The molecular clock, the circadian clock, and exploring protein surface pockets: the PLOS Comp Biol February Issue

Here are our highlights from February’s PLOS Computational Biology

 

The Molecular Clock of Neutral Evolution

Evolution is driven by genetic mutations. While some mutations affect an organism’s ability to survive and reproduce, most are neutral and have no effect. These neutral mutations can be used as a “molecular clock” to estimate, for example, how long ago humans diverged from chimpanzees and bonobos. Benjamin Allen and colleagues use mathematical modelling to study how the rates of these molecular clocks are affected by the spatial arrangement of a population in its habitat. The authors also apply their framework to the field of social network analysis, and show that the structure of sites such as Twitter affects the rate at which new ideas replace old ones.

 

The Interplay of the Cell Cycle and the Circadian Clock

The clustering of ZCOGs on zebrafish metabolic network. Image credit: Ying Li et al.

The clustering of ZCOGs on zebrafish metabolic network.
Image credit: Li et al.

The circadian timing system gates cell cycle progression in various organisms from unicellular microorganisms to mammals. Although a number of factors have been implicated in linking the circadian clock with the cell cycle, little is known about the contribution of metabolic processes to this interaction. Ying Li and colleagues show that cell cycle, metabolism and the circadian clock are intertwined through consistent circadian expression of genes in de novo purine synthesis in the zebrafish.

 

Exploring Protein Surface Pockets

Image credit: Johnson et al.

Image credit: Johnson et al.

Despite considerable effort, there are few examples of small molecules that directly inhibit protein-protein interactions. This presents a challenge for predicting ligand activity. John Karanicolas and colleagues describe a novel computational approach to exploring the ensemble of surface pockets accessible to each member of a protein family, and show that this can be used to predict those family members with which a given ligand will interact. This approach presents a new avenue for designing highly selective inhibitors of protein-protein interactions.

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Metrics and Impact – Looking Beyond Research Articles

Forms of impact: one size doesn’t fit all. Image credit: flickr user Micky Aldridge

Forms of impact: one size doesn’t fit all.
Image credit: flickr user Micky Aldridge

The PLOS Biology magazine section features perspectives, essays, unsolved mysteries, community pages, and other pieces written by thought-leaders and rising stars from all walks of biology and beyond. These articles put forward new ideas, propose policy changes, highlight initiatives and tools of value for the community, explain research for those outside a specific field – but don’t typically report the results of original research. If journal-level metrics are misleading when it comes to the evaluation of any individual research article’s quality or impact, they are irrelevant for non-research content.

 

Yet these articles have broad-ranging impact and are extremely valuable. You don’t have to take my word for it (I get paid to run the PLOS Biology magazine, after all, so I’m hardly an unbiased source of information) – take a look at Article-Level Metrics (ALMs) instead.

 

Among all PLOS Biology articles published in 2014, the most read article – with more than 66K views and downloads – appeared in our magazine and laid out Best Practices for Scientific Computing. The paper went viral on twitter, with nearly 1K tweets and comments such as “A+ paper on integrity of analytical software” and “Where have you been all my life?”. Similarly, in 2013, the article that garnered the most attention by readers and social media users was again a magazine article: Holly Bik and Miriam Goldstein’s An Introduction to Social Media for Scientists. The social media world went a-tweeting and a-liking the piece, which has been viewed more than 140K times since its publication.

 

ALMs are freely available for every PLOS article – and a quick summary of key metrics appears in a handy box at the top right of the article page. Clicking on the metrics tab will take you to a more detailed breakdown of metrics for the article. Want to dig deeper? Go to http://article-level-metrics.plos.org/

ALMs are freely available for every PLOS article – and a quick summary of key metrics appears in a handy box at the top right of the article page. Clicking on the metrics tab will take you to a more detailed breakdown of metrics for the article. Want to dig deeper? Go to http://article-level-metrics.plos.org/

PLOS Biology magazine articles inform, but they also set standards in the field. In 2010, Carol Kilkenny and colleagues put together the ARRIVE Guidelines for Reporting Animal Research. These guidelines were drawn up by a group of statisticians, editors, and funders on the initiative of the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research, in order to improve reporting standards in pre-clinical research. The ARRIVE guidelines were endorsed by more than 300 journals and the major UK funding bodies; and the article has been cited more than 400 times in Scopus.

 

Our magazine articles make you think – Losos and colleagues’ roadmap of Evolutionary Biology for the 21st Century was recommended by colleagues on F1000Prime, garnered more than 40K views since its publication in 2013, and was bookmarked more than 400 times on Mendeley. The articles also surprise – who would have suspected that even in the 21st century there is a sex bias among researchers who study genital evolution? (As one of the several media outlets that covered this piece noted, Biologists Prefer the Penis.)

 

As well as all of these, the PLOS Biology magazine articles educate, generate debate, highlight, engage, call to action… Impact takes several different forms – and without article-level metrics it’s impossible to capture it.

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Starch, Oil, Water and Arsenic: New Plant Translational Research

by Christina Kary

 

Image Credit: Phil Dubois, Flickr

Image Credit: Phil Dubois, Flickr

PLOS launched a Collection last year, “The Promise of Plant Translational Research”. Here’s an update on how it’s going, and where we hope to go from here.

 

In my former life as ‘Plantina’ (I can thank my friends for that one), I worked on a small cut-flower farm in Maryland before heading off to grad school. These days, when I’m not in front of a computer screen, you’re still likely to catch me with my fingers in the dirt, potting this or that, or tending to my little patch of green in San Francisco. So I couldn’t be more delighted to highlight the new advances we’ve added to this Collection—and encourage you to submit your plant research discoveries to PLOS Biology as we continue to expand upon it.

 

In the face of increasing competition for land and water resources, feeding our ever expanding population will require breakthroughs to improve agriculture in ways that are safe, sustainable, and environmentally sound. PLOS is committed to supporting plant translational research – the development of basic plant research findings into new tools to improve crops. As you’ll see, the new papers we’ve added to our Collection exemplify how basic research is leading to exciting innovations in plant technology. These discoveries have the potential to touch our everyday lives in a myriad of ways—from improving food safety by limiting toxins in crops, to helping plants adapt to climate change, influencing household products, and finding better ways to produce biofuels.

 

Making Starch from Scratch

Today we’re publishing a brand new addition to our Collection. Our diets depend upon staple foods that contain starch—a carbohydrate that plants make to store energy—including rice, wheat, corn, potatoes and cassava. Starch is not only a major food component; it’s also used to produce pharmaceuticals and paper.  Indeed, civilizations were built upon the development of starch crops. Yet we still don’t fully understand how plants make starch. In the paper we’ve just published, Samuel Zeeman and colleagues characterize a factor that is involved in synthesizing starch components. This discovery points to a new gene to target for biotechnology to modify starch, with the potential to influence our diets as well as household items.

 

Generating Barrels of Seed Oil

Image credit: Christina Kary

Image credit: Christina Kary

Another addition to our Collection just added earlier this month also presents powerful tools to improve plant products that we rely on each day but often overlook. All plants contain oils in their seeds that are used in everything from cooking oils (sunflower oil makes me smile) to oils used in soap, cosmetics, and even paint. Nannan Li and co-workers recently isolated a new protein that is found in the membranes of plant chloroplasts—the biochemical machines in plant cells that convert the sun’s energy into fuel. They show that this protein transports fatty acids, the building blocks for plant oils, across chloroplast membranes. This knowledge could be applied to increase oil and biofuel production in plants. Further, because structural relatives of this factor exist in all vertebrate mitochondria—the powerhouses of our cells—this study opens up possibilities for the development of new transport systems, even in animals, that could impact our lives in unexpected ways.

 

Surviving the Flood

A study from our Collection that published in September 2014 may lead to new strategies to help crops adapt to low oxygen availability. But why is this important? Plants experience sub-optimal oxygen conditions during events such as floods—flooding causes root hypoxia. This is a key problem that must be solved if our crops are to adapt to global warming, given the likelihood of increased flooding as our climate changes. It turns out that only a few of the molecular components that allow plants to adapt to fluctuating oxygen levels are known. Research carried out by Beatrice Giuntoli and co-authors uncovered a mechanism that regulates how plants sense oxygen, identifying a factor that allows plants to modulate the response to hypoxia. This work presents new opportunities for breeding crops that can resist floods—traits that may prove key to food security as plants adapt to environmental change.

 

Keeping Arsenic off Our Plates

Image credit: doi/10.1371/journal.pbio.1002009

Image credit: doi/10.1371/journal.pbio.1002009

The final paper I’ll highlight here, published in December 2014, is one that I find particularly compelling. Much of the world’s groundwater contains arsenic, a toxin that has been linked to cancer and heart disease. Arsenic accumulates in irrigated crops, and its ingestion through foods presents a serious risk to human health. Because rice absorbs arsenic more readily than other grains, this problem disproportionately affects people in countries where rice is a staple and the water is contaminated. While we know that plants eliminate arsenic, we don’t know how they accomplish this. In their study, Dai-Yin Chao and collaborators identify a new gene that plants require to reduce arsenic accumulation. This work provides an important new resource for the development of foods with low arsenic levels—with the potential to improve food safety for untold numbers of people.

 

PLOS launched this Collection because we believe that discoveries with translational potential should be published in Open Access journals. We aim to spur discussion about the need for translational research and communicate the findings to the widest possible audience.

 

But how can we encourage public discourse about promising advances in plant translational research? Going back to the garden now, my thoughts drift to summer trips home to Michigan or Maine. When visiting family, it seems I always end up spending time face-down, pulling weeds. Thinking of the name on my dad’s barn in Maine—Grand View Farm—it strikes me that we’re all going to need to expand our ideas about how agriculture can be transformed to accommodate our increasingly demanding world.

 

So where do we go from here? Check out the fantastic new additions that we’ve just published in PLOS Biology. Spread the word about translational research by sharing your favorites. Help us build this Collection by submitting your discoveries to one of our journals (PLOS Biology, PLOS Pathogens, PLOS Genetics, PLOS Computational Biology and PLOS ONE are the most relevant), so that to that those who would most benefit can access your findings without barriers.

 

We’d like to thank all of the researchers who have submitted their work in response to our call for papers. We’re grateful to our advisory Academic Editors for their advice on this Collection: Jeffrey Dangl, Sophien Kamoun, and Susan McCouch. We also 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”:

 

PROTEIN TARGETING TO STARCH is Required for Localising GRANULE-BOUND STARCH SYNTHASE to Starch Granules and for Normal Amylose Synthesis in Arabidopsis by David Seung, Samuel C. Zeeman and colleagues.

FAX1, a Novel Membrane Protein Mediating Plastid Fatty Acid Export by Nannan Li, Katrin Philippar and colleagues.

A Trihelix DNA Binding Protein Counterbalances Hypoxia-Responsive Transcriptional Activation in Arabidopsis by Beatrice Giuntoli, Pierdomenico Perata and colleagues.

Genome-wide Association Mapping Identifies a New Arsenate Reductase Enzyme Critical for Limiting Arsenic Accumulation in Plants by Dai-Yin Caho, David E. Salt and colleagues.

 

Christina Kary is an Associate Editor at PLOS Biology.

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Chromosome Biology: You’ve Come a Long Way, Baby

It might be hard to believe, but 2015 marks ten years of PLOS Genetics! To celebrate ten years of hard work, research, and immense dedication from our Editorial Board, we are featuring posts from ten of our editors about the discoveries that they have found exciting and paradigm-shifting in the last ten years. First up is Beth Sullivan, PLOS Genetics Associate Editor, on the last ten years of chromosome biology.

Beth Sullivan is a Principal Investigator and Associate Professor at Duke University Medical Center in Durham, NC.

Beth Sullivan is a Principal Investigator and Associate Professor at Duke University Medical Center in Durham, NC.

I saw my first mammalian chromosomes under the light microscope when I was a high school student during the 1980s. The 46 X-like bodies stained with Giemsa dye were evenly distributed in the microscope’s field of view. They were beautiful and I was enchanted. As I inspected them more closely, I wondered why the chromosomes were different sizes. Why did they have different patterns of light and dark bands? Why were they pinched in the middle? Then and there, I vowed to understand these questions, and pledged to study chromosomes for the rest of my life. (Teenagers can be so dramatic.)

Within ten years, I was immersed in the field of chromosome biology. I went to graduate school, where I ultimately worked with a leading cytogenetics researcher. Under his mentorship, I studied the formation and behavior of a common human chromosomal abnormality known as Robertsonian translocation.

In the 1990s, chromosome biology was mainly defined by cytogenetics – karyotyping by G- and R- banding. In 1991, FISH (fluorescence in situ hybridization) was developed. With the help of molecular cloning and PCR, FISH provided a way to fluorescently visualize chromosomes or specific parts of chromosomes, as well as identify abnormalities.

At the same time, other methods to study chromosomes were being used elsewhere, particularly by Ulrich Laemmli and his protégé William Earnshaw who leveraged biochemical and high-resolution microscopic approaches to study the chromatin basis of mitotic chromosomes.

By the time I started my postdoc with Gary Karpen at the Salk Institute in the early 21st century, it was possible to look at chromosomes in three dimensions or as stretched DNA or chromatin fibers, and it was even possible to build chromosomes from scratch. Today, genome editing technologies like CRISPR and TALENs are making it feasible to quickly create and visualize almost any type of genome rearrangement.

When I was asked to write about one discovery that I considered the most exciting in chromosome biology within the last decade, I quickly realized it would be difficult to choose just one study. Although I was tempted to select one of the many advances from my field of centromere biology*, I instead selected a study that continues to excite me every time I re-read the manuscript. It’s the one that causes students to say “wow!” whenever I teach it in my human genetics or medical genetics classes.

The Lawrence Lab's strategy to apply X chromosome dosage compensation to Trisomy 21. Using genome engineering (Zinc Finger Nucleases), the lab inserted the XIST gene into the extra chromosome 21 in induced pluripotent stem cells (iPSCs) derived from a Down Syndrome patient. Excitingly, the XIST gene was transcribed and the long non-coding XIST RNA coated the extra chromosome 21, shutting off gene expression and shifting chromosome 21 gene dosage toward a normal diploid state. (Figure used with kind permission of Jeanne B Lawrence; http://www.umassmed.edu/cellbio/labs/lawrence/research-interests/research-human-genetics/)
The Lawrence Lab’s strategy to apply X chromosome dosage compensation to Trisomy 21. Using genome engineering (Zinc Finger Nucleases), the lab inserted the XIST gene into the extra chromosome 21 in induced pluripotent stem cells (iPSCs) derived from a Down Syndrome patient. Excitingly, the XIST gene was transcribed and the long non-coding XIST RNA coated the extra chromosome 21, shutting off gene expression and shifting chromosome 21 gene dosage toward a normal diploid state. (Figure used with kind permission of Jeanne B Lawrence)

This pioneering work came from Jeanne Lawrence’s group and was published in the journal Nature in 2013 (Jiang J et al. Translating dosage compensation to trisomy 21. Nature 500:296-300; freely available through PMC).

The premise of the study was to explore “chromosome therapy” as a strategy to correct genetic imbalance created by trisomy (a state in humans in which there are 47 chromosomes instead of the normal 46 in each cell). The researchers focused on Trisomy 21, or Down Syndrome, the most common trisomy in humans (1:300 live births).

Down Syndrome is defined by the presence of an entire or partial copy of an extra chromosome 21 (HSA21). Patients have intellectual and cognitive disabilities, as well as heart defects, motor impairments, blood disorders, and increased risk of early Alzheimer disease. The syndrome exhibits vast phenotype (symptomatic) variability that remains unexplained. This is partly because of incomplete knowledge of Down Syndrome critical genes and the cell and developmental processes affected by increased HSA21 dosage.

The Lawrence lab is probably best known for studies of X chromosome inactivation (XCI), the process by which one of the X chromosomes in mammalian females is functionally silenced. This event equalizes gene dosage between females (XX) and males (XY). XCI largely depends on the expression and spreading of a large non-coding RNA called XIST exclusively from the inactive X. XIST RNA moves from the site where it is produced and spreads along the length of the X. Its appearance and distribution on the inactive X is accompanied by a series of epigenetic (sequence-independent) protein and DNA changes that essentially turn off ~700 genes on the chromosome.

In the 1990s, cytogenetic studies of translocations between HSAX and autosomes (non-sex chromosomes, i.e. X or Y) had shown that XIST could spread, at least partially, into autosomal material and silence genes. The Lawrence group speculated that insertion of XIST onto one of the extra HSA21s in cells from a Down Syndrome patient might shut down the chromosome. This would result in a cell that contained only two functional HSA21s.

The group introduced nearly the entire XIST cDNA (21kb) into cultured induced pluripotent stem cells (iPSCs) derived from a male Down Syndrome patient. To ensure precise insertion of XIST into HSA21 only, they used genome-editing tools called Zinc Finger Nucleases (ZFNs). These modified proteins were engineered to recognize a specific DNA sequence on HSA21. They would create a break at this sequence that was then repaired by inserting the cassette containing the XIST gene.

Amazingly, the genome editing strategy was successful! XIST RNA was produced on the targeted HSA21 and it visibly spread over the entire HSA21, recapitulating many of the epigenetic features normally associated with an inactive X. Even more exciting, the authors showed that HSA21 genes, including APP, a gene linked to Alzheimer’s disease, were silenced on the XIST-targeted HSA21.

The chromosome silencing strategy in iPSCs also revealed new information about how the extra HSA21 affects brain development. Corrected neural progenitor cells showed higher levels of neural progenitor cell growth and proper rosette formation compared with uncorrected cells that took much longer to grow to the same cell number and to form rosettes. Because neurogenesis follows a prescribed temporal path, these findings imply that some of the irregularities in Down Syndrome brains may be due to delayed developmental timing of neurogenesis.

A seminal study of this type naturally leaves many unanswered questions – Are other features of Down Syndrome corrected? Is gene silencing on the HSA21 consistent across the entire chromosome? Despite these unanswered questions, what made this a fascinating and notable piece of work to me was the way in which it elegantly united three distinct biological processes – X inactivation, gene silencing, and consequences of chromosome abnormalities – into a beautiful story that is grounded in basic research, but cues up the translational option of a unique type of gene therapy.

From this clever line of experimentation, we now know that a silencing mechanism specific to the X chromosome can be co-opted to silence genes on an unrelated chromosome. Could this occur on other chromosomes? Could one partially silence a chromosome or a subset of genes on a portion of a chromosome? How viable will this therapy be in a whole organism?

I expect to read more from this group and others as they extend and improve the technology. And if nothing else, I look forward to more inspiring and groundbreaking studies like this one in the next ten years of chromosome biology!

——————————————-

*If you have the time, check out these studies that rocked the chromosome biology world in the last decade and made my short list for this post:

1. Controllable Human Artificial Chromosomes (2008)

2. Creation of Neocentromeres/De Novo Centromeres at Unique Locations (2009, 2013)

3. The Three-Dimensional Genome (3C, 4C, 5C, HiC)

 

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Understanding images: A giant single-celled plant

This continues our series of blog posts from PLOS Genetics about our monthly issue images. Author Daniel Chitwood discusses January’s issue image from Ranjan et al

Author: Daniel H. Chitwood

Competing interests: Daniel H. Chitwood is an author of the article discussed in this blog.

Frond apex of C. taxifolia, producing young pinnule primordia. Image Credit: Daniel H. Chitwood.

Frond apex of C. taxifolia, producing young pinnule primordia.
Image Credit: Daniel H. Chitwood.

Multicellularity – especially in animals – is considered to be an important prerequisite for complex morphologies that it can enable. Land plants, too, are multicellular organisms that possess exquisite architectures comprised of leaf, stem, and root-like structures. Remarkably, from the mosses to the flowering plants, these organs arose independently multiple times during land plant evolution – an example of convergent morphology, suggesting functional significance conferred by similar structures.

But plants comprise many more lineages than just the land plants, and also include the green algae. Among the green algae are a plethora of shapes and forms [1]. There are single celled flagellated species like Chlamydomonas, and some green algae species can form spherical colonies, like in Volvox. Other multicellular lineages of green algae, like Trentepohlia, even became terrestrial, independently of the land plants, sometimes forming symbiotic lichens.

Some green algae are giant, single celled organisms with varied and complex morphologies; Acetabularia, with an anchoring rhizoid and mushroom-like cap, possesses a single, giant macronucleus. Grafting experiments between Acetabularia species with different shapes provided some of the first evidence that the nucleus contains genetic information [2]. Other siphonous algae, like Caulerpa, are true coenocytes, with multiple, numerous nuclei. Caulerpa species have been argued to be the largest free-living single celled organisms in the world, with stolons sometimes meters in length iteratively producing fronds that can be up to 60-80 cm long. One particular species, Caulerpa taxifolia, is especially interesting. It has been dubbed the “killer alga” and has been argued to have invaded coastal ecosystems around the world. Within its cytoplasm are endosymbiotic bacteria that may help in the uptake of nutrients from the holdfast, and it can completely regenerate itself if fragmented.

C. taxifolia possesses beautiful feather-like fronds emerging from a running stolon with holdfasts – features that convergently resemble land plants – showing that multicellularity is not required for the archetypal land plant form. Moreover, C. taxifolia challenges some of the corollaries of cell theory, e.g. the idea that organism-level properties are an emergent property of cellular phenomena.

C. taxifolia Image credit: The Southwest Regional Office of the National Marine Fisheries Service.

C. taxifolia
Image credit: The Southwest Regional Office of the National Marine Fisheries Service.

If an organism consists of only a single cell, concepts like “tissue” and “organ” lack meaning; and yet C. taxifolia exhibits convergent land plant morphology. How?

In this issue of PLOS Genetics, we describe an intracellular transcriptomic atlas of gene expression within the giant-celled species C. taxifolia [3]. Predominant patterns of gene expression progress in a basal-apical direction, from the holdfast and stolon to the frond apex. Remarkably, the genes associated with these expression patterns track the progression of the gene expression process. Thus DNA polymerase II transcripts are highly expressed in the holdfast, and transcripts associated with nuclear activities, such as DNA replication, recombination, and repair, chromatin metabolism, and RNAi pathways are almost exclusively restricted to the stolon and basal frond region. Moving apically, translation-related transcripts are found in the frond rachis and pinnules, and at the frond apex, transcripts related to vesicular trafficking are enriched. Perhaps the most striking finding is that conserved groups of genes are co-expressed between organs of a land plant (tomato) and the pseudo-organs of C. taxifolia. For example, the stolon of C. taxifolia exhibits molecular homology with the meristematic tissue of tomato, consistent with this pseudo-organ producing lateral appendages, such as the frond and holdfast.

Donald Kaplan had eloquently argued for an “organismal theory” in plants rather than cell theory [4]. He asserted that cellular phenomenon had less to do with plant morphology than processes occurring at an organismal level. He even went so far as to argue that land plants are siphonous, exhibiting properties similar to giant coenocytes like Caulerpa, namely because of their symplasm and plasmodesmata. Caulerpa is the manifestation of organismal theory, and our work shows how the repercussions of organismal theory are borne out at a molecular level, where cellular compartments correspond to pseudo-organs, and gene expression patterns are conserved between morphological structures within a cell (Caulerpa) and between the cells comprising tissues (tomato and other land plants).

There is much more work to do. Are all the nuclei equally active in Caulerpa? Does the predominance of transcription-related transcripts and RNAi machinery in the stolon suggest these processes only occur there, implying long-distance molecular transport? If Caulerpa does exhibit nuclear dimorphism, does it follow a somatic/germline divide? And if not, do individual nuclei accumulate lineage-specific mutations, and what are the implications at a population genetic level? The novelty of a single celled organism convergently arriving at the same morphology as land plants is unique, and certainly the mechanisms that enabled such a feat will challenge fundamental assumptions about plant development.

1.      Cocquyt E, Verbruggen H, Leliaert F, De Clerck O (2010) Evolution and cytological diversification of the green seaweeds (Ulvophyceae). Mol Biol Evol. 27: 2052-61.

2.      Hämmerling J (1953) Nucleo-cytoplasmic relationship in the development of Acetabularia. J Intern Rev Cytol 2: 475-498.

3.      Ranjan A, Townsley BT, Ichihashi Y, Sinha NR, Chitwood DH (2015) An intracellular transcriptomic atlas of the giant coenocyte Caulerpa taxifolia. PLoS Genet. 11: e1004900.

4.      Kaplan DR, Hagemann W (1991) The relationship of cell and organism in vascular plants. Bioscience 693-703.

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Predicting anticancer drug activity, identifying cancer-driving mutations, and the adaptability of the human brain: the PLOS Comp Biol January Issue

Here are our highlights from January’s PLOS Computational Biology

Predicting Anticancer Drug Activity

There is increasing evidence that altering different functional regions within the same protein can lead to dramatically distinct phenotypes. By focusing on individual regions instead of whole proteins, Adam Godzik and colleagues are able to identify novel correlations that predict the activity of anticancer drugs. The authors also show how associations found between protein regions and drugs – using only data from cancer cell lines – can predict the survival of cancer patients. All the associations described in the paper are available from http://www.cancer3d.org.

 

Identification of Constrained Cancer Driver Genes

A signal in a three-dimensional NMR spectrum being assigned to a specific nucleus of the protein backbone. Image Credit: Markus Niklasson

A signal in a three-dimensional NMR spectrum being assigned to a specific nucleus of the protein backbone.
Image Credit: Markus Niklasson

Cancer genome sequencing projects result in vast amounts of cancer mutation data, but our understanding of which mutations are driving tumor growth and which are selectively neutral is lagging behind. Functional interactions among mutations can result in mutational dependencies, and these mutations then display low marginal mutation frequencies across tumor samples, complicating the identification of these drivers. Niko Beerenwinkel and colleagues present a new computational method for calling candidate driver mutations by discriminating dependent mutations from independent ones based on their dynamical patterns of occurrence.

 

The Adaptability of the Human Brain

The human brain is a complex system in which the interactions of billions of neurons give rise to a fascinating range of behaviours. Across situations involving rest, memory, focused attention, or learning, the brain dynamically switches between distinct patterns of activation. Jean M. Carlson and colleagues apply new techniques from dynamic network theory to describe the functional interactions between brain regions as an evolving network. By examining patterns of neural activity during rest – an attention-demanding task – and two memory-demanding tasks, the authors identify groups of brain region interactions that change cohesively together over time, both across tasks and within individual tasks.

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This Week in PLOS Biology

In PLOS Biology this week, you can read about shrinking the gap between patients and researchers, cookie-cutting membrane perforators, the breakdown of a cozy relationship between flies and bugs, how worms fight selfish DNA, and fine-tuning signaling pathways.

 

 Getting Patients into the Lab

In a new community page, Marion Mathieu, Constance Hammond and David Karlin describe a lab-based training programme to help patients with genetic and autoimmune diseases better understand the scientific method and how research works in practice. This helps to foster partnerships between patient groups and medical experts.

 

How Perforins Punch a Hole through Membranes

Image credit: 10.1371/journal.pbio.1002049

Image credit: 10.1371/journal.pbio.1002049

Natalya Lukoyanova, Stephanie Kondos, Helen Saibil, Michelle Dunstone & colleagues use a combination of structural methods which reveal the complex process by which the perforin-like fungal toxin Pleurotolysin rearranges its structure to form a pore that punches a hole in target cell membranes. The Although the study was performed on a fungal toxin, similar proteins perform important roles in our immune cells to protect us by destroying infected cells, cancerous cells, and bacteria. See the amazing video here.

 

 

 

 

When Wolbachia Mutualism Breaks Down

Performing genetic studies on symbiotic organisms is inherently challenging. An elegant experimental evolution approach by Ewa Chrostek & Luis Teixeira reveals that a strain of the symbiotic bacterium Wolbachia that over-replicates and shortens the life of its fruit fly host owes this property to the amplification of a small region of its genome. Read the accompanying Primer by Nicole Gerardo.

 

Dynamic Evolution of Small RNA Pathways in Nematodes

Image credit: 10.1371/journal. pbio.1002061

Image credit:
10.1371/journal.
pbio.1002061

Peter Sarkies, Eric Miska and colleagues have conducted a survey of the nematode phylum which reveals loss of the Piwi/piRNA pathway in several lineages, but RNA-dependent RNA polymerases control transposable elements in its absence. Their approach involved starting from the well-known situation in the model organism Caenorhabditis elegans and then doing a broad study of small RNAs—and the proteins that make and then use them—across the entire nematode phylum. Read more in the accompanying Synopsis.

 

 

 

Positive and Negative Feedback in TGFβ Signaling

Image credit: doi:10.1371/journal.pbio.1002051.g004

Image credit:
10.1371/journal.
pbio.1002051

Cells depend on signals from their microenvironment to carry out their normal functions and coordinate responses. A new research article by Wenchao Gu, Roger Patient and colleagues found that the LIM domain binding protein Lbd2a mediates both positive and negative feedback via transcription factors of the SMAD family, thereby fine-tuning the regulation of transcription in response to transforming growth factor β signalling during embryonic development.

 

 

 

 

Category: Biology, Cell biology, Cell signalling, Community, Developmental biology, Disease, Education, Genetics, Genomics, Microbiology, Molecular biology, Outreach, PLOS Biology, Research | Leave a comment

The ethics of big data: Focus Feature

Written by Jason Papin, Deputy-Editor-in-Chief for PLOS Computational Biology

There has been a recent explosion of big data due to the development in mobile technologies which quickly and easily connect to the Internet. This “big data” onslaught (a term I use cautiously, given its ill-defined and “buzzy” use) has catalyzed the opening of numerous research avenues. With these exciting new research opportunities comes the much needed consideration of ethical challenges; many of which would not have been predicted a short time ago. These ethical challenges that accompany the use of “big data” in biology and medicine are the subject of a new Focus Feature in PLOS Computational Biology.

Focus Feature Steve Rainwater/Flickr

Focus Feature
Credit: Steve Rainwater/Flickr

The editors of PLOS Computational Biology have developed the Focus Feature concept as a vehicle to group together papers of interest, either newly published or pulled from the journal archives, to provide a forum for discussion of cutting-edge topics in the field. Phil Bourne (Founding-Editor-in-Chief of PLOS Computational Biology and serves as the Associate Director for Data Science at the National Institutes of Health of the United States) writes an Editorial to accompany this initial Focus Feature and as a companion to a new paper by Effy Vayena  and colleagues.

The paper by Vayena et al. published on 9th February, 2015 discusses the development of “digital epidemiology” and how big data from social media are enabling the development of early disease detection strategies as well as other applications. The recent massive outbreak of Ebola, with reports of early detection from social media data analysis, is an excellent example of the power of the potential in the field. With these developments come unique ethical questions that the community needs to tackle. This paper by Vayena et al. delineates many of the ethical considerations and provides ideas on frameworks to address these concerns.

Three other papers published in PLOS Computational Biology are also featured in this Focus Feature, highlighting related considerations. Marcel Salathé and colleagues write about the genesis of “digital epidemiology” which has emerged as a field with the advent of mobile technologies and social networks. Thus they have provided an opportunity to address outstanding questions on disease and health dynamics in ways that have been impossible previously.

Map generated by more than 250 million public tweets Credit: Salathé et al.

Map generated by more than 250 million public tweets
Credit: Salathé et al.

Openness of data and methods has been critical for the development of computational biology, yet there are privacy concerns emerging with personal genomics data that need to be considered. Dov Greenbaum and colleagues discuss these issues for the field and review technological and legal developments that may mitigate particular aspects of these concerns.

Furthermore, Yann Joly and colleagues share experiences and lessons from the International Cancer Genome Consortium on balancing concerns regarding data access and privacy, including a discussion of a tiered access system as a possible strategy to appropriately mitigate issues that arise.

The PLOS Computational Biology editors hope that Focus Features will perform a valuable role in the community, serving as a nexus of work of central concern in the field.  The ethics of big data will be an increasingly important consideration and these papers will bring these issues to the forefront of community discussion.

The Ethics of Big Data Focus Feature consists of the following papers:

Ethical Challenges of Big Data in Public Health Vayena et al.

Confronting the Ethical Challenges of Big Data in Public Health Philip E. Bourne

Digital Epidemiology Salathe et al.

Genomics and Privacy: Implications of the New Reality of Closed Data for the Field Greenbaum et al.

Data Sharing in the Post-Genomic World: The Experience of the International Cancer Genome Consortium (ICGC) Data Access Compliance Office (DACO) Joly et al.

 

Category: Biology, Community, Computational biology, Data, Debate, PLOS Computational Biology, Uncategorized | Leave a comment

This week in PLOS Biology

In PLOS Biology this week, you can read about a fundamental step in the making of plant oils and the pitfalls of material transfer agreements.

 

Fatty Acid Export in Plants

Image credit: 10.1371/journal.pbio.1002053

Image credit: 10.1371/journal.pbio.1002053

Oils from plant seeds provide the basis for many aspects of modern life that are taken for granted – for example making cooking oil, soap, fuel and cosmetics. The fatty acid component of triacylglycerides is where the bulk of the energy is invested. In plants these start life in the chloroplasts – but the crucial mechanism by which they get out of the chloroplast for further processing is unclear. Nannan Li, Katrin Philippar & colleagues found a novel protein – FAX1, that mediates the export of free fatty acids across the inner membrane of chloroplasts so that they can be processed in other plant cell organelles to generate oils, waxes, and other lipids. Read more in the synopsis.

 

 

Image credit: Louise Maybank

Image credit: Louise Maybank

Material Transfer Agreements: Use and Misuse

Material transfer agreements (MTAs) ostensibly exist to facilitate the exchange of materials and associated data between researchers as well as to protect the interests of the researchers and their institutions. In a new Perspective, Tania Bubela, Jenilee Guebert & Amrita Mishra argue from a position of pragmatism and proportionate risk that these agreements are unnecessarily burdensome and obstructive and in most cases could (and should) be replaced by simpler tools.

 

Category: Biology, Debate, Molecular biology, Plant biology, PLOS Biology, Policy, Research, Resources | Leave a comment

Toward True Public Engagement in Science

As California struggles with a measles epidemic brought on by vaccine-refusing parents and surveys reveal that 80 percent of Americans support mandatory labeling on foods that contain DNA, it might appear that efforts to bridge the gap between scientific facts and how people views those facts have failed miserably.

But the issue is complicated. Simply throwing facts into the gap does little to bridge the divide – vaccine refusal is a good case study for this — because values often play a greater role than facts in determining public attitudes toward science. A better path to aligning public views with the facts of science, some have argued, is through public engagement — not as a way to bend people to the goals of scientific initiatives but as a way to open the process of scientific decision-making to public scrutiny.

The urgent need for true public engagement hit home for us at PLOS Biology several years ago, when one of our authors received devastating news.

Shortly before dawn on August 15, 2010, a small army of anti-GMO activists broke into an experimental vineyard in Colmar, the heart of France’s Alsatian winegrowing region. Within minutes, members of Les Faucheurs Volontaires (Voluntary Reapers) had uprooted 70 transgenic rootstocks and hacked them to bits.

The “reapers,” hell bent on destroying what they saw as anathema to France’s sacred heritage, obliterated seven years of work worth more than $1.5 million dollars in less time than it takes to drink a glass of the region’s famous Riesling.

The Colmar experimental vineyard, with Pinot Meunier grapevines grafted onto transgenic rootstocks before anti-GMO activists destroyed all 70 plants.

The Colmar experimental vineyard, with Pinot Meunier grapevines grafted onto transgenic rootstocks before anti-GMO activists destroyed the vineyard.

The attacks were particularly demoralizing for our author, Jean Masson, who directed the project for the French National Institute for Agronomic Research. Well aware of local antipathy to genetic engineering, he’d taken measures to make the research – designed to boost the inbred rootstocks’ tolerance of an ancient foe, the devastating grapevine fanleaf virus — more palatable to GMO opponents, which, in France, were legion.

His scientists had inserted a gene from the virus into the rootstock’s genome — leaving the fruit-bearing vines GMO-free — hoping the rootstocks would express just enough viral proteins to trigger the plant’s immune defenses, acting like a vaccine.

But even more important, Masson had taken careful steps to engage community members in the research process by creating a “monitoring committee” made of local winemakers, environmentalists, organic growers, neighbors and others with a stake in the project to help the scientists design their experimental protocol.

Masson had approached PLOS Biology just two months before the attack with a potential article demonstrating how the committee, using an approach called “interactive technology assessment,” had integrated the input of diverse stakeholders to shape the path of technological innovations in the heart of French winegrowing country, where resistance to innovation runs deeps.

Masson’s article was under review when he learned that his vines had been destroyed. The monitoring committee and the paper describing his ITA approach were all that remained of the research when the reapers were through.

Devastating as the attacks were, they did not erase Masson’s success in working with such an innovation-shy community to apply modern technologies to an age-old problem. It was that success that inspired us to consider what meaningful public engagement might look like.

How does public debate around emerging technologies change if people with diverse interests are invited to participate in research projects in meaningful ways rather than simply brought on as window dressing to indicate public approval? What if different viewpoints were considered as technologies were being developed, before a specific application became a fait accompli? If environmentalists’ concerns about the ecological effects of designing crops to withstand high levels of herbicides had been integrated into decisions governing the use of transgenic crops, for example, would Midwestern farmers have been able to imperil the monarch butterfly by decimating the only plant it uses to reproduce?

These are questions many scientists don’t often think about or even think are important, even though funders often build “public attitude” research into their grants. And they are not solely scientific questions. Science does not operate in a vacuum but, in pluralistic societies at least, in a complex environment with diverse and genuine competing interests where access to decisions that affect the public good is supposed to matter.

That’s why we asked social scientists who study the intersection of science and society to help us curate a series to explore the promise of true public engagement. We launched the Public Engagement in Science series four and a half years ago, with Masson’s article. Today, we have a thriving collection overseen by Claire Marris, director of Biotechnology, Pharmaceuticals and Public Policy Research Group at King’s College London.

The series has covered issues ranging from participatory medicine to the practice of hiding safety data under claims of confidential business information. Most recently, we ran a pair of articles that argued for transparency in the research-grant funding process — one argued for an incremental approach while the other called for more radical measures — so that researchers and the taxpayers who support them can see the decisions that lead to a successful proposal. Researcher reaction to the articles, including a sampling of responses on Twitter, was captured by Chris Woolston in Nature.

A theme that runs through the series is the need to move beyond seeing public engagement as a means to achieve predetermined ends – usually increasing public support for a particular initiative — toward engagement as an end in itself. What this means in practice is initiatives that aim simply to boost public acceptance of science but do not offer a mechanism for the discussion of different viewpoints and concerns is not public engagement but marketing.

The idea is not to provide a platform for zealots like the anti-GMO reapers or anti-vaccination diehards but to provide a space for open, reasoned discussion of ethical and social issues associated with the development and application of biotechnologies. It is not unreasonable to debate whether scientists should use the tools of synthetic biology to resurrect long-extinct species just because they can and because some think it would be cool to see ice age behemoths walk the earth again. It is not unreasonable to debate whether a genomics startup with a mission to “democratize creation” should be allowed to sell DNA kits to “anyone in the world” who wants to become a genetic designer.

Lest anyone doubts the need for finding approaches that accommodate divergent views on science-related issues, a new study from the Pew Research Center and the American Association for the Advancement of Science shows just how differently scientists and nonscientists (aka the “general public”) see the world. The biggest divide, perhaps not surprisingly, concerns the safety of genetically modified foods: 57% of nonscientists view GM foods as generally unsafe to eat compared to 88% of AAAS scientists who say GM foods are generally safe.

In the study, the Pew Research Center notes that it has made a “more deliberate and formal commitment to study the intersection of science with all aspects of society” … “because scientific advances and challenges are influencing an ever-greater share of American and global life. The pace of innovation and the urgency of scientific issues have captured a growing share of policy energy and at times generated more and more dispute.”

When Masson and his colleagues invited public scrutiny of their work to use genetic engineering to help grapevines fight an ancient nemesis, they never intended to change the minds of entrenched anti-GMO ideologues. Their goal was to offer the community a chance to look behind the curtain, to see science in action and demystify the process of genetic modification, and help identify questions that might even strengthen the work to find a pathway of innovation that worked for a change-resistant community.

In the end, Masson and his colleagues noted, although participants often engaged in heated debates, a shared commitment to respecting different viewpoints as well as the demands of science allowed them to “rise above a binary confrontational mode of ‘for or against.’”

Inviting people to influence the way technologies of broad interest to society might be applied through public engagement initiatives will not necessarily increase public acceptance of those technologies. But that’s not the point. Taxpayers shell out billions of dollars to underwrite research every year. It’s in everyone’s interest that they have a stake in the output of the research they fund.

Category: Biology, Biotechnology, PLOS Biology | 9 Comments