Populations within populations: drug resistance and malaria control

Image design: Serial/Trash

Malaria claims a million lives a year, a majority of which are children, and threatens the lives of billions more within its tropical ranges. It is caused by Plasmodium, a parasite that uses mosquitoes as a way of getting in to and out of humans. Initial infection from the bite of a carrier mosquito is followed by the parasite’s massive proliferation and colonisation of the host’s blood, causing a suite of debilitating symptoms and providing a parasitized food source for the next mosquito. In the absence of a vaccine, prevention and treatment remain our only effective weapons against malaria. Today, the most effective treatment regime relies heavily on artemisinin, a compound from an Asian herb that effectively targets the parasite within red blood cells. But, as was the case for previous anti-malarial drugs, the spectre of artemisinin-resistant Plasmodium strains is rising. Worryingly, as there is currently no clear fall back to artemisinin, a global spread of resistance will seriously harm our ability to tackle the disease.

The research of Miotto, et al. was stimulated by the observation that resistance to artemisinin, and indeed some of its forebear drugs, appears to originate in the same part of the world: the remote mountains of western Cambodia. To tackle the question of why drug resistance originates here, the researchers sought clues within the parasite’s genome. They had previously developed a technique to isolate Plasmodium DNA directly from the blood of infected patients: a blood sample is taken, white blood cells removed (this removes a lot of the human DNA content which can complicate analysis), and DNA extracted and sequenced using modern sequencing technology. For this work they do not require the parasite genome sequenced in its entirety; rather, they seek sufficient coverage to allow reliable identification of variability between samples.

The researchers collected samples from infected patients in west Africa and southeast Asia, including four sites in Cambodia, one in the east and three in the west. A global survey of the genetic data revealed that the Asian and African populations have distinct patterns of genetic variation, consistent with their geographical isolation. Within the Asian sample, the story was a little more complex. Samples from western Cambodia were notably distinct from those in eastern Cambodia and Thailand. The western Cambodian populations were also ‘structured’, that is, the population was split into subpopulations, each with their own distinct genetic signatures. The subpopulations were also relatively inbred, lacking in genetic diversity, which is often a signature of a recent expansion from a small, homogenous population. Crucially, the researchers were able to show that the subpopulations that predominate in western Cambodia showed artemisinin resistance, as infected patients responded poorly to treatment. Thus, while the distinct subpopulations of Plasmodium in western Cambodia are genetically distinct, they present the same problem: artemisinin resistance.

Image Source: Shutterstock Copyright: GuoZhongHua

The beauty of these kinds of genomic studies is that as well as just looking at the variation between groups accross the genome, on a global scale, we can zoom in and focus on the individually varying regions to ask whether these parts do anything relevant. The researchers made the important observation that the western Cambodian subpopulations harbour a number of genetic changes associated with drug resistance, including alterations to genes which control the entrance of molecules into the cell. One of the subpopulations even harboured mutations in genes involved in preventing mutations, raising the intriguing possibility that a general increase in mutability of the genome may provide more drug resistance mutations.

Identifying the source of emerging drug resistance, both in terms of geography and underlying genetic causation, is a critical task if we are to control its spread. Hence the importance of this work for malaria control. The fact that there are multiple, independent artemisinin-resistant subpopulations shows that there are many routes for a parasite to become resistant. In practical terms the genetic signatures within the resistant strains can be used as biomarkers for artemisinin resistance in any sample of Plasmodium DNA, allowing health authorities to monitor its spread. Furthermore these genetic signatures will add to our biological understanding of how the parasites evolve to resist the drug.

We are still however left with our opening question: why Cambodia, specifically why Western Cambodia? The authors propose a number of potential contributory factors, including the potential higher mutation rate, heavy use of drugs and local isolation of the populations (favouring inbreeding) due to the remoteness of the region. General features of host-parasite interactions are thus married with particularities of the region to provide a potent reservoir of drug resistance. Whatever the underlying causes, the next imminent step will be containment of these variants to prevent their global spread.

This summary by Aidan Maartens was shortlisted for Access to Understanding 2014 and was awarded third prize. It describes research published in the following article, selected for inclusion in the competition by the Wellcome Trust:

Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

PMCID: PMC23624527

O. Miotto, J. Almagro-Garcia, M. Manske, B. MacInnis, S. Campino, K. A. Rockett, ... D. P. Kwiatkowski.

Nature Genetics (2013) 45(6), 648-655.

Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2014 there were 10 articles to choose from, selected by the Europe PMC funders. The articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.

Look out here and on Twitter @EuropePMC_news for further competition news and other Europe PMC announcements.   

A night at the Oscars

By Aidan Maartens, Post-doc student at the Gurdon Institute 

Note: Aidan was awarded third place in this year's Access to Understanding competition. Check back tomorrow to read his winning entry! Congratulations Aidan!

It ended in a pub with a group of us - some entrants, some science-communications people, and one of the judges of the competition - struggling to hear each other over the pub quiz in the background. It had started a couple of hours beforehand, in a reception hall slowly filling up with guests and a rising swell of echoing conversations. We were ushered in to the lecture hall, and a few talks later the awards were announced, photos taken, hands shaken, and conversations had with a bunch of nice people who were in some way linked to the competition. Someone jokingly described it as the science writing Oscars; the pub trip was, then, the glamorous after-party.

Aidan after receiving his award from Sir Mark Walport. 

My motivations to enter Access to Understanding are probably common to most of the applicants: we get some sort of pleasure from writing, and like the chance to get out of the bubble of day to day research while still doing something connected to science. The articles on offer were in a way typical scientific papers, not the blockbuster, creating-synthetic-life or finding-the-Higgs-boson type papers. This is not to denigrate them at all, rather to say that they were more representative of the incremental nature of much scientific progress. The upshot was that writing a summary was a little more challenging, as the message and impact of the work was a bit more nuanced.

I would recommend this sort of competition to other scientists for a number of reasons. Even if you don’t particularly like writing, it’s a good skill to practice. You might even get to learn something new - for me, how next generation sequencing was revolutionizing the way scientists understand drug resistance in malaria. Finally, it lets you, for a few hours at least, get away from your own project and use another part of your brain. Perhaps you’ll get a new perspective on your project when you get back to it.

Beat box: How the brain processes rhythm

Image Source: Serial/Trash

People have little trouble recognising and following the beat in a piece of music. We can even continue to play the beat in our minds once a song has finished. However, despite the ease with which we carry out such a task, the brain activity which underpins it remains a topic of investigation.

Finding the beat – why does it matter?

We’re all familiar with the niggling irritation of a song that’s stuck in our heads. However, few of us are aware that our knack for holding a beat in our thoughts actually makes life easier. The capacity to identify patterns in streams of sound supports many forms of human behaviour, including moving, speaking and listening. 

If the ability to generate this internal rhythm is disrupted, such as in Parkinson’s disease, problems begin to arise. People with Parkinson’s disease have difficulty with psychological tasks, such as holding a beat in their minds, as well as with practical tasks, such as walking. The more we know about the regions of the brain that are causing these difficulties, the more effective we will be in designing treatments to combat them. Previous research suggests that a set of brain structures known as the basal ganglia are involved in identifying and following a beat.

What are the basal ganglia?

The basal ganglia are a network of brain regions that are involved in movement and action. Many of the regions within the basal ganglia appear to play a role in the processing of rhythm. One such region is the putamen, a round structure near the centre of the brain. Studies measuring levels of brain activity have found that the putamen is active when a person is listening to a beat. However, it is not clear whether the putamen is merely identifying the presence of the beat, or whether it is actually helping us to recreate that beat in our minds.

How can we tell what the putamen is doing?

Jessica Grahn and James Rowe designed a study which allowed them to distinguish between these two possibilities. They began their work by creating small snippets of sound. Some of the sound-bites contained a beat, while others did not. These ‘non beat’ sound-bites involved sounds which were not arranged in any rhythmic order. The researchers then combined the order of the sound-bites to create different sequences. These sequences fell into one of four key groups: (1) no beat, (sequences with no beat present), (2) new beat, (sequences in which participants heard a non beat followed by a beat), (3) beat continuation, (sequences with two versions of the same beat), and

(4) beat adjustment, (sequences where the original beat got faster or slower).

The researchers asked the participants to listen to the different sequences whilst a scanner measured how their brain responded. In order to measure this brain activity, they used functional magnetic resonance imaging, often know as fMRI. This is a form of brain imaging that allows us to see which regions of the brain are involved in which tasks. It does this by measuring the amount of oxygen that a specific brain region is using relative to other regions. If a region is using a lot of oxygen, it suggests that the region is ‘active’, that is, it’s involved in carrying out the task.

Image Source: Shutterstock Copyright: GrandeDuc

What did the researchers find?

They found that the putamen responded differently to different beat sequences. When there was no beat, the putamen wasn’t active. Similarly, when participants heard a new beat, the putamen didn’t respond. By contrast, when participants heard the same beat twice, the putamen was highly active. It was also active, but to a lesser extent, when the sequence involved the same beat played at different speeds.

These results suggest that the putamen was not responding to the presence of a beat per se, but was processing the continuation of the beat across the sequence. This supports the theory that the putamen is involved in our ability to recreate a beat in our minds.

Why is this important?

Prior to this study, researchers knew that the putamen was related to beat processing, but they didn’t know what its specific role was. This study showed that the putamen is important for the mental generation of a beat.

In addition to advancing our knowledge of the putamen’s role in beat processing, these findings have notable clinical implications. People with Parkinson’s disease are capable of identifying a beat in a piece of music, but have difficulty when it comes to reproducing the beat in their own minds. The research shows that this pattern of symptoms could be caused by damage to the putamen. Consequently, it highlights the necessity of focusing on the putamen as a target for future treatment of Parkinson’s disease.

This summary by Elizabeth Kirkham was shortlisted for Access to Understanding 2014 and was awarded first place. It describes research published in the following article, selected for inclusion in the competition by the Medical Research Council:

Finding and feeling the musical beat: Striatal dissociations between detection and prediction of regularity

PMCID: PMC3593578

J.A. Grahn & J.B. Rowe.

Cerebral Cortex (2013) 23(4), 913-921.

Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2014 there were 10 articles to choose from, selected by the Europe PMC funders. The articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.

Look out here and on Twitter @EuropePMC_news for further competition news and other Europe PMC announcements.   

"Can you read my mind?"

By Elizabeth Kirkham, PhD student at the University of Sheffield

Note: Elizabeth was the winner of this year's Access to Understanding competition. Check back tomorrow to read her winning entry! It has also been published by eLife. Congratulations Elizabeth!

My background is in psychology, which means that over the years I’ve learned to steel myself against the inevitable question: “Can you read my mind?” Unfortunately, my ability to produce a witty reply is only slightly better than my ability to read minds, so an awkward pause is pretty much the best my questioner can hope for. Undoubtedly many of those asking this question are joking (though I can’t be sure, I can’t read their minds). Nevertheless, when the first thing that people associate with psychology is something psychologists can’t actually do, it’s clear that something needs to change.

This change won’t materialise unless the wider public see what it is we really do all day. Open access publications, which allow people to read papers without a subscription fee or one off payment, are a great start to making science more accessible to everybody. However, the presence of jargon can make these publications difficult to follow – even scientists within the same broad field can struggle to understand the terms used in their colleagues’ publications. 

Scientific knowledge is advancing rapidly, fueled by the advent of new technologies. Research as a discipline is also progressing, having undergone fundamental changes over the past two decades.  Thanks to these developments, the previously arduous process of searching for information has been condensed into seconds; instead of skimming through pages and pages of books and journals, we can find hundreds of relevant articles merely by pressing a few keys. Scientific research is expanding. Findings are no longer hidden within the walls of universities and libraries, but accessible to millions of people around the world.

However, finding information and comprehending its meaning are often two very different things. This theme was at the heart of the Access to Understanding ceremony 2014. The speeches given by Sir Mark Walport (Chief Scientific Advisor to the Government) and Sharmila Nebhrajani (CEO of AMRC and chair of judging panel), among others, highlighted the need for more people who can translate research articles into accessible language. Additionally, we as scientists can make our research available to a wider audience, by working on plain English summaries and clear explanations of our findings. My own field, Cognitive Neuroscience, is only a few decades old, but has already facilitated huge leaps forward in our understanding of the human brain. That said, expanding knowledge within the academic community is one thing, translating it into real change is quite another.

Elizabeth Kirkham receives her first place award

from Sir Mark Walport, 24 March 2014

I hope that initiatives like Access to Understanding will continue in their endeavours to make science accessible to a broader audience. The power of scientific discovery should not be stifled by an inability to communicate its relevance beyond the laboratory. Perhaps wider communication could also save future generations of psychologists from having to answer that dreaded question. After all, even if we could read minds, we’d never get the ethical approval to do so.

Can a garbage strike in nerve cells cause Parkinson's disease?

Image design: Serial/Trash

New research challenges common beliefs about the origin of the disease and draws attention to the nerve cells’ ability to tidy up.

Parkinson’s disease is a devastating neurological disorder where nerve cells in the brain slowly degenerate and die. The disease especially affects a certain type of nerve cell, the dopaminergic nerve cells, which are located in a small area of the brain called the substantia nigra. The dopaminergic nerve cells here are very important for motor function and as the number of nerve cells decrease, the patients are affected by debilitating tremors and mobility problems. Actor and Parkinson’s patient Michael J. Fox describes it “like having a 4-year-old child climbing around on your lap all the time, pulling on your arms and legs.”¹

Despite many years of research the exact cause of Parkinson’s disease is still unknown. One thing we know for certain is that the dopaminergic nerve cells build-up clumps of protein and leftover material, called Lewy bodies. The major component of Lewy bodies is a-synuclein, a protein therefore thought to be a primary causative factor for Parkinson’s disease. The fact that mutations in the a-synuclein gene increase the risk of developing Parkinson’s disease supports this theory.

Garbage disposal and power plants

Another suspect thought to play a role in Parkinson’s disease is the proteasome; a big protein complex, which is part of the cells “garbage disposal” system and can degrade non-functional proteins.

If unusable proteins are not disposed of, they clutter up the nerve cell and can form so-called pale bodies. These are small precursors of Lewy bodies.

Pale bodies and Lewy bodies are actually thought to protect the nerve cell by gathering the non-functional proteins in areas where they cannot disturb important processes in the nerve cell – akin to hiding your mess in the closet to prevent it from cluttering up your room. It is, however, only a temporary solution and eventually the nerve cells die.

A third culprit is the mitochondria; the cell’s power plants, which have numerous functions including production of energy from glucose. Extensive research points to dysfunctional mitochondria as a major contributor to Parkinson’s disease. For one thing, worn-out mitochondria are a large component of pale bodies.

Image Source: Shutterstock Copyright: Mopic

Modified mice

To investigate the interaction between a-synuclein, proteasomes and mitochondria researchers from the University of Nottingham used genetically modified mice. The DNA of the mice was changed so that certain genes were not expressed. This allowed the researchers to evaluate the exact effect of the proteins that the genes encoded. The research group had previously developed mice, which could not produce the most commonly used form of proteasomes, the 26S proteasomes, in their dopaminergic nerve cells. The garbage disposal system in these mice therefore did not work properly and they quickly developed extensive nerve cell death and pale bodies comparable to the ones seen in Parkinson’s patients.

The research group then set out to explore the importance of a-synuclein in this process. They did this by modifying the mice further, to obtain mice that in addition could not produce a-synuclein. This made it possible for them to compare the mice that lacked both 26S proteasomes and a-synuclein with the mice that only lacked 26S proteasomes. Surprisingly they found no differences: both type of mice showed equal amounts of nerve cell death and pale bodies. Since a-synuclein is thought to be essential to this process, the predicted outcome would be that the mice lacking a-synuclein are less affected and have lower amounts of pale bodies. This however is not the case.

In addition to looking at the amount of pale bodies, they also examined the content of the pale bodies and found it to be the same with or without a-synuclein. As expected they found the main component of the pale bodies to be the third suspected contributor to Parkinson’s disease: mitochondria. This points to a link between inefficient proteasomes and lacking disposal of worn-out mitochondria.

The role of a-synuclein

The surprising conclusion of this study is that a-synuclein is not essential for the development of pale bodies and that lack of functional proteasomes alone can lead to neurodegeneration in mice. More research is needed to tell if the pale bodies seen in the mice will develop into Lewy bodies and especially, if the results can be transferred to human nerve cells. If they can, it means that researchers studying Parkinson’s disease might have to re-evaluate their whole idea of how the disease originates. Instead of seeing a-synuclein as a primary causative factor, it might just be one of the major contributors along with others like proteasome and mitochondria dysfunction. This is of great importance for understanding the cause of Parkinson’s disease and development of new effective treatments in the future.

1. http://nexneuro.com/2010/02/11/michael-j-foxs-personal-battle/

This summary by Helle Bogetofte was shortlisted for Access to Understanding 2014 and was commended by the competition judges. It describes research published in the following article, selected for inclusion in the competition by Parkinson’s UK:

Pale body-like inclusion formation and neurodegeneration following depletion of 26S proteasomes in mouse brain neurones are independent of α-synuclein

PMCID: PMC3559752

S. M. L. Paine, G. Anderson, K. Bedford, K. Lawler, R. J. Mayer, J. Lowe and L. Bedford.

PLoS One (2013) 8(1), e54711

Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2014 there were 10 articles to choose from, selected by the Europe PMC funders. The articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.

Look out here and on Twitter @EuropePMC_news for further competition news and other Europe PMC announcements.

A night of winners!

Last night marked the Access to Understanding 2014 science-writing competition award ceremony.

At its heart, the competition is a celebration. It celebrates the commitment and enthusiasm of early career researchers to share scientific advances with an interested public audience.  It’s also a celebration that all of the articles that entrants could write about (spanning cancer to neurodegeneration, malaria to arthritis) are freely available from Europe PMC – along with over 2.8 million others. They were put forward by the Europe PMC funders, who each expect their researchers to make their articles freely available, or open access, so that anyone can read them.

©The British Library Board

Of course, access does not always equate to understanding, as research articles often use highly specific technical language. The Access to Understanding competition bridges this gap by encouraging researchers to explain research to a non-specialist audience making it truly accessible. Entries were judged on accurate representation of the research, as well as how easy it was to understand.

We were honoured that Sir Mark Walport (Chief Scientific Advisor to the UK Government) joined us to give a keynote presentation in which he told us how important 'access to understanding' is in his role to advise ministers on often complex and critical scientific issues - it's necessary for him to clearly explain the science 'without changing the message' and it's also important that he gets clear briefings from his many advisors about the areas of science that don't fall into his personal sphere of expertise. Sir Mark then went on to present the awards.

The overall winner of the Access to Understanding 2014 science-writing competition is Elizabeth Kirkham, a PhD student in the Department of Psychology at the University of Sheffield, for her entry, ‘Beat box: how the brain processes rhythm’, explaining the brain structure involved in beat prediction.

Elizabeth Kirkham and Sir Mark Walport ©The British Library Board

Second place was awarded to Elizabeth McAdam, CRUK London Research Institute, for her entry, ‘Reforming rheumatoid arthritis treatment: a step in the right direction’. Third place went to Aidan Maartens, Gurdon Institute, University of Cambridge, for his entry ‘Populations within populations: drug resistance and malaria control’.

As a new element of the competition, entries were opened up to public vote and after collecting votes for nearly a month, Simon Denegri (NIHR’s National Director for Public Participation and Engagement in Research) presented the People’s Choice award to Lucia Aronica, Max F. Perutz Laboratories, for her entry ‘How healthy eating could starve out cancer’.

Left to right: Aidan Maartens, Elizabeth Kirkham, Elizabeth McAdam, Lucia Aronica
©The British Library Board

Six other entrants were commended by the judging panel for writing the best summary of their respective article. All the entries are available to read in the competition booklet. Over the next few weeks these entries will be posted here, and all of them will be permanently associated on Europe PMC with the article about which they were written.

Stay tuned to the blog or twitter for future posts about the competition. 

Thank you to all who entered the Access to Understanding 2014 competition, the judges and those who voted in the People’s Choice award. And big congratulations to this year’s winners!

Europe PMC and the British Library are the partner organisations who bring you the Access to Understanding competition. Read more about the award ceremony on the British Library's Science Team's blog: Access to Understanding Awards 2014: Everyone's a Winner 

By Anna Kinsey and Rebecca Withers

Vote now for Access to Understanding’s first ever People’s Choice Award

We are pleased to announce the launch of our first ever People’s Choice Award for the Access to Understanding science-writing competition! This award gives you - the public - the opportunity to read our shortlisted entries and have your say.

Our entrants rose to the difficult challenge of writing plain English summaries of research articles (all available from Europe PMC), which cover fascinating cutting-edge science including combining drug therapies to treat cancer, brain scanning to better understand specific function, a new way to assess effectiveness of arthritis treatments, and an analysis of malaria resistance around the world. The People’s Choice award gives a voice to those for whom the summaries have been written and allows us to reward the best.

Read and vote for the 10 shortlisted entries here. Our rigorous judging process has ensured the scientific accuracy of the accounts; what we really want to know is whether you like them!

Image Source: Shutterstock Copyright: bikeriderlondon

The competition will remain open until 12.00 on 24 March 2014, and the winner will be announced that evening at our awards ceremony. You can vote for as many articles as you like, once a day. We encourage you to share any and all comments at any time.

When you have finished reading and voting, don’t forget to tell your family, friends and colleagues. We know these exceptional pieces will be of interest to all!

By Anna Kinsey and Rebecca Withers

To stay up-to-date with Europe PMC news you can also follow us on Twitter @EuropePMC_news