial trace attention bias towards either positive or negative images, and then gave them ABM training to induce a positive bias in one group and a negative bias in the other. We then re-tested participants to see if their initial attention biases had changed, and whether their performance varied according to which version of the serotonin transporter gene they had. Both groups contained some people with short versions of the serotonin transporter gene and others with long versions.

Attention bias testing involved briefly presenting two images at the same time, side-by-side on a computer screen. One image was highly positive [e.g. a smiling baby] and the other was highly negative [e.g. a snarling dog]. Both images disappeared after half a second and one of them was replaced with a symbol. We measured how quickly a participant was able to identify the symbol, and used this to calculate their attention bias. For example, if someone was more tuned into the positive, they were slightly faster at finding the symbol when it appeared in the location where the positive item had been, compared to when it appeared where the negative item had been.

Each participant’s response time was measured 128 times, in which there was equal probability of the symbol replacing either the positive or negative image.

ABM training was conducted in almost the same way as attention bias testing. Over hundreds of trials, people saw pairs of images flash up on the screen, followed by a symbol. The difference between this and the testing was that the symbol always replaced the positive image during positive attention bias training, and always replaced the negative image during negative training.

We were orientating people’s attention system towards either positive or negative information [depending on which training group they were in], even though they weren’t really aware that the symbol was always appearing behind the same type of image.

What did you find out?

People with a short serotonin transporter gene developed stronger biases over an hour’s training session than those with long versions of the gene. The unexpected finding was that this was true for both negative and positive information. In other words, people with short forms of this gene were more sensitive to the emotional significance of their surroundings, irrespective of whether that environment was positive or negative. This means that they are likely to be far more reactive to very negative situations, such as a car crash, putting them at higher risk of developing emotional vulnerability.

On the other hand, when they experience something very positive such as a supportive relationship, they may be able to benefit from it far more than someone with a long serotonin transporter gene would. This supports the idea of short serotonin transporter genes as ‘adaptability’, rather than ‘vulnerability’ genes, or what you might call a “make you or break you gene”.

In healthy people, a trace attention bias is not likely to have a dramatic effect on a day-to-day basis. The idea is that these biases are not particularly damaging in themselves, but over time they really do start changing brain states. If you imagine someone with a small negative attention bias who experiences negative events 8 or 9 times every day, over a month, a year, or many years, that could really build up to produce a different brain state and a different world view.

We’re arguing that the kind of biases that people have in their attention plays a causal role in the development of emotional vulnerability. In other words, if people are tuning into the more negative aspects of their surroundings, it can make then more reactive to stress.

What are you planning to do next?

I’m hoping to follow up this work. The idea is to look in more detail at how patients with different versions of this gene respond to various therapies for anxiety disorder and depression, such as ABM procedures, cognitive behavioural therapy and drug therapy. It would be really nice to see whether the type of serotonin transporter gene that a patient has makes a difference to how beneficial those treatments are.

That would be the first step towards a much more ‘personalised medicine’ approach, in which genetic information about a person with anxiety or depression could help with decisions about how to treat them. I also think that there is a lot of work to be done to understand the basic science behind cognitive biases and how they impact on emotional disorders.

This study was funded by a University of Essex Research Promotion Fund Grant and a Wellcome Trust Project Grant.

References

• Lonsdorf TB, Weike AI, Nikamo P, Schalling M, Hamm AO, & Ohman A (2009). Genetic gating of human fear learning and extinction: possible implications for gene-environment interaction in anxiety disorder. Psychological science, 20 (2), 198-206 PMID: 19175757
• Fox, E., Zougkou, K., Ridgewell, A., & Garner, K. (2011). The Serotonin Transporter Gene Alters Sensitivity to Attention Bias Modification: Evidence for a Plasticity Gene Biological Psychiatry, 70 (11), 1049-1054 DOI: 10.1016/j.biopsych.2011.07.004