Tumor evolution and microbial forensics: the PLOS Comp Biol March Issue

Here are some highlights from March’s PLOS Computational Biology

 

Spatial Heterogeneity in Drug Concentrations

Image Credit: Fu et al.

Schematic section view of an “onion-structured” solid tumor with the nearest blood vessel located in the centre. Image Credit: Fu et al.

Acquired resistance is one of the major barriers to successful cancer therapy. There is increasing evidence that the tumor microenvironment influences cell sensitivity to drugs and thus mediates the evolution of resistance during treatment. Feng Fu and colleagues use mathematical models to investigate the effect of drug heterogeneity on the probability of escape from treatment and the time to resistance, and the results provide new insights into understanding why cancers tend to quickly become resistant.

 

Evolution and Phenotypic Selection of Cancer Stem Cells

Image Credit: Enderling

Cells of different organs at different ages have an intrinsic set of kinetics that dictates their behaviour. After transformation into cancer cells, these kinetics – that determine initial cell and tumour population progression dynamics – will be inherited. However, due to subsequent genetic mutation, cancer cell kinetics can change, and favourable alterations that increase cellular fitness will manifest themselves and accelerate tumor progression. Heiko Enderling and colleagues present a computational model of cancer stem cell evolution during tumor growth.

 

Microbial Forensics

Can the cellular state and environmental conditions of an organism be inferred from its gene expression signature? To investigate this question, Ilias Tagkopoulos and colleagues create an extensive normalized gene expression compendium for the bacterium Escherichia coli, and then construct an ensemble method to predict environmental and cellular state. Functional analysis of the most informative genes provides mechanistic insights and palpable hypotheses regarding their role in each environmental or genetic context.

Category: Biology, Cancer, Cell biology, Microbiology, PLOS Computational Biology, Uncategorized | Tagged , , , | Leave a comment

Deep Reads: Daisy Hessenberger’s evolving perspective on Gerald Durrell’s books

Our third Deep Reads blog post, ‘Deep Reads: Daisy Hessenberger’s evolving perspective on Gerald Durrell’s books’, was written by Daisy Hessenberger, who has recently completed her PhD at the University of Cambridge. Her main scientific interest has always been evolution, and during her PhD she investigated the occurrence of extreme hybrid traits. On the topic of her research, she says: “I worked with a delightful unicellular Green algae (Chlamydominas reinhardii). After getting different strains to mate, I compared the genetics and epigenetics of the hybrids.” Besides science, her interests lie in travelling, cooking, and writing whatever comes to her mind.

One thing has always fascinated me: how did the process of evolution lead to the incredible biodiversity we find in our world? It’s this question that drives me to research the epigenetic component of the formation of hybrid traits, the black box of evolution. But my initial curiosity into evolution and species diversity was born when I read Gerald Durrell’s books.

The first of his books that I read, Catch me a Colobus, describing the first of many collection trips that Gerald took to Africa, opened up my young mind to the breadth of complexity and environments found in our world. I also got my first taste of the impact human society has on animal conservation. The second, My Family and Other Animals, taught me that biodiversity could be found closer to home, and that even an aspiring 10-year-old naturalist could make some profound (and often amusing) discoveries. He recounts countless hours spent observing animal behaviour, from the fights involved in the courtship of tortoises to the differing levels of care provided by sparrow fathers.

colobus-280706_1280

A Colobus Monkey. Image from: Pixabay.

Whether they were some of Gerald Durrell’s more amusing books (cue chasing escaped tapirs in Menagerie Manor), or more academic in nature (such as The Stationary Ark – a collection of essays on how to ethically run a zoo), I was always captivated by the diversity of animals and behaviours that he documented. Be it describing the inhabitants of his garden or his adventures on the many collection and TV trips around the world, these books portray the glory of the natural world and why we must protect it.

As I learnt more about the environment and conservation at school, I reread The Stationary Ark and Gerald Durrell’s own account of setting up his zoo in Jersey, A Zoo in my Luggage; except this time I questioned the need for zoos and the accompanying ethical issues with a more critical eye. The more serious messages in his novels became apparent to me and it was this realization that steered me from wanting to go to veterinary school to studying evolutionary biology. The joy of a young naturalist turned into the drive of a young scientist. As I progressed through my academic career, at each and every stage of my development I found myself rereading those books with a new perspective.

At an undergraduate level, I learnt about cultural inheritance and epigenetics, both inherited separately to the underlying DNA code. My mind reeled; the network that evolution worked on had grown even more complex. Given this personal paradigm shift, I questioned the enchanting behaviour captured in Gerald Durrell’s words. The megapode bird (also known as the incubator bird) incubates its eggs underground and keeps them at the correct temperature using fermentation of vegetation. To keep the temperature stable, the male measures the temperature with his beak or tongue (scientists are yet to confirm which) and adjusts the structure of the nest as needed. How had this adaptation evolved? Could culture or epigenetics play a role? I decided to aim my academic career at understanding how such a plethora of variation could have evolved.

Now at a graduate level, I’ve had the opportunity to try to answer some of my questions, drawn from some of Gerald Durrell’s writings. Specifically, I’m researching the potential effect that small RNAs could have on hybrid phenotypes in a unicellular alga. With the results I hope to establish a firmer understanding of how these intriguing molecules can affect the evolution of hybrid traits. I am still seeking answers to many of my questions and will do so for some time. As I approach the next stage of my scientific career, I’m sure that new discoveries will lead me to reread Gerald Durrell’s books in a new light. As science advances faster and faster, it’s important not to forget tomes of natural history, as their descriptiveness can remind us of our initial inspiration and put into context the importance of our work. Taken even further, with many species of plants and animals under threat, there is no guarantee that the biodiversity which so inspired Gerald Durrell will always be around to comment on, and we may eventually have to rely on his words alone.

megapode

A megapode bird. Image credit: Vicki Nunn

We at PLOS Genetics are looking for new submissions for our Deep Reads blog series and would love to find out more about the books that have inspired you as a scientist. Have any books introduced you to a captivating new scientific concept? Or made you think about something in a completely different way? Perhaps there’s a biography of a prominent scientist that you found particularly moving. If so, please get in touch.

Selected posts will be published on PLOS Biologue and should be no more than 800 words with one or two images. Entries should relate to a book (either fiction or non-fiction) with a genetics/genomics component.

Please send entries to plosgenetics@plos.org by 1st June, 2015 and we’ll be in touch if yours is chosen.

Category: Uncategorized | Leave a comment

Any Questions about our Data Policy?

by PLOS Biology, PLOS Genetics and PLOS Computational Biology

Publication is the end of one journey, but the beginning of another (longer) one, where the ideas and the underlying data that shaped them take on a life of their own. As part of our commitment to fostering scientific progress through scholarly communication, we’re hoping to ensure the more lasting utility of published research down the line.

As we’ve discussed before, an open access paper is enhanced enormously if it’s directly linked to the openly available data from which it was constructed.  Data availability enables replication, reanalysis, new analysis, interpretation, or inclusion into meta-analyses, and facilitates reproducibility of research.

With this in mind, we updated our data access policy in March 2014, and we’ve been listening closely to the discussions that ensued. Researchers across different subject areas have raised questions about our policy and how it applies to their work.  This has helped us gain a deeper awareness of those areas in the policy that needed clarification and elaboration, as well as a deeper appreciation of the challenges associated with information scarcity.

In the hope of addressing these, we’ve released an expanded set of FAQs across each of our journal sites.  These include:

  • more detail on specific data types (sensitive data, big data, etc.)
  • general information on data deposition
  • more detail on PLOS’ submission requirements for data

We’ve also re-organized the information to accommodate the expanded content. While we hope this will give you a more accessible up-front information source, we also encourage you to send any more specific inquiries to respective journals. And as this is an ongoing process, we’ll add to the FAQs over time to continue to provide better support for the data access policy. As always, we welcome feedback (data[at]plos[dot]org).

 

Category: Advocacy, Data, Open access, PLOS Biology, Policy, Publishing, Research | 1 Comment

Understanding Images: Golden Retrievers Contribute to Cancer Research

This continues our series of blog posts from PLOS Genetics about our monthly issue images. Author Kerstin Lindblad-Toh discusses February’s issue image from Tonomura et al

Author: Kerstin Lindblad-TOH, Professor Uppsala University, Co-Director SciLifeLab Sweden and Director of Vertebrate Genome Biology, Broad Institute of MIT and Harvard.

Competing interests: Kerstin Lindblad-Toh is an author of the article discussed in this blog.

Golden retrievers carry risk haplotypes predisposing to two different cancers. Image credit: Mike Lappin

Golden retrievers carry risk haplotypes predisposing to two different cancers. Image credit: Mike Lappin

Cancer is a common disease in both humans and dogs, affecting as many as 50% of individuals in both species. Finding genes and mutations affecting both disease onset and progression would allow for a better understanding of disease mechanisms, and the potential for more accurate diagnosis and treatment guidance. In this issue of PLOS Genetics, we identify two new loci associated with two canine cancers and provide insights into their role in the disease mechanisms.

 

Human and dog cancers similar in type, but more easily mapped in dogs

Dogs and humans suffer from many of the same cancers, including lymphoma, breast cancer, melanoma, bone cancer, and hemangiosarcoma. Some cancers are common in both species, including breast cancers and lymphoma, whereas others such as osteosarcoma and angiosarcoma/hemangiosarcoma are common in dogs but relatively rare in humans. The rarity of these cancers in humans can make them hard to study. Purebred dog breeds are an attractive model for these rare cancers because the breed structure contributes not only to an enrichment for specific cancers in certain breeds, but also to making the gene mapping process more efficient. While in humans thousands or tens of thousands of samples are needed for genome-wide association mapping, in dogs complex diseases such as cancers can be mapped with only a few hundred patients and controls.

 

Lymphoma and hemangiosarcoma both coupled to reduced T-cell activation

Our study mapped lymphoma and hemangiosarcoma in purebred golden retrievers. Surprisingly, both diseases mapped to two loci on chromosome 5, together accounting for ~20% of the risk for these diseases in golden retrievers. The loci contained several genes, but no mutations changing the protein sequence were found to correlate with the genetic variants associated with the cancer risk. Instead, expression analysis of B-cell lymphomas showed that the two loci affected the expression of multiple genes. One identified risk locus down-regulates several nearby genes including TRPC6, a Ca2+-channel involved in T-cell activation. The second risk locus overlaps the vesicle transport and release gene STX8, but changes the expression of >100 genes spread across the genome. Many of these genes are involved in activating immune cells, particularly T-cells. Thus, the disease mechanism for B-cell lymphoma and hemangiosarcoma appears to act through a dysregulation of the T-cell mediated immune response to the tumor.

 

Implications of findings

The findings from this study have potential benefits for both human and canine cancer patients. While further work is necessary to identify additional risk factors contributing to the risk for lymphoma and hemangiosarcoma in golden retrievers and other breeds, there is an opportunity to use the current findings to help cancer patients. Since dogs are patients receiving clinical care just like humans, there is a need for both genetic tests that allow the assessment of disease predisposition and diagnosis, as well as the potential for more personalized treatment options based on genetic risk factors. We are therefore examining how these canine inherited risk factors affect the clinical picture, tumor mutations and treatment outcomes for our canine patients, with the hope of developing better disease regimens. Importantly, these cancers have sufficient similarity to their respective human cancers that the same genes and pathways identified in the dog are likely to play a role also in the human cancer.  Therefore, clinical trials in dogs showing correlations between genetic risk factors and treatment outcomes could also inform human cancer treatment.

 

ResearchBlogging.org
Tonomura, N., Elvers, I., Thomas, R., Megquier, K., Turner-Maier, J., Howald, C., Sarver, A., Swofford, R., Frantz, A., Ito, D., Mauceli, E., Arendt, M., Noh, H., Koltookian, M., Biagi, T., Fryc, S., Williams, C., Avery, A., Kim, J., Barber, L., Burgess, K., Lander, E., Karlsson, E., Azuma, C., Modiano, J., Breen, M., & Lindblad-Toh, K. (2015). Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers PLOS Genetics, 11 (2) DOI: 10.1371/journal.pgen.1004922

Category: Biology, Blog, Cancer, Community, Genetics, Image, PLOS Genetics | Tagged , , , , , , , , , , , , | Leave a comment

A Crisis at NCRIS – Australia’s Science Infrastructure under Threat.

by Ginny Barbour

(updated March 16th – see foot of post)

The Murchison Widefield Array. Image credit: Natasha Hurley-Walker/Wikimedia

The Murchison Widefield Array. Image credit: Natasha Hurley-Walker/Wikimedia

There’s a high-stakes game of chicken currently being played out in Australia that has everyone who uses science infrastructure (that’s, well, pretty much every scientist then) in Australia biting their nails with anxiety. The issue is this. The government of Prime Minister Tony Abbot has had a woeful year in attempting to get its budget passed. One after another, the key issues that were laid before the Parliament last year have been either voted down, or not even made it to a vote. Almost the last one, an attempt to reform higher education funding – something that everyone agrees needs to happen, just not how – is now the subject of frenzied negotiations. But the bizarre issue is this – somehow this higher education reform has been tied to continued funding for science infrastructure – specifically the National Collaborative Research Infrastructure Strategy (NCRIS) – and this money comes directly from the federal government.

 

This programme of science infrastructure, which was set up in 2004, has slowly, and quietly – in that way that infrastructure tends to happen – been built up to a point where Australia leads the world in some crucial areas. Examples include monitoring on the Great Barrier Reef, the Australian National Data Service, the Australian Synchrotron, etc. – far-sighted, innovative programmes and structures. However, this funding has never been long-term but always subject to renewal, though that in the past has always happened. And the money is not large – A$150 million yearly to keep facilities going that have already had A$2.5 billion invested into them – and on the background of an annual science budget of A$9 billion.

 

I’ve no idea what political solutions there might be here so it’s hard to not have a terrible feeling in the pit of your stomach when watching this stand-off from the sidelines. Headlines such as “The science community begs the government to continue funding vital research infrastructure” are, for once, not hyperbole. Without funding, facilities will shut down in months. One manager reports that staff are already seeking employment elsewhere.

 

Is this getting the international attention it deserves? – I’m pretty sure not. It’s not even getting that much in Australia where the airwaves and newspapers and hence politicians have their attention primarily focussed in almost macabre hour-by-hour detail on the fate in Indonesia of two Australians convicted of drug smuggling. By contrast, when the US government was brought to its knees in 2013 by the crisis over the 2014 Appropriations Bill, the world watched.

 

Scientists in Australia, including heads of many institutions, are doing what they can to explain why this all matters so much – there have been many excellent, carefully considered articles written, a Getup Campaign and a twitter campaign – #Ncrisis – is gaining traction. Even cartoonists realise the absurdity of the situation, with Schrödinger’s cat being invoked.

 

This crisis might not have the same apparent economic reverberations on other economies as the US one but science around the world will suffer – and that essentially means we all will suffer – if common sense doesn’t prevail and everyone pulls back from the brink.


 

March 16th Update

Over the past several days the funding debate has intensified with the CEO of Universities Australia noting that the level of uncertainty in university funding would not be tolerated in any other business  -“Endless tweaking of funding rates make planning for this industry impossible.” The Vice Chancellors of the Group of Eight Universities even took out a paid advertisement in several newspapers calling the decision “dumb”. In Canberra this afternoon, to much relief, the link between funding for NCRIS and University fee reform was broken and NCRIS funding restored – for one year more at least – though the long term funding of this vital infrastructure remains to be determined.​


 

Ginny Barbour is currently the Medicine and Biology Editorial Director for PLOS.  She is also the Executive Officer at the Australian Open Access Support Group, a position she took up in Feb 2015 and for which she will be leaving PLOS at the end of March 2015. She is also the Chair of COPE (an unpaid position). The views in this piece are personal and not those of her employers. She is based in Brisbane, Australia.

 

Category: Funding, Policy, Research, Resources | Leave a comment

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.

Category: Community, Evolution, Genetics, PLOS Computational Biology, Research | Tagged , , , , | Leave a comment

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.

Category: Metrics, PLOS Biology | 1 Comment

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.

Category: Biology, Biotechnology, Community, Plant biology, PLOS Biology, Publishing, Research | Leave a comment

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!

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*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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