A new tool to help everyone understand and evaluate health research

Healthcare concept vector image [Converted]

Understanding Health Research is a new online tool designed to help the public and patients understand and assess research papers.  In this guest blog, Dr Amy Nimegeer and Chris Patterson from the project team tell us more about the website and how they hope it will help people make better informed decisions on health.

Every day we are hit with a barrage of health information from many different sources – friends, social media, newspapers, TV, magazines, and radio. A lot of this information seems to be based on scientific research but is contradictory, with scientists seeming to say, for example, coffee will give us cancer one week and coffee will keep us healthy the next. Not only can these mixed messages make it difficult for us to make healthy choices, it can also undermine public confidence in the usefulness of science.

Some of these contradictions are down to genuine disagreement between scientists, and some are down to research being poorly reported in the media. More fundamentally, we might not have these problems if more people had been taught to critically appraise research evidence. Scientific papers can be dense and unfriendly, but having the skills to read a piece of research and judge its quality and usefulness can help us all to be more critical of the health claims we come across, and allow us to make better informed decisions for ourselves and others. Unfortunately, evidence suggests that many of us lack the confidence and skills to critically access health information . After all, if healthcare professionals struggle to evaluate health research, what chance does everyone else have?

Help is at hand

To help tackle this problem, we have developed a free online tool called Understanding Health Research, launched this month to support non-scientists through the process of understanding and interpreting health research papers. The tool was a collaboration between researchers at the University of Glasgow, University of Oxford, University of Cambridge and the London School of Hygiene & Tropical Medicine, and was funded by the Medical Research Council’s Population Health Science Research Network.

So what does Understanding Health Research actually do? The tool is an online resource that walks the user through a series of questions designed to highlight key aspects of research. First a set of general questions examines vital issues including whether the paper was peer reviewed and who funded the research. Next, the user is helped through the process of determining what type of research it is, and answers a series of questions specific to the methods being used. This is crucial, because, just as different research methods are used to answer different research questions, different questions are relevant to assessing the quality of different methods.

Finally, the tool gives the user a summary of the answers they gave and what those answers might mean. Rather than giving a definitive judgement about whether the research is good or bad, the tool is designed to highlight the important aspects of the research in question and empower the user to make up their own mind. In truth, research is rarely completely good or completely bad – every study has limitations, and nearly every study has some merit. The key to using research effectively is to weigh up those strengths and weaknesses, as well as considering how relevant the research is to the specific circumstances that you are interested in.

Building knowledge

Older woman at computerAs well as the main critical appraisal tool, the Understanding Health Research website is full of useful information and background reading. We offer a guide to the essential step of learning how to read a scientific paper, as well as introductions to complex, but important, scientific concepts such as the difference between correlation and causation. As well as providing our own resources, we recognise that Understanding Health Research is just one part of a larger puzzle of health literacy, and we encourage our users to make use of other excellent resources, such as NHS Choices Behind the Headlines and Sense about Science’s Ask for Evidence campaign.

Understanding Health Research was made with input from a broad range of people with an interest in using health evidence, ranging from members of the public to academics. We designed our tool to be useful to as many different types of people as possible. Reading scientific research can be difficult, and scientific concepts can be complex, but we believe that by taking it step-by-step, everyone can understand health science. To find out how effective the tool is, we plan to carry out a formal evaluation, and to keep improving it in response to feedback from users. If you have any thoughts about Understanding Health Research, please do not hesitate to contact us, and together we can help to demystify scientific research for everyone.

Dr Amy Nimegeer & Chris Patterson

Amy and Chris are researchers at the MRC/CSO Social and Public Health Sciences Unit, University of Glasgow.

Images credits: Healthcare vector – Shutterstock/Hilch; Woman at computer – Shutterstock/Mik Lav

Immunology update – August 2016

Welcome to the next installment of our regular monthly slot where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past four weeks.

Potential mechanism to reboot immune system after bone marrow transplant

ViSNE plot of immature T-cells in thymus
A ViSNE plot of immature T-cells in the thymus. Highlighted in red is a population of T-cell progenitors that colonise the thymus and give rise to all T-cells.

The populations of some immune cell types, in particular T cells, are slow to recover following bone marrow transplant, but the reason for this is not known.  Using murine models, researchers at the University of Birmingham have discovered a new in vivo mechanism involving the thymus that could help to explain this phenomenon.

They found that Lymphotoxin β receptor, a cell surface molecule, controls the entry of T-cell progenitors to the thymus, both in a healthy state and during immune recovery following bone-marrow transplantation. Importantly, the team also found that, in mice, antibody-mediated stimulation of this receptor following a bone marrow transplant increased the number of donor-derived T-cells and boosted initial thymus recovery.

Writing in Journal of Immunology, lead author and BSI member, Professor Graham Anderson explains, “Post-transplantation, T-cell progenitors derived from the bone marrow transplant can struggle to enter the thymus, as if the doorway to the thymus is closed. Identifying molecular regulators that can ‘prop open’ the door and allow these cells to enter and mature, could well be a means to help reboot the immune system.” The team now hope to expand their studies to see if the same molecular mechanism functions in humans.

Read the press release

Read the full article: Lucas et al. 2016 Journal of Immunology doi:10.4049/jimmunol.1601189

What scales the T-cell response?

One question that has baffled immunologists is how the immune system manages to proportionally scale its response in relation to any threat it encounters. In this thought-provoking article, published in Trends in Immunology, Professor Michael Dustin and Dr Viveka Mayya from the University of Oxford set out their hypothesis for how this occurs.

BSI member Professor Michael Dustin, explains, “While an overwhelming T-cell response might on the face of it sound effective, it brings risks of immunopathology, where an over-active immune system destroys healthy human tissue, not just the invading disease-causing pathogen.  Scaling the immune response is therefore a safer option, and we know that is what happens. Until now, however, no one had suggested how the body does that.”

They hypothesise that the scale of the T-cell response to an infection could be mediated through their interactions with dendritic cells. Several studies have shown that T-cells slow down and accumulate around dendritic cells when an infection is severe, i.e. their interaction length is prolonged.  The authors discuss the reasons why they think this interaction length may be the key factor in determining immune response severity.

Read the press release

Read the full article: Mayya & Dustin 2016 Trends in Immunology 37 513–522 doi: http://dx.doi.org/10.1016/j.it.2016.06.005


New therapeutic target for autoimmune diseases

New research, published in Scientific Reports, has discovered a potential novel strategy to treat a variety of autoimmune diseases, such as multiple sclerosis or psoriasis. Dimethyl fumarate is a drug that is known to be effective against a variety of autoimmune diseases because of its anti-inflammatory properties.  However, its molecular target and mode of action were not known until now.

Through a combination of in vitro and in vivo studies, researchers from the University of Dundee led by BSI member Dr Simon Arthur found that dimethyl fumarate targets the actions of a particular group of enzymes in the body called E2s, some members of which are active in inducing inflammation. “This suggests that more selective inhibitors of E2s may be well tolerated and validates these enzymes as targets for future drug development,” commented Dr Arthur.

Read the press release

Read the full article: McGuire et al. 2016 Scientific Reports doi: 10.1038/srep31159

Image credits: ViSNE plot of immature T-cells in the thymus – University of Birmingham; T lymphocyte – NIAID

The fight against yellow fever

Yellow fever virusLast week, the World Health Organization (WHO) reported one of its largest emergency vaccination campaigns for the yellow fever virus in Africa – in Angola in southern Africa and its northern neighbour, the Democratic Republic of Congo. The outbreak has already claimed more than 400 lives and sickened thousands more.

This is also the first time such a large outbreak of yellow fever has needed to be controlled in densely populated urban regions. Health workers in the region now have the enormous task of vaccinating more than 17 million people before the rainy season starts in September, which presents ideal breeding conditions for the mosquitoes that spread the virus.

The virus

The yellow fever virus is transmitted by two species of mosquitoes of which the main type, Aedes aegypti, thrives in urban environments. Although most people experience either minor symptoms (such as fever, muscle ache and nausea) or none at all, a small minority of those infected go on to enter a second, more toxic disease stage.  This is marked by serious symptoms such as jaundice (yellowing of the skin and whites of the eyes), kidney failure and bleeding from the mouth, nose, eyes or stomach. Up to half of people that experience these more serious symptoms will die.

Great challenges ahead

During the course of the Zika epidemic in South America, labs arounds the world have been in a race to come with an effective vaccine. Yet for the yellow fever virus, a safe and effective vaccine has been available since the 1930s – a single dose or two can protect an individual for the rest of their lives.  In 1951, the Nobel Prize in Medicine or Physiology was given to Max Theiler for the development of the vaccine and so far this remains the only time that a Prize has been awarded for the development of a vaccine.

Projet Amazone Vaccin fièvre jauneHowever, the current global production of yellow fever vaccine can’t sustain the present rate of vaccination needed to give everyone at risk a single dose. This is partly attributed to a year-long laborious process of manufacturing the vaccines in pathogen-free eggs. Since December 2015, 19 million doses of the vaccine has already been given to people in affected areas, and now the global emergency stockpile is critically low with only 5 million doses remaining. Angola alone has a population over 21 million people. Prior to the report of the first outbreak there in December 2015, the country was not considered at risk so most people are not vaccinated. Therefore, the WHO plan to dilute the vaccine fivefold in the hope that it will provide shorter-term protection for 12 months to as many people as possible.

Aside of the logistics from carrying out such mass immunisation programme, there is an added problem of storing the vaccines. Yellow fever vaccines need to be refrigerated with ice packs due to the lack of reliable electricity and sources of fuels for generators.

Clearly having a safe and effective vaccine is only the first step towards combating mosquito borne diseases. With accelerated urbanisation in Africa and the growing emergence of mosquitoes such as Aedes aegypti that thrive in urban environments, the world needs to develop strategies that allow us to monitor and respond quickly and effectively to such disease outbreaks.

Yeping Lu, Communications Intern, British Society for Immunology

Image credits: Yellow fever virus – Sanofi Pasteur/Flickr (CC BY-NC-ND 2.0) ; Yellow fever manufacturing facility in France – Sanofi Pasteur/Flickr (CC BY-NC-ND 2.0)

Immunology update – July 2016

Welcome to the third installment of our new regular monthly slot where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past four weeks.

Genetic link to flu transmission in chickens

ChickenNew work, published in the journal Scientific Reports, shows that some chickens may have genes that significantly reduce their susceptibility to spreading and catching flu. Researchers at the Pirbright Institute, along with colleagues from Francis Crick Institute and University of Oxford, examined two genetically distinct lines of chickens that differ in their susceptibility to catching flu. They found that, within the resistant line, any bird that did catch flu only shed the virus through its respiratory tract for a short period. In comparison susceptible birds shed the virus through their respiratory tract for longer as well as shedding virus through their faeces, a key transmission route for spreading the flu virus within bird populations.

BSI member and lead researcher Dr Colin Butter said, “It is important for us to understand how different genetic lines of birds react to influenza viruses, so that we can begin to understand the spread of the disease. Our results are valuable in emphasising the important role a ‘host’ plays in the spread of avian flu, and also in highlighting a number of factors relating to the chain of infection and control mechanisms which are affected by the route of infection.” The team hope these findings will pave the way for more research into the precise biological mechanisms behind genetic resistance, which may have major implications for poultry breeding, as well as human flu treatments, in the future.

Read the press release

Read the full article: Ruiz-Hernandez et al. 2016 Scientific Reports doi: 10.1038/srep26787

Markers of neutrophil activity may help sepsis diagnosis in severe burn patients

B0004153 White blood cell - polymorphonuclear leuc

The rapid diagnosis of sepsis remains a major challenge in patients with severe burns whose injury may mask many of the classic diagnostic biomarkers.  It is vital that sepsis is diagnosed as quickly as possible as any delay can significantly increase the risk of death. Researchers from the University of Birmingham set out to determine if biomarkers of neutrophil function may be accurate in predicting which patients will go on to develop sepsis.  Writing in the Annals of Surgery, the team studied markers of neutrophil activity and function, a key type of white blood cells which responds to immediate infection threats.  Through studying 62 patients with severe burns, they found that immature granulocyte count, neutrophil phagocytosis and plasma cell free DNA show significant potential as biomarkers.

BSI member and study author Professor Janet Lord said, “Our data showed that immature granulocyte count could accurately discriminate between septic and non-septic patients, even with the complications that systemic inflammatory response syndrome has caused for other potential biomarkers. In addition to this, when we used a combination of two or more of our biomarkers, the discriminatory power was further enhanced.” The team now plan to see if using these markers to decide which patients should receive antibiotics at an earlier stage results in reduced sepsis levels.

Read the press release

Read the full article: Hampson et al. 2016 Annals of Surgery doi: 10.1097/SLA.0000000000001807

How our immune system recognises pathogens

Every antigen receptor is composed of three regions – V (variable), D (diversity) and J (joining) – each of which have multiple versions. The shuffling, or recombination, of these allows the immune system to recognise the vast array of pathogens that it encounters.  Researchers at the Babraham Institute have developed a new technique to study this process called VDJ sequencing (VDJ-seq), a DNA-based next-generation-sequencing technique that quantitatively profiles recombination products.

Writing in Cell Reports, the team used this technique to take a look at the V gene found in an immune cell type in mice. They found that not all V segments were used with the same frequency, implying the involvement of complex regulatory mechanisms with epigenetic features.

“Understanding the VDJ recombination process is important because it is the first determinant of receptor diversity, said BSI member and study author Professor Anne Corcoran. “Having a precise readout of which V, D and J segments are used advances our understanding of the process of recombination and how this is regulated. These findings have implications for immune disorders and aberrant VDJ recombination in cancer.”

Read the press release

Read the full article: Bolland et al. 2016 Cell Reports DOI: http://dx.doi.org/10.1016/j.celrep.2016.05.020

Image credits: Chicken, credit: Steven Turner/Flickr CC-BY 2.0; Credit: University of Edinburgh, Wellcome Images CC BY-NC-ND 2.0

Immunology update – June 2016

Welcome to the second installment of our new regular monthly slot where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past four weeks.

Cancer drugs could target autoimmune disease

Uveitis in mouse eye
Image showing damage caused by uveitis in the untreated mouse eye (left) and the treated eye (right)

Researchers from University College London and King’s College London have examined the effectiveness of using drugs that are currently being trialled in cancer patients to treat autoimmune disease in mice.

Having discovered a genetic ‘key’ (called P-TEFb) that is important in both cancer cell growth and immune cell differentiation, they tested the drugs on a mouse model for uveitis, an incurable eye condition in which the immune system mistakenly attacks healthy tissue leading to inflammation of the uvea (the middle layer of the eye).  Writing in Cell Reports, the team state that they found the condition was significantly less severe in mice given the cancer drugs compared to controls.

BSI member Dr Richard Jenner from UCL explains, “Blocking this genetic key, called P-TEFb, prevents the immune system from mobilising such an aggressive response.  P-TEFb is important for a lot of cellular processes, and drives uncontrolled growth in cancer cells. A variety of drugs that target this pathway are currently undergoing trials for a range of cancers, and we hope to adapt these to target autoimmune conditions in future.”

Read the press release

Read the full article: Hertweck et al. 2016 Cell Reports DOI: http://dx.doi.org/10.1016/j.celrep.2016.05.054


Calcium channel blocker may be effective therapy against fungal disease

CryptococcusThe fungus Cryptococcosis neoformans is found throughout the world. People can become infected with it through breathing in its spores; however, generally the fungus only causes disease in those with weakened immune systems, in particular people with HIV/AIDS.  It is a difficult disease to treat as the fungus hides inside the patient’s own white blood cells.

Researchers from the University of Birmingham have discovered that a drug more commonly used for the treatment of angina may be an effective agent against cryptococcosis infection.  Through in vitro studies, they found that, instead of targeting the fungus directly, the drug (a calcium channel blocker called fendiline hydrochloride) stimulates the white blood cells to fight the disease more effectively. BSI member and lead researcher Professor Robin May explained, “Fungi are intrinsically more difficult to target than bacteria, because they are much more closely related, evolutionarily, to humans. Finding an essential pathway in a fungus that you could inhibit, which doesn’t exist in humans, is very difficult. Therefore the approach of stimulating your own immune system to kill the fungus, instead of killing it directly through treatment, is potentially more powerful.”

Whilst this work is still at an early stage, it shows the potential of using calcium channel blockers to target immune system activity to combat this type of disease. The work was reported in the International Journal of Antimicrobial Agents.

Read the press release

Read the full article: Samantaray et al. 2016 International Journal of Antimicrobial Agents DOI: http://dx.doi.org/10.1016/j.ijantimicag.2016.04.018


Immune system activity linked to likelihood of heart attack

Researchers from Imperial College London and University College London have found that people who have higher levels of IgG antibodies in their blood have a lower overall risk of heart attack.

Current tools used to assess cardiovascular risk are relatively imprecise. Writing in the journal EBioMedicine, the team set out to examine whether levels of different types of antibodies were correlated with the risk of adverse cardiac events.  They found that, in patients with hypertension, the total IgG serum level was independently associated with risk of coronary heart disease events.  IgG serum levels also came out as being a better predictor of who was most at risk of having a heart attack than the current methods used.

BSI member, Professor Dorian Haskard, co-senior author and BHF Professor at Imperial College London, said, “These very interesting findings linking the immune system to protection from heart disease have grown out of years of previous research funded by the British Heart Foundation. The study focused on patients under treatment for high blood pressure, and we now need to know if the link also applies to other groups at risk.”

Read the press release

Read the full article: Khamis et al. 2016 EBioMedicine doi:10.1016/j.ebiom.2016.06.012

Image credits: Uveitis in mouse eye  – (c) Hertweck et al. 2016 Cell Reports DOI: http://dx.doi.org/10.1016/j.celrep.2016.05.054Cryptococcus –  (c) Wikimedia Commons/Nephron

Polio vaccination: real world challenges and solutions

Girl receiving oral polio vaccineTo what ends will a health worker go in order to reach children who need protection from disease? Volunteers walk miles, often barefoot, across rocky terrain and over rivers, often to reach just four families with a cooler bag containing precious shots of polio vaccine.  I learned about the work of these vital health professionals who vaccinate in remote, mountainous regions when I visited the Bill and Melinda Gates Foundation in Seattle recently, for a meeting which brought together different groups to talk under the theme of ‘taking risks’.

Real world challenges

One speaker was Ananda Bandyopadhay, ‘epidemiologist and polio eradication foot soldier’ according to his Twitter handle, who is also one of the Foundation’s senior program officers.  “It isn’t a vaccine that matters in the real world – what matters is the vaccination.  A vaccine in a vial, sealed off, is zero percent effective.  The challenge is reaching people,” he stated, showing a slide of an 80-year-old female volunteer walking with some determination through mud in an Afghan village to reach two young children who needed a polio vaccination.

Polio (wild virus) incidence according to WHO’s Case Count, 19/08/15. Yellow = 1-10, orange = 21-30 confirmed cases

From a worldwide tally of 350,000 polio cases in more than 125 countries in 1988, the map has now shrunk to two countries, Pakistan and Afghanistan, where the wild strains of the polio virus still exist.  There were just 74 cases reported last year.   This represents a tremendous step forward, but if we want to eradicate polio for good, it’s vital to keep up the momentum of the vaccination programme to stop any resurgence of this highly infectious disease.  But this is not easy. Apart from the geographical challenges of mountains and floods, the threat comes from groups who for religious reasons do not want to see families vaccinated.  “I never imagined I would see a situation where health workers are killed because they are going out to protect children,” said Bandyopadhay.

Some of the volunteers demonstrate immense resilience in reaching these remote communities, so do the planners, the monitoring staff and the logistics teams.  The world is so tantalisingly close to seeing the eradication of polio for good, but there is still more to do.  The positive news is that the global surveillance system, based on unparalleled partnership working, which was set up to fight polio has had a long lasting impact,  with some of the lessons learnt now being used to combat the Zika virus, and to control measles outbreaks.

Role of the Gates Foundation

So partnership in polio has been about overcoming seeming insurmountable barriers – geographical, political, financial, scientific.  I met the Gates Foundation’s CEO, Sue Desmond-Hellman, a former cancer physician and biotechnology leader, who spoke about how they deal with the setbacks and frustrations of advances not coming as quickly as they would always want.  She has just taken the step of publishing a letter which sets out the organisation’s successes and failures, in a move designed to help open up the work of the Foundation to a wider audience amid concern that sometimes there is ‘fuzziness’ around its aims.

The Gates Foundation, with its $40 billion fund, has the financial and political clout to bring people together, but as Desmond-Hellman points out, “in-country partners are critical to creating and demonstrating innovative approaches that are grounded in local realities.”  During my two days at the Foundation, I heard the staff talk a lot about the ‘real world’ and the fact that their aspirations can be quickly bogged down by inertia and a lack of understanding.  Desmond-Hellman said she had learned a lot about the essential importance of the supply chain. “The critical factor is that our partners have the capability to implement a supply chain effectively and the more that we can be clear about this capability need, the better the partnership will be,” she explained.  But as she puts it, solving problems takes time and capacity building is slow work, so their slogan of being ‘impatient optimists’ sometimes means the impatience will grow because the ‘real world’ cannot allow things to happen.

The global view

Last week saw members of the World Health Assembly meet to discuss the latest evidence regarding polio eradication.   As Dr Margaret Chan, Director General of the World Health Organization, said, “We have never been so close. During a fortnight in April this year, 155 countries successfully switched from trivalent to bivalent oral polio vaccine, which protects against the two remaining wild strains (type 1 and 3), making this the largest coordinated vaccine withdrawal in history. I thank you and your country teams for this marvellous feat.”

In our work at the British Society for Immunology, we do much to support those researchers working to understand immune responses and push back the barriers to vaccine development, but we should also celebrate those out in the field working to deliver the vials.

Jo Revill, Chief Executive, British Society for Immunology

If you have any thoughts on this article, please leave a comment or email media@immunology.org.

Images: Girl receiving oral polio vaccine (C) CDC Global; World map (C) Pazuzupa/Wikimedia Commons

Immunology update – May 2016

Welcome to our new regular monthly slot where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past four weeks.

Differences in individuals’ immune responses linked to flu vaccine effectiveness

Colorized transmission electron micrograph of negatively stained SW31 (swine strain) influenza virus particles.

Scientists aiming to develop a method to predict who will and won’t respond optimally to the seasonal flu vaccine have identified key differences in individuals’ immune responses.

Researchers, led by Dr Gregory Poland and Dr Richard Kennedy from the Mayo Clinic, set out to examine how differences in an individual’s immune cells correlate to their response to the seasonal flu vaccine. They found that there was a significant difference in response to the flu vaccine between individuals.  People who had a better antibody response to the vaccine after 28 days had higher levels of HLA-DR (a cell surface protein which is a marker for immune stimulation) on a specialised type of dendritic cell.  Prior to vaccination, these people also had more B cells in their blood with more CD86 (a cell surface protein that allows the immune system to be activated quickly in response to a threat).

“Ultimately, we hope that increasing our understating of how the immune system functions at a cellular level will allow us to develop more effective vaccines,” commented Dr Poland.

Read the press release

Read the full article: Kennedy et al. 2016. Immunology doi: 10.1111/imm.12599


Do pathogens cause type 1 diabetes?

Pancreatic beta cellsType 1 diabetes is an autoimmune condition where the insulin-producing beta cells of pancreas are destroyed, leading to the need for life-long insulin replacement.  Killer T-cells have previously been implicated as playing a major part in initiating this destruction of beta cells – however, it is as yet unclear what the triggers to this case of mistaken identity might be.  Now BSI members Dr David Cole and Professor Andy Sewell from Cardiff University have used the Diamond Light Source to shine powerful x-rays into isolated killer T-cells from a patient with type 1 diabetes to elucidate what makes these cells go rogue and destroy beta cells.

They found that these killer T-cells are highly ‘cross-reactive’, and respond to a variety of pathogen-derived antigens, which could lead to the breaking of self-tolerance and to the development of autoimmune disease, such as type 1 diabetes. Dr Cole commented, “We identified part of a bug that turns on killer T-cells so they latch onto beta cells. This finding sheds new light on how these killer T-cells are turned into rogues, leading to the development of type 1 diabetes.”

The team hope that this increase of our understanding into the mechanisms behind the development of type 1 diabetes will eventually lead to new ways to diagnose, prevent or treat type 1 diabetes.

Read the press release

Read the full article: Cole et al. 2016. Journal of Clinical Investigation 126 2191–2204. doi:10.1172/JCI85679.


The importance of resting phases in B cell development

B lymphocyte cellResearchers from the Babraham Institute have discovered a new mechanism used by B cells to rest up between developmental events.  B cells, which manufacture antibodies and are key players in our adaptive immune response, need to undergo several developmental stages before reaching maturity.

Writing in Science, the team found two RNA binding proteins, ZFP36L1 and ZFP36L2, are key in dictating the timings of these stages.  Both of these proteins were found to promote cell quiescence by blocking other RNA messages that instruct the cell to start dividing.  Mice without these proteins saw a 98% reduction in the number of mature B cells they possessed.

BSI member and senior author, Dr Martin Turner, said, “Our findings shed light on the intricate control and coordination of the cell cycle and show that these binding proteins probably form part of a common mechanism to regulate quiescence, not just one specific to developing B cells.”

Read the press release

Read the full article: Galloway et al. 2016. Science 352 453–459 doi:10.1126/science.aad5978

Image credits: Swine flu virus – (C) NIAID; Pancreatic beta cells – (C) Furcifer paradalis on Flickr via CC 2.0; B lymphocyte – (C) Blausen gallery 2014. Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762

Better experimental design through statistics

White mouse in gloved handFor my birthday, I want to go to a seminar about the better use of statistics in animal experiments, said no 9 year old, ever. However, add 30 years and there I was. So why, instead of going to the zoo, was I at a stats seminar?

The fault in our p’s

There is increasingly recognised to be a problem with reproducibility in all areas of biological research. This is a particular issue when it comes to studies using animals. Poor reproducibility has contributed to a failure to turn pre-clinical discovery studies into successful medicines. There are a number of causes of this problem, including unreliable research reagents, confirmation bias and the flawed use of statistics, a lot of which can be overcome with better experimental design, in particular better stats. As best I understand it (and I am not a statistician), using p<0.05 means that 1 in 20 studies is ‘significant’ by chance and therefore we see results as positive when they are not. Due to some complicated statistical sleight of hand involving alpha, beta and normal distributions, it could be the case that as much as 60% of significant results are in fact untrue (though it would be better to follow some actual statisticians to check how this works).

Times are a changin’

But why should you care? It is/ought to be a given that we should all do better science. However career pressures – the need to publish positive results in glossy journals may lead to practices that are not in line with best scientific practice. This can lead to a number of tricks that are used consciously or unconsciously to make a more positive story – p-hacking, HARKing (hypothesising after the results are known) etc. However publishing is not the only career pressure; we all need to bring in grant funding. Both the UK and US funders are using this as a tool to change research practice. The funders have updated their guidance (for example, the MRC and NC3Rs) to ensure more rigour in experimental design in grant applications.

Je-S kidding

In 2012, an assessment by review board members about the quality of the justification for animals in research found that the reason for animal usage and selection of species was ok, but the statistical justification was either absent or plain wrong. It used to be that grants could be awarded conditionally, subject to amendment if there were issues with the statistics.  As of next year, grants can be rejected if the quality of the justification of animal usage is not good enough, without the opportunity to amend the application post award. Let me repeat that, because we are all inclined to spend 90+% of effort in perfecting the case for support and then fill the rest of the form out in a mad dash. Grants may be rejected, without a chance to amend post-award, if the case for animals is poor. Stating ‘We did this because we always have,’ won’t cut it anymore.

Get it right

Desk and computerWhat follows are some steps that can help you improve the stats part of the justification for animal usage. Obviously this will not automatically get you funding – if it did, I’d be unlikely to share it, would I. But hopefully it will help you frame your application in a clearer way. NB, don’t spend all your word count on the stats, you still need a case for animal usage/species etc.

Step 1 – PICO. Put a single sentence at the beginning of the animal justification explaining in brief what you are aiming to do. Try using PICO: P (population) – to who, I (intervention) – what will you do, C (control) – what will you compare against, O (outcome). Consider your unit of measurement, e.g. 100 sections from a single liver is still n=1.

Step 2 – describe the effect size. What is the biological effect you are looking for, ideally in a human? This should be drawn from your own experience of the disease area. One of the speakers made the very good point that a positive outcome in animal studies is seldom the actual endpoint we are interested in, i.e. human disease. Think about what a real world biologically significant effect would be and justify why that would be important in a patient. This should be informed by your expertise in the area. An example using blood pressure – 160mm is bad, 120mm is good, the ‘effect size’ of a blockbuster drug would be a 40mm drop in blood pressure. (Effect size can be modified by variability – but use a stats package or check with a statistician).

Step 3 – Using your real world effect size, perform a power calculation. Power calculations enable you to give an actual value for the number of animals needed for each study that will lead to real, reproducible results. ‘We use n=6 because everyone else does’ or ‘We use n=5 because that’s how many fit in a cage’ apparently is not good enough. There are four main elements for a power calculation: you need to state all four, and justify why. The four parts are – level of type 1 error (false positives, α or p value normally 0.05), level of type 2 error (false negatives, β normally 20%), the effect you are looking for (see above) and variability (this has to be based on real world data – yours or from literature). There are lots of stats packages that once you have this info can work out the power for you, this one works.

Step 4 – How will you reduce unconscious bias? Use the ARRIVE guidelines as a checklist, try the NC3Rs Experimental Design Assistant. Think about how you will blind, normalise, randomise etc. There are some worked examples on the MRC site which might help.

Step 5 – GET ADVICE FROM A STATISTICIAN. Did I mention I am not a statistician? If you are reading this as your sole guidance you are in trouble! There are multiple caveats with the approach I have suggested: it is clearly not going to work for all cases, discovery science/ hypothesis-free work will need other approaches, multiple time points and repeated sampling change the weighting of the p value (think multiple coin tosses – the chances of six heads is the same as the chance of H,T,T,T,H,H). Since most programs of work are complex and multi-endpoint it is not possible to do a detailed power calculation for each part, one approach would be to do the analysis for the major arm of the work to demonstrate you know what you are doing.

On the whole my birthday trip to the stats seminar was, surprisingly, much better than a trip to the zoo (then again I don’t really like zoos that much). It was very thought provoking about improving experimental design and a step towards better more reproducible science as a community.

The seminar was organised by the NC3Rs and MRC, but I am writing on my own behalf and the opinions stated here are mine.

John Tregoning

John Tregoning studies the immune response to respiratory viral infections. He has been a PI since 2008 and is a Senior Lecturer at Imperial College London. You can read more of his writing here or follow him on Twitter at @DrTregoning.


Further reading

Academy of Medical Sciences 2015 Reproducibility and reliability of biomedical research: improving research practice.

Percie du Sert N 2016 Improving the design of animal experiments: the Experimental Design Assistant. Immunology News, March 2016, 24.

Gut feeling

E coli bacteria

This April, the British Society for Immunology supported the event ‘Gut Feeling’ at the Edinburgh International Science Festival through our Communicating Immunology grant scheme.  Here, event chair Adam Hart tells us more about the session and why bacteria can be a useful science communication tool.

Bacteria are sometimes considered a hard-sell in the world of science communication and it must be said this is not without reason. The list of things working against them is considerable: they are very small; they lack charisma (I’m sorry, but they do); some of them cause some pretty horrific diseases; and they aren’t particularly visually appealing. Whilst all these things are true to some extent, we should not give up hope. The key to engaging people with bacteria in my opinion is to major on just how good they are at doing ‘bacterial things’, just how neat many of those things are, and just how important bacteria are to pretty much everything on the planet. And of course, appealing to an audience’s natural sense of introspection doesn’t hurt. There’s nothing like the realisation that something directly affects your health and well-being to make you pay attention.

The gut microbiota revolution that has been fomenting, and fermenting for that matter, for the last few years is exactly what’s been needed to turn people on to the wonders of the prokaryotic world. Following up on a successful Cheltenham Science Festival event, I found myself at the Edinburgh International Science Festival in April to chair a session focussing on gut bacteria and their relationships with our health, supported by the BSI’s Communicating Immunology grant scheme. As in Cheltenham, the main speakers were Professor Fiona Powrie and Dr Lindsay Hall and once again the event was a sell-out.

Lindsay kicked off proceedings with a brilliant exposition of bacterial biology in general and the human microbiota in particular. With a simple but clever demonstration involving 3 kilograms of sugar and some hastily bought trays (thank you Argos), the smallness and abundance of our bacterial passengers were brought to life. A variety of plates from a willing volunteer back at Lindsay’s lab allowed the audience to see first-hand some bacterial colonies and to appreciate the human body as a complex, structured and surprising ecosystem. Many people, even those attending science festival events, have a limited knowledge of bacteria and Lindsay’s whistle-stop tour of both the basics and the cutting edge (not-yet-for-sale sequencers the size of a pen drive anyone?) brought everyone up to speed in a lively and engaging way.

Fiona then took up the reins, delving into the relationships between our gut microbiota and our immune system. With a careful mix of facts, cartoons and analogies Fiona guided a receptive audience through a frankly remarkable maze of connections and complexity. As well as inflammatory bowel disease and other inflammation-linked conditions, Fiona introduced us to the latest ideas on the relationships between microbiota, immunity and cancer. Throw in a little obesity and mental health and the audience were left in no doubt as to the scope and range of the work currently being undertaken.

A packed audience in Edinburgh

Events such as these can often stand or fall on the quality of audience participation. Having had an incredibly enthusiastic crowd in Cheltenham I had requested, and got, a 90-minute slot for ‘Gut Feeling’, with the last 30 minutes reserved solely for audience questions. The audience did not disappoint, with a host of fascinating and insightful questions exploring diet, faecal transplants, probiotics, antibiotics and the next 5–10 years of research among many other topics.

What events such as ‘Gut Feeling’ show is that with the right platform bacteria allow you to smuggle an awful lot of science in to your science communication activities! As well as bacteriology we covered, albeit not always with equal depth, immunology, anatomy, oncology, ecology, neurology, digestion, endocrinology, histology and histopathology. Bacteria might not have the immediate charisma of, say, meerkats or honeybees, but they certainly make up for it in surprising and interesting science.

Adam Hart, Professor of Science Communication, University of Gloucestershire

Adam is author of the book ‘The Life of Poo’.

More information on the BSI’s Communicating Immunology grants is available on our website.

Image credits: E.coli bacteria from NIAID (CC-BY-2.0); audience image © Adam Hart