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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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.

 

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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.

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Introducing the Research Resource Identification Initiative at PLOS Biology & PLOS Genetics

Reproducibility is one of the holy grails of effective, open biomedical literature. But too often resources (e.g. model organisms, software, antibodies) are not reported with sufficient detail to ensure others can replicate or expand upon the results. Today sees PLOS Biology and PLOS Genetics linking in with an exciting pilot study using the principles set out by a Force11 group, the Research Resource Identification Initiative (#RII). Through the use of unique Resource Identifiers (RRIDs), authors will be able to cite the resources that they use in their manuscripts. This initiative will be completely optional for PLOS authors.  We strongly encourage our PLOS Biology and PLOS Genetics authors to use these RRIDs though wherever possible to identify their model organisms, antibodies or tools; use standard RRIDs that exist in the RRID portal, or create new ones as needed if there isn’t one already. You then simply add your RRIDs to the text of your manuscript; at their first mention (usually the materials and methods section) and we encourage that you add a separate section at the end of the manuscript if you have a longer list of accession numbers. Information can now be found on RRIDs here for PLOS Biology and here for PLOS Genetics

 

How exactly do RRIDs work? The Resource Identification Initiative has three criteria for RRIDs:

  1. Machine readable
  2. Free to generate and access
  3. Consistent across publishers and journals

Right now the feasibility of the system is being tested using three categories of resources – model organisms (mice, zebrafish, and flies), antibodies and tools (i.e. software and databases). Finding or creating the appropriate RRID for your resource couldn’t be easier. A Resource Identification Portal has been created where you can search across different databases, such as The Antibody Registry. Once you have found your resource, you can use a “Cite this” button to be shown the proper citation to insert into your manuscript. For example: Model organism:  “Subjects in this study were Fgf9Eks/Fgf9+ mice (RRID:  MGI:3840442)”.

 

What if my resource doesn’t exist in the database? The Resource Identification Portal allows you to make new entries using the “Add a Resource” option on their homepage. This makes it very easy to generate a new RRID.

 

The Research Identification Initiative so far: This project was an outcome of a meeting held at NIH on June 26th, 2013. A diverse range of journals and publishers are on board with the project – for example Journal of Neuroscience, F1000 Research, Peer J, Nature and Mendeley. By the end of 2014, over 200 papers contained RRIDs. Publications currently reporting RRIDs can be found in Google Scholar or PubMed.

 

If you’re wondering what is the value? Imagine that you’re evaluating what antibody to use, if you can easily track all papers that have used various antibodies previously, you can assess how well the antibody works in others’ hands in different scenarios, and thus be better able to choose which one to use for your study. Or, if you have generated an antibody and made it freely available, you’ll be able to see how frequently it is used by others, and to gain proper recognition via RRID citations for your materials.

 

We hope that this initiative is successful in helping to promote reproducible science. The possible benefits to authors also seem great – including saving time looking for reagents and tools and eventually being able to aggregate and compare findings on a particular animal model.

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This week in PLOS Biology

In this bumper week for PLOS Biology, you can read about bat navigation, transmission of longevity, new neurons for old brains, how yeast anticipate change, a serious downside of illegal drug laws, and how to prioritise conservation efforts.

 

Why Do Bats Fly Differently in Light Versus Dark?

Image credit: Jens Rydell

Image credit: Jens Rydell

Bats are extremely skilful aviators that can manoeuvre accurately using either echolocation or vision. A model of animal flight guidance by Nadav Bar, Yossi Yovel & colleague suggests that bats use estimates of angular velocity and time-integrated sensory information to find their targets, and explains why bats fly straighter in the light than in the dark.

 

Yeast Longevity is Transmissible

Though calorie restriction has long been known to extend lifespan and healthspan in multiple model organisms, the intrinsic mechanisms remain unclear. In a new research paper by Szu-Chieh Mei & Charles Brenner, substances secreted by calorie-restricted yeast are found to induce longer life in other yeast cells, suggesting that intercellular communication is a component of this phenomenon, even in a single-celled organism.

 

Adult Neurogenesis: Are Humans like Rodents?

This new essay by Aurélie Ernst & Jonas Frisén discusses recent work on the birth of new neurons in the human adult brain, examining how it compares to that in other mammals. Although the rates of production of new neurons are the same, humans lack neurogenesis in the olfactory bulb, but show neurogenesis in the striatum. The authors explore the evolutionary changes that may have led to these differences and speculate about the function of adult neurogenesis in humans (particularly striatal neurogenesis), addressing the possibility of taking advantage of neurogenesis for therapeutic purposes (especially in disorders that can affect the striatum, such as Huntington’s disease, Parkinson’s, and stroke).

 

Strategies for Anticipating Change

Image credit: Flickr user Reza

Image credit: Flickr user Reza

Free-living microbes have a challenging existence, entirely beholden to the vagaries of their environment. However, two studies on the unicellular yeast Saccharomyces cerevisiae show that it is sometimes beneficial to anticipate change, and evolution can capitalise on this. Both studies – one by Jue Wang, Michael Springer and colleagues, and one by Ophelia Venturelli, Hana El-Samad and colleagues – look at the way in which yeast cope when faced with a mixture of sugars (imagine rotting fruit lying on the grass in an orchard), one of which is preferred over the other. The yeast consume the preferred sugar (glucose, say), but at some point must decide to make the costly switch to being able to metabolise the less preferred nutrient (galactose). The first paper shows that yeast turn on genes needed for galactose hours before the glucose runs out, but the degree of anticipation varies between wild strains, with each strategy subject to distinct trade-offs. The second paper shows that even within a population of genetically identical yeast, a subset of individuals gambles on change by activating genes pre-emptively.

 

Illegal Drugs Laws: Blocking Research for 50 Years  

Victor

Image credit: Flickr user Victor

Did you know that heroine is a Schedule 2 drug, whereas cannabis is a Schedule 1 drug in the UK? In a passionate new Perspective, David Nutt describes how the laws on illegal drugs have stifled research and development of treatments for brain disorders for more than 50 years. Research on ‘illegal’ drugs before they were made illegal clearly showed therapeutic potential that has never been able to be realised. Here, the author makes concrete suggestions on how to clear these obstacles to research.

 

Conservation Priorities: Restoration? Protection? Both?

Roberto Verzo

Image credit: Flickr user Roberto Verzo

When it comes to habitat conservation, surely prevention is better than cure; we should protect forests as national parks rather than plant new trees, shouldn’t we? A new research article by Hugh Possingham, Michael Bode & Carissa Klein uses a modelling approach to address the question of when we should prioritise protection and restoration strategies. For their two case studies, they found that sometimes restoration is more cost-effective than habitat protection – dependent on the relative costs of the two actions, the rate of habitat loss and the time lag between restored habitat being as useful as intact habitat for securing species and ecosystem services.

 

 

Category: Biology, Climate, Debate, Ecology, Environment, Evolution, Microbiology, Neuroscience, PLOS Biology, Policy, Research | Leave a comment

This Week in PLOS Biology

In PLOS Biology this week, you can read about the the next 10 years of microbiome research, low-cost antimicrobial screening as an educational tool, and a potential new diabetes drug.

 

Transmission and Control of Ebola Virus Disease

Following on from last week’s modelling paper on Ebola in Liberia, you can read a Primer by Gerardo Chowell & Hiroshi Nishiura, which gives more information on the challenges of characterising this disease, and sets the research article in context.

 

Where next for microbiome research?

Image credit: Flickr user Filip Goč

Image credit: Flickr user Filip Goč

The last decade has seen a staggering transformation in our knowledge of microbial communities. In this unique Perspective article, Matt Waldor draws together seven short pieces in which diverse authors speculate as to what the next ten years might hold in store. Topics covered include food, agriculture and the microbiome, synthetic biology, and microbiome evolution.

 

Learning through Antimicrobials

Eucalyptus trees supply one of the antimicrobials tested (Image credit: Eug, Wikimedia Commons.)

Eucalyptus trees supply one of the antimicrobials tested (Image credit: Eug, Wikimedia Commons.)

Antibiotic resistance is a major worldwide public health issue. Increasing antibiotic resistance and the decline in new ones being approved motivates the search for novel antimicrobial agents, especially from natural sources. A new community page by Karishma Kaushik, Vernita Gordon & colleagues describes their hands-on experimental module aimed at young scientists from developing countries. They learn cutting-edge science in physical, chemical and biological systems that can be used to help the search for new antimicrobial agents (including those from plants like eucalyptus – pictured).

 

Targeting Diabetes: A Selective Epac2 Agonist

Two cAMP analogues (Image credit: Holger Rehmann)

Two cAMP analogues (Image credit: Holger Rehmann)

cAMP is a small molecule produced by cells that activates proteins involved in a wide range of biological processes, including olfaction, regulation of gene expression, insulin secretion, and many others. A new research article by Frank Schwede, Holger Rehmann & colleagues focuses on insulin secretion by the β-cells of the pancreas. They designed a cAMP analogue that specifically only activates Epac2, one of the cAMP-responsive proteins in the signalling cascade. That such selective targeting is therefore possible may open up new options for treatment of diabetes.

 

 

 

Category: Bioinformatics, Biology, Cell signalling, Computational biology, Education, Evolution, Microbiology, PLOS Biology, Research | Leave a comment