Author: Roli Roberts

You Just Read my Mind…

STOP PRESS!Scientists decode words from brain signals, fueling hopes for mind reading!” “Mind-reading device could become reality!” “Scientists make telepathy breakthrough!” “Secrets of the inner voice unlocked!” – just some of the sensational headlines that greeted a PLOS Biology research article a couple of years ago. OK, so I might’ve put the exclamation marks in myself, but the science behind the claims was indeed pretty extraordinary.

Spectrograms of the original stimulus (top) and reconstructed speech (bottom). doi:10.1371/journal.pbio.1001251.g002

Spectrograms of the original stimulus (top) and reconstructed speech (bottom). doi:10.1371/journal.pbio.1001251.g002

I’ll talk more about the study itself in a moment, but how do you know when you’ve published a great paper? Traditionally it would be a matter of counting journal citations, but that captures only one strand of the complex set of influences that a paper can have. Now we can separate out these strands and follow them, each with its own characteristic. The quick spike of Twitter, the steady spread on Facebook, the rash of saves in Mendeley, of citations in F1000Prime, the complex dynamics of html page views, PDF downloads, secondary coverage in scientific and popular media and in the blogosphere, and – yes – the slow-burn of journal citations. Each has its own time course, its own demographic (age, field, background) and its own texture. And each speaks to a subtly different aspect of the work’s appeal.

There are methodological papers that emerge unnoticed and become citation classics, and there are papers on intriguing animal behaviour that are splashed across the tabloids but have single-figure citations. Two very valid forms of impact, but back in 2012 we published a truly fascinating paper, and two years of metrics show that it managed to hit both buttons very firmly.

Much of neuroscience arguably involves subjecting an animal to a stimulus and then trying to find out how the brain responds. This paper describes a spookily successful attempt to achieve the reverse – looking at the brain’s activity and trying to reconstruct the stimulus that must have caused it. By placing electrodes directly in contact with the auditory cortex, they were able to “mind-read” the words that the person had heard. Listen to this incredible recording of spoken words paired with their “mind-reading” reconstruction:

 

Red circles show the position of electrode arrays on the surface of the superior and middle temporal gyrus. doi:10.1371/journal.pbio.1001251.g001

Red circles show the position of electrode arrays on the surface of the superior and middle temporal gyrus. doi:10.1371/journal.pbio.1001251.g001

Normally the human cerebral cortex lies nicely protected by the cranium, but in this study the authors were able to exploit an extraordinary opportunity. Medics removing tumours or epileptic tissue from highly sensitive parts of the brains of fifteen patients were eager to keep their patients awake so that they could check that they didn’t affect anything crucial. This gave the authors a 10-12 minute window of time when the cortex of an alert patient was exposed to the atmosphere.

During this period an array of electrodes was placed on the surface of the auditory cortex and recordings were made while single words were spoken to the patient. The signals received were used to construct a computational model of the relationship between the stimulus (“Waldo”) and the representation in the brain. This relationship could then be flipped to reconstruct a passable (and recognisable) reproduction of the original spoken word (“Woodor”).

Read the full paper for the details of research, listen to the astonishing audio file of the reconstructed speech, and for a lively discussion with authors Brian Pasley and Bob Knight, I strongly recommend that you listen to Ruchir Shah‘s excellent PLOS Biology podcast (some more remarkable recordings of the speech stimuli and their paired reconstructions appear at 11:15-12:10). In their discussion, they reveal that a long-term translational aim is to use the brain activity elicited by people’s imagined words to drive a prosthetic speech device for those who are unable to speak.

To date the paper has received nearly 85,000 page views, including over 9,000 PDF downloads, and has been cited 66 times already (see more metrics here). It’s the 48th most saved PLOS article in Mendeley of all time, is cited in two Wikipedia entries (“Thought Identification” and “2012 in Science“), and has respectable Facebook activity (21 likes, 467 shares, 33 posts). Twitter looks a bit thin on the ground because we only started collecting stats 5 months after the paper was published, so missing the main spike. But as well as the healthy academic attention, the article attracted massive press coverage that taps liberally into the memes of mind-reading and telepathy, and has inspired bloggers from Wales to Brazil. Now that’s a great paper.

 

Category: Biology, Computational biology, Debate, Neuroscience, PLOS Biology, Publishing, Research | 1 Comment

PLOS Biology Paper Wins Omenn Prize for Viral Evasion Story

We talk to the authors of a PLOS Biology research article published last May that has just won the Omenn Prize for the best article published in 2013. The Omenn Prize is awarded annually by the Evolution, Medicine, & Public Health Foundation to authors of articles related to “evolution in the context of medicine and public health,” and the winner was picked from a tough long-list of 47 papers. Four other papers, including two from our sister journal PLOS Pathogens, were cited for “honorable mention” (Graves et al. Huijben et al.).

 

The PLOS Biology paper looks at how an essential mammalian protein – the transferrin receptor, TfR1 – evolves in the face of contrasting selective pressures. TfR1 is a protein that sits on the membrane of our cells and mediates the regulated uptake of iron. TfR1 is stuck in the horns of a dilemma. On the one hand, it has to be able to bind its functional partners – the iron-loaded plasma protein transferrin, and a negative regulator protein called HFE; this requirement constrains the sequence and structure of TfR1 through evolutionary time. On the other hand, it has to evade viruses that exploit its handy cell-surface location, such as arenaviruses and the rodent retrovirus MMTV.

 

TfR1 can carry on binding transferrin and HFE while dodging viruses. DOI: 10.1371/journal.pbio.1001571

TfR1 can carry on binding transferrin and HFE while dodging viruses. DOI: 10.1371/journal.pbio.1001571

The authors compared sequences of TfR1 from various mammalian hosts and then expressed them on the surface of cells to check a) their ability to confer vulnerability or resistance to MMTV and arenaviruses such as Machupo, Junin and Guanarito virus and b) their ability to bind to transferrin. This image from the paper summarises the central finding – how TfR1 (green) manages to square this circle by evolving rapidly (red) to change the outer surfaces that are hijacked by viruses while keeping constant the central surfaces that it uses to bind transferrin and HFE (purple, blue).

 

First author Ann Demogines and lead author Sara Sawyer – both from the University of Texas at Austin – told us how the study first arose and then evolved into the paper that you can now read on our website.

 

Sawyer recalls the exact point at which the project started: “In the first year of my faculty position, Welkin Johnson invited me to give a talk at the New England Primate Research Center.  While I was there, I had a 45 minute meeting with his colleague, Mike Farzan [also a co-author]. Mike had just discovered TfR1 as the cellular receptor for arenaviruses, and suggested to me that this might be a molecule that is engaged in an evolutionary arms race.  While ideas like this often arise out of conversations between scientists, I remember having a gut reaction that this was something worth pursuing.”

 

Amino acids marked in red track virus binding sites on TfR1 (blue, grey) DOI: 10.1371/journal.pbio.1001571

Positively selected amino acids (red) hit the virus binding sites on TfR1 (blue, grey) DOI: 10.1371/journal.pbio.1001571

Demogines, who received $5000 from the Foundation, describes how the spectacular arrangement of the evolutionarily selected sites emerged: “I am still amazed to this day by the results of the evolutionary analysis.  We were able to take DNA sequence from just 7 species and computationally predict six sites under selection.  These sites were scattered on the linear diagram of the protein, and didn’t make much sense to us. But, when we placed them onto the 3D crystal structure they formed a beautiful ridge going straight down the outer surface of the receptor.  That was a great day in the lab.  We knew this had to mean something!”

 

Demogines goes on to think about the implications of her paper and related studies: “This work really gets me excited about the future of evolutionary analysis applied in biomedical research.  As we collect the genome sequences from more and more species, especially rodents and bats which are major reservoirs for zoonotic and potentially zoonotic viruses, we should be able to do this type of analysis more and more.  This type of analysis has many applications: allowing us to identify critical cofactors involved in the viral lifecycle, viral binding sites, and potentially novel drug targets. It can also be used to study interactions with bacterial pathogens, although this has not yet been extensively explored.”

 

If you’d like to find out more about this elegant study, why not read the article itself, or the accompanying Primer written by John Coffin:

 

“Dual Host-Virus Arms Races Shape an Essential Housekeeping Protein” by Ann Demogines, Jonathan Abraham, Hyeryun Choe, Michael Farzan and Sara L. Sawyer. DOI: 10.1371/journal.pbio.1001571

“Virions at the Gates: Receptors and the Host–Virus Arms Race” by John M. Coffin. DOI: 10.1371/journal.pbio.1001574

 

 

Category: Biology, Computational biology, Evolution, Microbiology, News, PLOS Biology, Research | Leave a comment

How Will We Feed the World?

Gates collection thumbnailPLOS has just launched a new Collection, “The Promise of Plant Translational Research”. Here’s why we did it, and what we hope to achieve.

 

The human race has a very serious problem; so serious that millions will die unless we solve it. It all started about 10,000 years ago. Up until then we’d lived as hunter-gatherers, and our humble lifestyle limited our numbers. But then we started to explore the benefits of exploiting the land more effectively, and agriculture was born. This technological suite of seed collection, sowing, irrigation, weeding and harvest allowed the same land to support many more of us.

 

Over the millennia we bred better crops (hexaploid wheat from emmer, maize from teosinte, paddy rice from Oryza rufipogon), systematically mechanised most aspects of the process (ox-drawn plough, seed drill, combine harvester), and artificially fertilised the soil (animal manure, the Haber process). And of course more food means more kids, and more kids need… You get the picture – a snowballing dependency on ever-improving the efficiency of our food production. All grown – by plants – using the solar energy that hits our finite planet.

 

Image Credit: Flickr user Frederic

Image Credit: Flickr user Frederic

The problem is that while population increases exponentially, food production increases only arithmetically. Seven billion souls – and counting – currently share our planet, with a projected population of nine billion by 2040. While the Green Revolution of the late 20th century went some way to keeping productivity in pace with demand, feeding these extra mouths will require a substantial increase in agricultural output while competing with the burgeoning population for valuable land and water resources. Furthermore, if a population is able to achieve food security, along with health care and education, people will tend to limit family size of their own accord, keeping population in check. So working to achieve food security for the world’s billions offers a constructive way out of the debacle.

 

PLOS recognises that many of these problems (and the need for attendant solutions) impinge directly on those people and countries least able to break through the pay-wall that many scientific journals use to guard their content. For translational plant research, more than most fields,  Open Access is crucial to maximise the availability and utility of research by those who need it most. We, and the rest of the scientific community, can facilitate information and knowledge exchange by promoting Open Access.

 

What our Collection aims to do is a) open up the debate about the urgent need for plant translational research, b) discuss the ways in which scientific research and technological advance can meet this need, and c) encourage the submission of such research to Open Access journals, like those of the PLOS family.

 

What can you do? Firstly, read the inaugural articles of the Collection that we’ve just published in PLOS Biology (see below). I’d recommend starting with the magnificently punchy Perspective by Ottoline Leyser, which lays out the scale of the problem and exhorts us to ignore red herrings and concentrate on the pressing task in hand. Secondly, submit your translational plant research to one of our journals (PLOS Biology, PLOS Pathogens, PLOS Genetics, PLOS Computational Biology and PLOS ONE are the most relevant) and make sure that the people who need to read it can!

 

We’re grateful to Jeffrey Dangl, Sophien Kamoun and Susan McCouch, who as academic editors of the Collection have provided us with advice and guidance throughout, including helpful comments on this blog post. We’d also like to thank the Bill and Melinda Gates Foundation for supporting the Collection.

 

 

New articles in PLOS Biology published as part of “The Promise of Plant Translational Research”:

 

New Horizons for Plant Translational Research: Jeffrey Dangl, Sophien Kamoun, Susan McCouch and Jane Alfred present an overview of the Collection.

Moving beyond the GM debate: In this Perspective, Ottoline Leyser calls for the public to move on from the common logical fallacy that anything natural is good, and anything unnatural is bad, and addresses the misconception that GM, as a technique, is specifically and generically different from other crop genetic improvement techniques.

Genome Elimination: Translating Basic Research into a Future Tool for Plant Breeding: This Perspective by Luca Comai discusses the contribution of the late Simon Chan to the invention of genome elimination, and ponders the future of his approach as a way of streamlining the optimisation of plant genotype.

 

Finally, four Essays explore the technological basis and real-life application of genetic and genomic research, genome editing, whole-genome sequencing and metabolic engineering to the improvement of food crops:

 

Lab to Farm: Applying Research on Plant Genetics and Genomics to Crop Improvement by Pamela Ronald.

Precision Genome Engineering and Agriculture: Opportunities and Regulatory Challenges by Daniel Voytas and Caixia Gao.

Harvesting the Promising Fruits of Genomics: Applying Genome Sequencing Technologies to Crop Breeding: by Rajeev Varshney, Ryohei Terauchi and Susan McCouch.

Key Applications of Plant Metabolic Engineering by Warren Lau, Michael Fischbach, Anne Osbourn and Elizabeth Sattely.

 

 

 

 

Category: Announcement, Biology, Climate, Community, Ecology, Environment, Genetics, Genomics, Open access, Plant biology, PLOS Biology, PLOS Computational Biology, PLOS Genetics, Research | 5 Comments

Why Do Scientists Ignore Female Genitalia?

Credit: Roli Roberts, with apologies to Rudolph Zallinger.

Credit: Roli Roberts, adapted from Rudolph Zallinger.

Humans have an odd attitude to genitalia. Indeed, more than 90% of you are reading this blog post merely because I put the word in the title. A new study shows that biologists, being human, also have an odd attitude to genitalia.

 

 

Sexual reproduction occurs across most of the animal kingdom, allowing us to shuffle our genes at the poker table of life. And in many cases this occurs by direct physical interaction between two sexes, usually by transfer of sperm from the male to the female via a neatly compatible USB interface known as genitalia.

 

Unlike the USB, where compatibility is in everyone’s best interests, because of sex’s central role in the evolution of sexual beings, every aspect of it is subject to subversion by strong selective forces, and therefore liable to rapid and apparently capricious change – courtship behaviour, plumage, and even the molecular mechanism that determines whether you’re male or female. But what about genitalia?

 

Genitalia are also subject to spectacular change, and the assumption is surely that, in the case of two such intimately apposed organs, male and female genitalia should co-evolve, each driven by those motivations that tend to drive other aspects of sex – the male to sow his oats as widely as possible, and the female to be choosy as to how she apportions the costly provisioning of a future infant.

 

The study of the evolutionary biology of animal genitalia is indeed a vibrant field, but apparently it has a problem. A big one. A paper just published in PLOS Biology reports a survey of hundreds of recent papers and finds that the field is massively biased towards study of male genitalia – almost half of the studies only address males, with most of the remainder looking at both sexes. The bias varies according to the evolutionary model involved, with an explicitly female-driven model (cryptic female choice) being even-handed, but the others being dominated by male-only studies (red):

 

Sex of genitals studied, by evolutionary model. Ah-King et al.

Sex of genitals studied, by evolutionary model. Ah-King et al.

 

So what are the reasons for this bias? The authors look at three of the more obvious explanations:

 

a)      Biological: Female genitalia don’t vary enough to drive evolutionary change.

b)      Practical: They do vary, and do drive evolution, but are devilishly hard to study.

c)       Intellectual: They do vary and drive evolution, and can be studied, but the field is intellectually blinkered.

 

The authors use examples to argue that the first two explanations are invalid, and that the field is intellectually hobbled by a blind assumption that male genitalia indulge in all sorts of evolutionary shenanigans, but “too often the female is assumed to be an invariant container within which all this presumed scooping, hooking and plunging occurs.” Author Malin Ah-King says  “We found that the most plausible explanation for the bias is the enduring assumptions about the dominant role of males, and unimportance of variation in female genitalia.”

 

But where do these assumptions come from? Although the tabloid stereotype of the scientist may be of a monkish, geeky male boffin whose real-life encounters with female genitalia are tragically infrequent, clearly many scientists are women. Barron and co show that the gender of the senior author on these papers doesn’t correlate with the genital sex bias, so that simple explanation can be excluded.

 

The authors are studiously restrained when it comes to speculating as to what might lie behind this bias in the field. Luckily as a blogger, I’m free from academic constraints and can indulge in some cod sociology. Here are some (obvious and intertwined) suggestions:

 

a) Even in the 21st century there’s a bizarre societal squeamishness about female genitalia that doesn’t apply to male genitalia. This plays out in the media in odd and prurient ways, including a sex bias in the severity of taboo words and a game of “chicken” as to how much one can get away with saying. Could this background be subliminally affecting career choice, study design, funding, or publication decisions? Surely as free-thinking scientists we’re above this sort of thing?

b) It’s easy to imagine a situation, say 50+ years ago, where an influential evolutionary role for females would have been an intellectually challenging concept for a heavily male-dominated and culturally sexist academe. Could this reluctance to acknowledge evolution’s equal opportunity policy have been propagated, via the inherently conservative conduits of textbooks and undergraduate teaching, down the decades?

c) Fields can be dominated by the ideas of one or two highly persuasive individuals or schools of thought. Perhaps one or two big-shots, possibly influenced by one or both of the above cultural issues, or possibly out of a feeling of confidence in their own correctness, put forward models for genital evolution that are still able to hold sway with 21st century men and women?

 

The likely answer is that it’s a little of all of these – a mixture of cultural milieu and historical contingency (a bit like evolution itself). Can this field be rescued? The authors take us on a whistle-stop tour of some of the more spectacular instances of the role of female genitalia in evolution, and Ah-King hopes “that this analysis can increase the awareness of gender bias and its impeding effects on research, and thereby enable a broadened understanding of genital evolution in the future.”

 

Read the paper:

“Genital Evolution: Why Are Females Still Understudied?” Malin Ah-King, Andrew B. Barron, Marie E. Herberstein. PLOS Biology DOI: 10.1371/journal.pbio.1001851

 

ResearchBlogging.org

Ah-King M, Barron AB, & Herberstein ME (2014). Genital evolution: why are females still understudied? PLoS biology, 12 (5) PMID: 24802812

Category: Biology, Blog, Data, Debate, Evolution, PLOS Biology, Publishing, Research | 1 Comment

Will Stem Cell Therapy Help Cure Spinal Cord Injury?

Experimental spinal injury in a mouse (DOI: 10.1371/journal.pone.0017126)

Experimental spinal injury (dark area) in a mouse (DOI: 10.1371/journal. pone.0017126)

Spinal cord injuries are mostly caused by trauma, often incurred in road traffic or sporting incidents, often with devastating and irreversible consequences, and unfortunately having a relatively high prevalence (250,000 patients in the USA; 80% of cases are male). High-profile campaigners like the late actor Christopher Reeve, himself a victim of sports-related spinal cord injury, however, have placed high hopes in stem cell therapy.

Stem cell therapy involves administering special self-regenerating cells (“stem cells“), with the hope that these cells will then colonise the damaged area, assume the properties of their neighbours and reinstate at least some of the function that’s been compromised by injury or disease. Stem cells have to be isolated from the patient or a donor, or generated afresh by tricking ordinary non-regenerating cells into becoming stem cells. Stem cell therapy has become fairly standard for re-colonising bone marrow that has been ravaged by cancer chemotherapy, but its application to other damaged tissues, including spinal cord injury, is still very much at the experimental stage.

In using stem cells for spinal cord injury, scientists are looking to repopulate damaged areas of the spinal cord (see the picture above), with the hope of improving the ability of patients to move (“motor outcomes”) and to feel (“sensory outcomes”) beyond the site of the injury. Many studies have been performed that involve animal models of spinal cord injury (mostly rats and mice), but these are limited in scale by financial, practical and ethical considerations. These limitations hamper each individual study’s statistical power to detect the true effects of the stem cell implantation. As explored previously on Biologue, there are also problems of bias (“It’s official – the animal study literature is biased… but whose fault is it?“).

Flickr user kittenfc

Lab rats (Image credit: Flickr user kittenfc)

How can we get round these shortcomings and find out how likely it is that stem cell therapy will improve the lot of spinal cord injury patients? This is the question addressed in a paper just published in PLOS Biology by Ana Antonic, David Howells and colleagues. They overcame the problem by conducting a “meta-analysis” – a sophisticated and systematic cumulative statistical reappraisal of many previous laboratory experiments. In this case the authors assessed 156 published studies that examined the effects of stem cell treatment for experimental spinal injury in a total of about 6000 animals.

Overall, they found that stem cell treatment results in an average improvement of about 25% over the post-injury performance in both sensory and motor outcomes, though the results can vary widely between animals. For sensory outcomes the degree of improvement tended to increase with the number of cells introduced – scientists are often reassured by this sort of “dose response”, as it suggests a real underlying biologically plausible effect. So the good news is that stem cell therapy does indeed seem to confer a statistically significant improvement over the residual ability of the animals both to move and feel things beyond the spinal injury site.

The authors went on to use their analysis to explore the effects of bias (such as whether the experimenters knew which animals were treated and which untreated), the way that the stem cells were cultured, the way that the spinal injury was generated, and the way that outcomes were measured. In each case, important lessons were learned that should help inform and refine the design of future animal studies. The meta-analysis also revealed some surprises that should provoke further investigation – there was little evidence of any beneficial sensory effects in female animals, for example, and it didn’t seem to matter whether immunosuppressive drugs were administered or not.

The authors conclude: “Extensive recent preclinical literature suggests that stem cell-based therapies may offer promise; however the impact of compromised internal validity and publication bias means that efficacy is likely to be somewhat lower than reported here.”

 

ResearchBlogging.org
Ana Antonic, Emily S. Sena, Jennifer S. Lees, Taryn E. Wills, Peta Skeers, Peter E. Batchelor, Malcolm R. Macleod, & David W. Howells (2013). Stem Cell Transplantation in Traumatic Spinal Cord Injury: A Systematic Review and Meta-Analysis of Animal Studies PLoS Biology, 11 (12) DOI: 10.1371/journal.pbio.1001738

Category: Biology, Neuroscience, PLOS Biology, Research, Stem cells | 3 Comments

We Have the Technology…

Modified logo wth text

“Gentlemen, we can rebuild him. We have the technology. We have the capability to make the world’s first bionic man. Steve Austin will be that man. Better than he was before. Better…stronger…faster.”

Readers of a certain age will tingle with recognition at those words, intoned over the intro to ’70s TV series “The Six Million Dollar Man“, promising the bodily reconstruction of a seriously injured astronaut. Back then it was distant science fiction, but fast-forward 30 years to 2003, and a very shiny new PLOS Biology published a paper in its second ever issue that did indeed “have the technology”.

First author Jose Carmena recalls the thrill of getting involved in a new model of publishing: “The open access idea was really exciting yet there was the risk and uncertainty of publishing in a new journal, especially as my paper came out in the second issue so there was still very little information available and lots of questions about the future of open access publishing in general and that of PLOS in particular.”

Synopsis figure In “Learning to Control a Brain-Machine Interface for Reaching and Grasping by Primates”, Jose Carmena, Miguel Nicolelis and colleagues described an astounding experiment that brought Steve Austin’s bionic arm closer to reality. Using monkeys with large numbers of electrodes implanted into broad swathes of their cerebral cortex, they recorded the activity of numerous neurons while the animals learned to perform a simple task of gripping and pushing a pole to reach and grasp a virtual object on a screen. The neuronal activity data were fed into a computer and used to develop a model for real-time prediction of the monkeys’ arm movements.

So far, so what? But then the authors played a trick on the monkeys. First they disconnected the pole and instead used the output of their computer model to drive the grasper on the screen. After an initial drop in performance, the monkeys soon learned to perform the task using their neurons alone – a true brain-machine interface. For some of these tasks the monkeys controlled a real robotic arm, making it squeeze a spongy object. Finally the authors took the pole away and found that the monkeys didn’t even try to use their arm muscles. Incredible. I’m guessing they did much the same thing with Steve Austin.

You can read the paper itself, or the accompanying Synopsis, for further details of how the authors studied what was going on in the monkeys’ brains. This early PLOS Biology paper has gone on to influence many subsequent studies, being viewed 53,850 times and cited 527 times to date. Our editorial board member Gerry Joyce describes it as “a mind-blowing paper that shows the breadth of PLOS and captured much attention in both the scientific and popular press.”

Carmena had just moved from robotics and engineering, and this was his first neuroscience paper. He remembers the study fondly: “Those years at Duke were were very intense and extremely rewarding.  I had the privilege to work side by side with my mentor, Miguel Nicolelis, with whom I learned a lot. The scientific atmosphere and collegiality in his lab was simply remarkable, it really felt like a big family.”

“The impact that this paper had in my career is huge, it basically gave me my dream job in Berkeley,” he adds. Carmena returned to PLOS Biology six years later to publish a further study that explored the long-term process of learning neuroprosthetic control in greater detail, the first paper from his own lab, and one that he feels helped him secure tenure.

Of course, just because they had the technology, it didn’t mean that we did, as Carmena recounts: “A couple of days after the paper came out I remember that Hemai Parthasarathy (our editor) told us that the servers at PLOS had collapsed because of the amount of traffic and downloads of the paper!”

 

collection logoSee the Tenth Anniversary PLOS Biology Collection or read the Biologue blog posts highlighting the rest of our selected articles.

 

 

ResearchBlogging.org
Carmena JM, Lebedev MA, Crist RE, O’Doherty JE, Santucci DM, Dimitrov DF, Patil PG, Henriquez CS, & Nicolelis MA (2003). Learning to control a brain-machine interface for reaching and grasping by primates. PLoS biology, 1 (2) PMID: 14624244

Category: Biology, Computational biology, Neuroscience, PLOS Biology | Tagged , | Leave a comment

Dude, Where’s My Data?

 

Q: Where do you look for scientific data?

A: In scientific papers, stoopid!

 

Sadly, of course, anyone who’s read a scientific paper will know that this isn’t true. Papers actually contain very little raw data, and mostly consist of analysis of the data and discussion of conclusions that can be drawn from the data. That’s OK up to a point, but what if you’re sceptical about the analysis and want to have a shot at doing it yourself? What if you’ve got a nifty idea about using the same data to address a completely different question? The chances are that you’ll have to look further than the paper itself, and, especially if the paper’s old, you may well find that the raw data no longer exist.

The conciseness of the modern scientific paper has presumably arisen historically because a) papers used to be constrained by the space available in old-fashioned printed formats, b) lots of data can obscure the central message of a paper, and c) we didn’t used to have much data anyway. These days we have online journals with unlimited pages, the possibility of substantial supplementary information files, and hyperlinks to robust data repositories, so surely, even with our terabyte-sized datasets, we don’t have to worry anymore?

Well, some fields are pretty good at this – it’s hard to imagine a paper reporting new genomic sequence or a new protein structure not having an accession number that will lead you directly to an online repository (GenBank, PDB, for example) containing the full sequence or coordinates (though I concede that in each of these instances, the sequence/coordinates already represent a level of interpretation of the raw data, which in turn will be less accessible). So although most of the ~300 GenBank entries that carry my name will never be of use to anyone, at least my unborn grandchildren will be able to look at them in puzzled indifference. However, it seems that there are many areas of science where we run the risk of losing most of the data upon which the literature is based.

In a Perspective just published in PLOS Biology, Bryan Drew and colleagues directly test their ability to retrieve the data that underlie one field of endeavour, and find a “massive failure” that they attribute to cultural problems. This piece, “Lost Branches in the Tree of Life”, tackles the specific problem of the “phylogenetic trees” that show the evolutionary relationship between different species (see a previous Biologue post of mine for more about phylogenetic trees).

Constructing trees of life involves the collection of data from organisms that are often rare or exotically located – these are very special data. The resulting publications always present trees as figure panels, but vary as to whether the topological and branch-length properties of the trees, and the sequence alignments themselves, are made available to readers by deposition in a database (e.g. Dryad, TreeBASE). Access to the alignments would allow you to check the original paper’s findings, add your own species, or combine data from different papers to make your own super-tree…

While the total number of phylogenetic papers grew though the years 2000-2012, Drew et al. found that those with archived data (green line) remained rare.

While the total number of phylogenetic papers grew though the years 2000-2012, Drew et al. found that those with archived data (green line) remained rare.

…and it was while making their own super-tree of life comprising nearly two million species that Drew and co-authors noted that of the 7500 papers they studied, data had been deposited for only one-sixth and were available on request from the original authors in a further one-sixth, leaving two-thirds of trees only available as figure panels in the original paper. Lest you assume that the authors were looking back into the Dark Ages before the internet, all papers examined were from the fully digital years 2000-2012. This represents a potentially irretrievable loss of the bulk of the data on which this field rests, and there’s little sign of any improvement.

In a separate Perspective, “Spatially Explicit Data Stewardship and Ethical Challenges in Science”, also just published in PLOS Biology, Joel Hartter and co-authors look at a broader issue of data management, stewardship and sharing across many types of scientific data. They note cultural differences between fields, especially regarding the basic tendency either to share or to guard data. They cover spatially explicit geographical and sociological datasets, and raise the peculiar ethical problems that can arise from the conflict between openness and confidentiality in these fields. These issues are particularly heightened when considering the potentially socially intrusive nature of crowd-sourced and geospatial data. The authors propose a series of measures intended to foster openness while protecting the diverse interests at stake.

Back in June we published a third plea for data availability, from Dani Zamir, “Where have all the crop phenotypes gone?” He also lamented the likely irreversible loss of huge bodies of valuable data generated by large-scale plant breeding programmes devised to map the genetic determinants of desirable (or undesirable) crop traits, and asked “how can we bring about a phenotype sharing revolution?”

In each case, across these disparate fields, we see very low levels of data availability, and it may be that some (many?) fields perform even worse than the dismaying one-sixth that Drew and colleagues saw in phylogenetics. In each instance, the Perspective authors identify the problems as largely cultural, and propose ways forward, asking journals and funding agencies to insist on deposition of valuable and sometimes irreplaceable data.

And it’s clear that journals are indeed spectacularly well-placed to police and incentivise the deposition, tracking, accessibility, and permanence of data associated with the papers that they publish. At the point of acceptance we have the authors over a barrel, and are in a great position to mandate deposition of all data for every paper. And why stop at the data? What about mathematical models and code used for the analysis, both of which are important resources and arguably a formal requirement for reproducibility?

In our guidelines we do insist on depositions (“All appropriate datasets, images, and information should be deposited in public resources.”), and we do try to ensure that the more obvious data are deposited, but I suspect that some slip under the radar. For these we rely on the authors recognising that data sharing is not only good for readers, but is also good for them, enhancing the longevity and (dramatic pause…) citeability of their work.

Want to read more? See other Biologue posts about Open Data and related issues by John Chodacki and  Theo Bloom.

Declaration of potential conflict of interest: I’m a PLOS Biology editor and an employee of PLOS.

 

 

Category: Biology, Data, Editorial policy, Publishing, Research | 12 Comments

A Virus Emerges – with a Human Helping Hand

Where do viruses come from? Like us, they are products of their genomes, and like our genomes, viral genomes are palimpsests of writing, overwriting, cutting and pasting, plagiarism and happenstance. Genes all have to come from somewhere originally, and Nature is a great recycler. Although some sections of genes have arisen recently by co-option of previously useless sequence, looking at most genes gives you a distinct feeling of déjà vu. Time and again handy functional modules appear in novel guises, doing sort of the same job, but in a slightly different context.

See what I did there? I pinched those last three sentences from something I wrote two weeks ago and changed a few bits so that it worked in this new piece. That’s what viruses do, driven by the need to re-purpose as they switch hosts, and fueled by encounters with new sources of genetic code – sometimes helped, as in the following amazing tale, by the unsuspecting hands of scientists.

A paper just published in PLOS Biology, “The Extraordinary Evolutionary History of the Reticuloendotheliosis Viruses”, describes a spectacular story of host-jumping, genome splicing and derring-do by a virus that has spread rapidly through bird populations in the last half-century. In this paper, Anna Maria Niewiadomska and Robert Gifford use what amounts to viral palaeontology to assemble what they rightly call “the extraordinary evolutionary history of the reticuloendothelial virus” (REV). There’s a superb accompanying Primer, “The Mongoose, the Pheasant, the Pox and the Retrovirus”, by Lucie Etienne and Michael Emerman that sets this in the context of other rapidly emerging and host-skipping infections, including those where humans have played an unwitting role.

The fireback pheasant, through which REV probably passed into birds.  Eva Hejda http://fotos.naturspot.de/

The fireback pheasant, through which REV probably passed into birds. Credit: Eva Hejda http://fotos.naturspot.de/ through Wikimedia Commons

Reticuloendotheliosis is a nasty disease of domesticated fowl that seems to have come from nowhere, and is also known to affect wild bird populations. Read the research article and the Primer to get the full detective story and to find out how the paleovirologists traced the path of REV through tissue samples, sequence databases and the scientific literature, but here’s what they think happened (contains plot-spoilers!):

a)      A retrovirus undergoes an ancient genome-splicing event, and starts infecting mammals tens of millions of years ago, leaving fossil traces in their genomes.

b)      At least 8 million years ago, one of its active descendants infects a range of Madagascan carnivore species, including some mongoose-like animals. There’s no evidence of its presence in birds until the 20th century.

c)       Somehow this virus ends up in a Borneo fireback pheasant in the Bronx Zoo in 1937. The implication is that the menagerie brings together exotic animals (and their viruses) that have previously never encountered each other, perhaps helping the virus jump from mammal to bird, becoming REV in the process.

d)      Malaria researchers manage to isolate the malarial parasite Plasmodium lophurae from this pheasant, and they keep the parasite stock going by infecting chickens, ducks and turkeys, presumably also transmitting the viral contaminant.

e)      At some point in this process, the ancient mammalian retroviral genome gets incorporated into the genomes of two bird viruses – a pox virus and a herpes virus.

f)       These viruses (REV and its derivatives) cause outbreaks in domestic and wild birds over the last 50 years, often triggered by contaminated vaccines, resulting in anaemia, suppression of the immune system and cancer.

 

I’ll leave the last word to Gifford: “We became intrigued by these viruses because their distribution in nature suggests something very unusual has occurred during their evolution. Unfortunately, the law of unintended consequences applies in the realm of infectious disease research. While we can’t escape that fact, we can use modern sequencing technologies to survey viral genetic diversity, so that changes in the ecology and evolution of important viral pathogens can be monitored and responded to more effectively. Our analysis of REV illustrates how such an approach might work.”

 

ResearchBlogging.org
Anna Maria Niewiadomska,, & Robert J. Gifford (2013). The Extraordinary Evolutionary History of the Reticuloendotheliosis Viruses PLoS Biology, 11 (8) DOI: 10.1371/journal.pbio.1001642

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It’s official – the animal study literature is biased… but whose fault is it?

 

Testing a new drug on human subjects is expensive, risky and ethically complex, so the vast majority of potential treatments are first tried out on non-human animals. Unfortunately similar issues also constrain the size of animal studies, meaning that they have limited statistical power, and the scientific literature is littered with studies that are either uncertain in their outcomes or which appear to flatly contradict each other.

 

Luckily statisticians have developed a workaround for this – the “meta-analysis”. To do this, scientists combine the data from a large number of published studies on the same treatment, ending up with a much more certain answer that’s tantamount to a super-study that uses the total number of animals from all the individual studies. Bingo! A much more solid basis for deciding on the merits of pursuing these treatments further.

 

But a study just published in PLOS Biology by Konstantinos Tsilidis, John Ioannidis and colleagues at Stanford University shows that a meta-analysis is only as good as the scientific literature that it uses. That literature seems to be compromised by substantial bias in the reporting of animal studies and may be giving us a misleading picture of the chances that potential treatments will work in humans. You can read the excellent Synopsis by Jon Chase for how the authors set about doing their study, but the key take-home is that more than twice as many studies as expected appeared to have statistically significant conclusions – something known as excess significance bias.

 

Rat cartoon finalWhat’s the explanation for this anomaly? Rather than wilful fraud, the authors of the PLOS Biology study suggest that this excess significance comes from two main sources. The first is that scientists conducting an animal study might analyse their data in several different ways, but ultimately tend to pick the method that gives them the “better” result. The second arises because scientists usually want to publish in higher profile journals that tend to strongly prefer studies with positive, rather than negative, results. This can delay or even prevent publication, or relegate the study to a low-visibility journal, all of which reduce their chances of inclusion in a meta-analysis.

 

The new work raises important questions about the way in which the scientific literature works, and it’s possible that the types of bias reported in the PLOS Biology paper have been responsible for the inappropriate movement of treatments from animal studies into human clinical trials. What do we do about it? Here are the authors’ suggestions:

  1. Animal studies should adhere to strict guidelines (such as the ARRIVE guidelines) as to study design and analysis.
  2. Availability of methodological details and raw data would make it easier for other scientists to verify published studies.
  3. Animal studies (like human clinical trials) should be pre-registered so that publication of the outcome, however negative, is ensured.

 

Well, these are all excellent, but most people would also say that there are problems elsewhere in the system – in the high-profile journals’ desire to a have a cute story with well-defined conclusions, and in the forces exerted on authors by institutions and funding bodies to publish in those high-profile journals. So whose fault is it?

 

The Institutions. Institutions (and funding bodies) feel driven to assess the “quality” of their employees’ work, and frankly, using the journal in which the work is published as a proxy for “quality” is an easy option – the peer reviewers and editors have already done the assessment job for them, and all they have to do is note down the impact factor. In this context, negative-result papers aren’t going to help the authors’ case. Even if they end up with the rosiest article-level metrics, they will end up tarred with a low impact factor.

The Authors. Authors may have the best intentions, but ultimately writing and submitting (and re-submitting…) a paper takes a substantial number of person-hours. These are hours that could be better spent doing experiments, writing grant applications, teaching, etc. How can writing a negative-result paper that will end up in a “low-profile” journal compete? Ioannidis and colleagues point out that many negative studies end their days at this stage – a collection of data on a hard-drive with no prospect of seeing the light of day. And those that do get submitted may have had to wait until the authors have done umpteen other more pressing tasks.

The Journals. There are some special journals out there, like PLOS ONE, that don’t make a judgement as to the importance of a study. In their eyes, positive- and negative-result papers should be published with equal probability. However, most journals, including PLOS Biology, make a call as to the perceived importance of a study. Some might disagree, but I would say that this is key to the “discoverability” of a paper, and that some flagging of important papers needs to occur, whether it’s pre-publication (as has happened traditionally) or post-publication (as some propose). Positive papers will almost always be seen as more important (with a few interesting exceptions), but what is essential is that the publication of negative results in a readily accessible journal is made as easy as possible; that publishers aren’t the barrier.

 

Yes, the pre-registration of animal studies should help incentivise authors to write and submit negative papers, but:

  1. Institutions and funding bodies need to release themselves from the tyranny of the impact factor and view positive and negative results as equally valid contributions to the literature.
  2. Authors need to recognise that negative studies can contribute substantially to scientific knowledge, both via meta-analyses and by more informal means, and it is their duty to ensure that failure to submit these studies doesn’t bias the literature.
  3. Publishers need to ensure that there is an accessible home for sound papers that have negative results.

 

PLOS ONE logoNow here’s a question –would PLOS Biology have published this study if it showed that there was in fact no excess significance in animal studies? I doubt it, but at least we would’ve cordially pointed the authors in the direction of PLOS ONE, where their study could be published without substantial delay.

 

Declaration of potential conflict of interest: I’m a PLOS Biology editor and an employee of PLOS. That said, these views are my own and don’t necessarily reflect those of PLOS.
ResearchBlogging.org

Konstantinos K. Tsilidis, Orestis A. Panagiotou, Emily S. Sena, Eleni Aretouli, Evangelos Evangelou, David W. Howells, Rustam Al-Shahi Salman, Malcolm R. Macleod, John P. A. Ioannidis (2013). Evaluation of Excess Significance Bias in Animal Studies of Neurological Diseases PLoS Biology, 11 (7) DOI: 10.1371/journal.pbio.1001609

Category: Biology, Blog, Data, Funding, Neuroscience, PLOS Biology, Publishing, Research, Review | 4 Comments

Mycobacteria get all the advantages of sex with none of the downside

 

Despite the sales pitch, sex is frankly a bit of a hassle, isn’t it? The champagne, the flowers, the desultory conversations in overpriced restaurants – and all with no guarantee of passing your genes onto the next generation. These costs, and the dependence on finding a mate, are massive downsides of sexual reproduction. And yet we’re all at it. From educated fleas to cold Cape Cod clams. Surely there must be something very special about sex to dissuade us from creeping off to our rooms alone and practicing binary fission?

 

And indeed there is. Asexual reproduction works very efficiently if you’re a bug capitalising on a set of genes that perfectly suit you to your environment, multiplying rapidly without having to find a mate. But if the environment changes, you’re stuck with that set of genes, and the future may not be too rosy for your offspring. This is where theory suggests the advantage of sex lies. What if two of you, with your slightly different sets of genes, could get together and shuffle your genomes to create different combinations of those genes, generating an array of subtly varied kids to explore strategies for survival in the new hard times?

 

Rotifers - great looking guys, but choosy about sex. From 10.1371/journal.pbio.0050255

Rotifers – great looking guys, but choosy about sex. From 10.1371/journal.pbio.0050255

Experiments bear this out – a paper published by PLOS Biology last year (also see the excellent accompanying Primer) used rotifers with the option to follow sexual or asexual lifestyles to show that while sex had a short-term cost, in the long term it does pay off. The study showed that this was indeed because sex breaks down fixed combinations of genes, and generates a wider range of characteristics in the offspring. In the long run, getting together with a mate and shuffling your genomes is a good bet on an uncertain future. And why stop at two sexes? – some critters go further and have seven.

 

That’s all fine and dandy for us eukaryotes, but why should bacteria miss out on all the fun? Can’t they reap the benefits of sex, too, or are they condemned to a monastic hereafter? We already know that many bacteria can transfer chunks of their genomes between individuals – a process known as conjugation. But to get the mosaic intermingling that sexual reproduction gives you, the bacterium would have to repeat conjugation umpteen times, bringing extra costs and delays.

 

Mycobacterium smegmatis. From 10.1371/journal.pone.0042769

Mycobacterium smegmatis. From 10.1371/journal.pone.0042769

A new study just published in PLOS Biology shows that some bacteria can have their cake and eat it. Keith Derbyshire and colleagues were looking at a relative of the TB pathogen, the dismayingly named Mycobacterium smegmatis (yes, that is where it was isolated from, and no, you’re unlikely to see it on the label of your favourite probiotic yoghurt). The authors allow different strains of M. smegmatis to conjugate and then analyse the genomes of the resulting transconjugants. Rather than containing a single substantial chunk of the donor strain, the transconjugant genomes were intricate patchworks of donor and recipient, showing a degree of shuffling that is reminiscent of sexual reproduction. They call this phenomenon Distributive Conjugal Transfer, and speculate that other related mycobacteria might use the same strategy to fast-track their way out of the potential evolutionary dead-end of asexuality.

 

Genetic mapping in Mycobacteria. Shared donor segments - just past 12 o'clock on this dial of transconjugant genomes - identify the gene that makes donors donors. From PLOS Biology.

Genetic mapping in Mycobacteria. Shared donor segments – just past 12 o’clock on this dial of transconjugant genomes – identify the gene that makes donors donors. From PLOS Biology.

The coolest aspect of the study is where the authors then exploit the distributive conjugal genetics of M. smegmatis in a manner strikingly akin to the linkage studies used by human geneticists to pinpoint the genes for diseases such as cystic fibrosis or Huntington’s disease. Instead of comparing sexual progeny with and without a disease, as human geneticists would have done, the authors compare mycobacterial transconjugants, asking whether they are donors or recipients in the conjugation process. Amazingly, by identifying which parts of the genome correlated with donor/recipient status, this enabled them to narrow the 7000 mycobacterial genes down to a list of 6 genes that must be responsible for determining who wears the trousers.

 

It remains to be seen how widespread this phenomenon is, and whether it stretches to globally important human pathogens like M. tuberculosis or M. leprae. Although these bugs haven’t quite joined us in our sexual revolution, the study shows that some bacteria do take the opportunity to mingle, and we can exploit the results to probe their genetics.

 

ResearchBlogging.org

Todd A. Gray, Janet A. Krywy, Jessica Harold, Michael J. Palumbo, Keith M. Derbyshire (2013). Distributive Conjugal Transfer in Mycobacteria Generates Progeny with Meiotic-Like Genome-Wide Mosaicism, Allowing Mapping of a Mating Identity Locus PLoS Biology, 11 (7) DOI: 10.1371/journal.pbio.1001602

ResearchBlogging.org
Lutz Becks, Aneil F. Agrawal (2012). The Evolution of Sex Is Favoured During Adaptation to New Environments PLoS Biology, 10 (5) DOI: 10.1371/journal.pbio.1001317

Category: Biology, Disease, Genetics, Genomics, Microbiology, PLOS Biology, Research, Uncategorized | Leave a comment