Understanding images: microRNAs contribute to hair loss and follicle regression

In a piece reflecting on this month’s PLOS Genetics issue image, author Zhengquan Yu discusses the research behind Yuan et al.

Author: Zhengquan Yu, State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China

Competing interests: Zhengquan Yu is an author of the paper discussed in this blog.

Immunoflorscent staining of hair follicles. Image Credit: Yuan and colleagues

PLOS Genetics May Issue Image. Immunoflorscent staining of hair follicles. Image Credit: Yuan and colleagues

Up to 60% of men experience some degree of hair loss in their lifetime. However, despite its prevalence, efficient treatment for hair loss is lacking. One of the key distinguishing features of hair follicles in baldness-affected areas is premature  regression. This leads to shorter hairs and excessive hair fallout. This month’s cover image features actively growing hair follicles with prominent layers of the outer root sheath surrounding the hair shaft cortex. In this issue of PLOS Genetics, we describe an essential role for a highly conserved microRNA, miR-22, in regulating the regression of mouse hair follicles. New insights into the mechanism of premature hair growth regression in mice enrich our understanding of the pathogenesis of hair loss.


The basics of hair loss

Because hair loss results from the premature termination of the follicle’s growth phase, it is essential to understand in more detail the mechanism underlying normal hair regeneration. During the active phase of the hair growth cycle, stem cell activity sustains an actively dividing population of epithelial cells at the base of the follicle called matrix cells. As progeny of the matrix cells move upward from the follicle base (or bulb), they differentiate into a hardened hair shaft, which emerges above the skin surface. Fully differentiated hair shafts consist of dead, but mechanically sound and highly cross-linked, keratin-filled cells. After a period of active hair shaft production, follicles activate an involution program, during which a large portion of epithelial cells die, and the remaining stem cells are reduced to a tight cluster underneath the skin surface. These follicles then remain dormant for some time; however, they can undergo activation and restart active hair shaft production.

Image credit: Aida. CC BY 3.0.

Hair loss. Image credit: Aida. CC BY 3.0. Licence.

The growth, regression, and resting phases together constitute the hair growth cycle, and this cycling can be influenced by a variety of local and systemic signaling factors. Consequently defects in hair cycling can arise from changes in the normal signaling milieu due to disease, aging, or injury. Commonly, in humans, scalp hair follicles enter resting phase prematurely, and hairs shafts become shorter and fall out, resulting in visible baldness. Therefore, identifying new signaling regulators of hair follicle regression will provide a better understanding of the hair loss pathogenesis mechanism and will likely identify novel therapeutic targets.


miR-22 induction causes premature hair loss by promoting follicle involution

Immunoflorescence of hair follicle. Image credit: Yuan and colleagues.

Immunoflorescence of hair follicle. Image credit: Yuan and colleagues.

To test the function of miR-22, we generated a genetic tool to induce miR-22 overexpression in mouse hair follicles, and interestingly, found that increasing miR-22 results in hair loss in mice due to the premature regression of actively growing follicles. Surprisingly, our data reveal that the expression of over 50 distinct keratin genes are markedly reduced by miR-22 and that silencing of keratin-mediated hair shaft assembly by miR-22 is a prerequisite for follicle regression. At the molecular level, we found that miR-22 directly represses multiple transcription factors, including Dlx3 and Foxn1, which positively regulate the expression of keratin genes.

Hair loss in mice. Image credit: Yuan and colleagues.

Hair loss in mice. Image credit: Yuan and colleagues.

Indeed, deletion of Dlx3 or Foxn1 closely resembles the hair loss phenotype caused by miR-22 induction. Thus, by suppressing Dlx3- and Foxn1-dependent keratin expression, miR-22 is sufficient to terminate hair differentiation. In addition, miR-22 contributes to follicle regression by repressing proliferation of hair stem cells and promoting their death. Collectively, miR-22 emerges as a key regulator of follicle transition from the growth to regression phase. There are hundreds of microRNAs expressed in a hair follicle [2], but most of them are not well studied. Our findings of the essential role of miR-22 highlight the importance of determining the combinatorial effects of the microRNA regulatory network in hair cycling.


Implications of findings

In the future, our findings are likely to benefit human hair loss research efforts. Androgenic alopecia, where premature regression of scalp hair follicles is induced by increasing androgen levels, is the most common hair loss disorder in humans. Interestingly, it has been reported that miR-22 is strongly induced in the liver in response to testosterone treatment [3,4]. Our unpublished data show that two binding sites for an androgen receptor are located in the promoter of both human and mouse miR-22. These findings support the hypothesis that miR-22 functions in the pathogenesis of Androgenic Alopecia, warranting future studies of miR-22 inhibitors as potential anti-hair loss drugs.


  1. Lee J, Tumbar T (2012) Hairy tale of signaling in hair follicle development and cycling. Semin Cell Dev Biol 23: 906-916.
  2. Mardaryev AN, Ahmed MI, Vlahov NV, Fessing MY, Gill JH, et al. (2010) Micro-RNA-31 controls hair cycle-associated changes in gene expression programs of the skin and hair follicle. FASEB J 24: 3869-3881.
  3. Delic D, Grosser C, Dkhil M, Al-Quraishy S, Wunderlich F (2010) Testosterone-induced upregulation of miRNAs in the female mouse liver. Steroids 75: 998-1004.
  4. Wang WL, Chatterjee N, Chittur SV, Welsh J, Tenniswood MP (2011) Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer 10: 58.


Yuan, S., Li, F., Meng, Q., Zhao, Y., Chen, L., Zhang, H., Xue, L., Zhang, X., Lengner, C., & Yu, Z. (2015). Post-transcriptional Regulation of Keratinocyte Progenitor Cell Expansion, Differentiation and Hair Follicle Regression by miR-22 PLOS Genetics, 11 (5) DOI: 10.1371/journal.pgen.1005253

Category: Biology, Blog, Genetics, Image, Molecular biology, PLOS Genetics, Uncategorized | Tagged , , , , , , , , | 3 Comments

New Charges of Climate Skeptic’s Undisclosed Ties to Energy Industry Highlight Journals’ Role as Gatekeeper

In theory, it shouldn’t matter where authors of scientific papers get their research funding, a longtime journal editor once told me. Papers should be judged on their own merits, not based on who funded the scientists who collected and analyzed the data. But in practice, as journals are increasingly recognizing, funding sources matter.

Thanks to documents obtained from court settlements, whistleblowers and investigations by reporters and U.S. congressmen, we know that corporations hire scientists to write studies that help delay regulations, defend products worth billions and discredit research to protect their bottom line.

Reviews of studies in several high-stake fields, including pharmaceutical research, chemical toxicity and passive smoking, have found a “funding effect.” Researchers who receive funding from industry in these fields, the reviews show, are more likely than those who don’t take industry money to publish results in line with the company’s interests.

That’s why the watchdog group Climate Investigations Center (CIC) has been investigating the funding sources of Wei-Hock “Willie” Soon, a scientist at the Harvard-Smithsonian Center for Astrophysics known for disputing the role of rising greenhouse gas emissions in climate change, in contrast to the overwhelming majority of climate researchers and the U.N.’s Intergovernmental Panel on Climate Change.

And now, as a report released by CIC and Greenpeace on Wednesday details, the group has turned its attention to the journals who publish his papers.

As a result, five journals, including an Elsevier ethics committee, are investigating charges that Soon failed to disclose financial ties to the fossil fuel industry in papers published by the journals since 2008. Soon characterized these papers as “deliverables” in grant reports to his corporate sponsors, CIC charges, citing documents obtained through the Freedom of Information Act from the Harvard-Smithsonian Center for Astrophysics.

The Soon investigation is intended to underscore the need for greater transparency in science publishing about conflicts of interest, CIC Executive Director Kert Davies told me. “This is a strong case study of how corporate interests have intentionally used the scientific literature,” Davies says.

CIC is also asking PNAS and Nature Geoscience to reassess papers Soon published in the journals in the past two years, when he did not disclose grants he received from utility giant Southern Co. and Donors Trust, a foundation that encourages anonymous donations to support limited government. Donors Trust received nearly $5 million from a Koch family foundation in 2013 alone.

Three of the journals do not have identifiable conflict of interest policies, according to the report. PLOS considers the disclosure of competing interests – which can include non-financial, professional and personal conflicts — as essential to the transparent reporting of research. Manuscripts submitted by authors who fail to declare such conflicts may be rejected immediately after a conflict comes to light. If a conflict is revealed after publication, journal editors will follow guidelines from the Committee on Publication Ethics and notify the community.

CIC has been corresponding with the journals since February, when the nonprofit and Greenpeace released documents showing that Soon had received over $1.2 million from fossil fuel interests since 2001 that he failed to disclose in at least 11 papers. The documents show that Soon accepted money from ExxonMobil Corp., the American Petroleum Institute, the Charles G. Koch Foundation and Southern Co., one of the largest electric utility companies in the United States valued at $40 billion.

Soon rarely talks to media outlets but reportedly said that funding does not bias his findings.

Charles Koch and his brother, David, regularly give millions of dollars to foundations and think tanks like The Heartland Institute – which sponsors an annual conference for global warming deniers, where Soon is a regular speaker – that support the fossil fuel industry that made them billionaires. Southern Co. remains reliant on coal-fired plants, a major source of carbon dioxide emissions, and supports voluntary measures to mitigate climate change.

Conflicts of interest can violate scientific ethics and skew scientific results as much as fabricating or manipulating research results can, argues Sheldon Krimsky, an adjunct professor in public health and family medicine at Tufts University who has long studied the funding effect. He argues that lack of transparency about conflicts of interest to reviewers, journals and readers should be considered scientific misconduct.

The full extent of biased corporate influence on the scientific literature is difficult to measure. To guard against it, academic institutions and scientific journals must be more vigilant against dubious research crafted to serve a corporate agenda, Naomi Oreskes, a Harvard historian of science who documents industry strategies to bend science to their interests, told The New York Times.

Courtesy AAAS

Courtesy AAAS

The key point, as Oreskes argued in a 2004 paper in Environmental and Science Policy, is not that support from industry is intrinsically problematic. “Rather,” she wrote, “the issue is that the research is supported by a sponsor who wants a particular result…and the researchers know in advance what that outcome is, producing an explicit conflict of interest, which undermines the integrity of the research performed.”

Journals can uphold their duty as guardians of scientific integrity by doing a better job of enforcing their conflict of interest policies, perhaps by tailoring practices that ensure compliance with data and animal research policies to codes of scientific conduct. Failure to do so threatens not just the public’s trust in the results of the research they fund, but the integrity of science itself. With corporate funding of scientific research now outpacing government funding, the difference between theory and practice regarding the potential for biases from industry funding is too great – and the stakes too high – to be ignored.

Category: Advocacy, Editorial policy, Funding, PLOS Biology, Policy, Publishing, Research | 5 Comments

Suffering for Science: Balancing the Costs and Benefits of Animal Research

Think for a moment, if you will, of all the chemicals that you conscientiously and unconsciously are exposed to everyday. Banal, daily-life things like toothpaste, cosmetics, food additives, pharmaceuticals. They are composed of manufactured chemicals, synthesized and tested in a lab. You have probably never doubted the safety of your toothpaste or the efficacy of your pain reliever, but that comfort and assurance doesn’t come for free. The testing of safety and efficacy of the chemicals that we subject our bodies to depends on the use of animals that may suffer for our conveniences.


Image credit: Flickr user Mycroyance http://tinyurl.com/noe58b9

How do we – as a society – balance the cost of animal research with the benefits? Who decides how many and how much animals suffer for the conveniences of our daily lives? Are there other alternatives? In PLOS Biology we have recently published two Perspectives that looks closely at these questions and propose meaningful ways to think of these moral dilemmas and possible steps forward.


In “The Challenging Road Towards a Unified Animal Research Network in Europe” Emma Martinez-Sanchez and Kirk Leech of The European Animal Research Association (EARA) advocate for scientists and research organizations to increase transparency and openness about the use of animals and the scientific research and developments gleaned from their work. By increasing communication, scientists can combat misinformation. Through advocacy and outreach that explains the unique benefits of animal research, as well as efforts to reduce the use of animals, the public can form an accurate picture of animal research. The authors encourage applying the 3R strategy (Replacement, Reduction and Refinement) during experimental design and the ARRIVE guidelines (Animal Research: Reporting in Vivo Experiments) when publishing animal studies.


One field that relies heavily on animal research is chemical safety assessment. Natalie Burden, Fiona Sewell, and Kathryn Chapman of the National Center for the Replacement, Refinement and Reduction of Animals in Research (NC3R) write in their Perspective “Testing chemical safety: What is needed to ensure the widespread application of non-animal approaches?” about the pressure to replace animal models. Currently animal models are considered the gold standard for determining if manufactured chemicals are safe for human use, exposure, or consumption. However, recent legislation in Europe that bans the testing of cosmetics on animals is propelling the development and use of non-animal techniques to assess chemical safety.


Burden and colleagues describe the challenges of moving away from animal models in the chemical safety field. The foremost challenge is in the development and acceptance of non-animal techniques that are able to accurately predict toxic effects. Replacing animal models will likely require a combination of techniques including in vitro methods, next generation sequencing and ‘omics’ technologies, and computational modeling. This will require not only the development of new techniques, but a standardization of the interpretation of results,and a cohesive regulatory process.


While our current scientific understanding and regulatory organizations require the use of animal testing to answer some key scientific questions, such as determining chemical safety, there are significant benefits to moving away from animal models. Scientists, research organizations, and regulatory bodies need to cooperate and work together to improve alternative techniques and their acceptance so that animal use can be reduced.

Category: Debate, PLOS Biology, Policy, Research | Tagged , , | 3 Comments

Convex Clustering and Synaptic Restructuring: the PLOS CB May Issue

Here are some highlights from May’s PLOS Computational Biology

Convex Clustering: An Attractive Alternative to Hierarchical Clustering

May Issue Image: Hi-C Chromatin Interaction Networks Predict Co-expression in the Mouse Cortex. Image Credit: Ms. Annelies te Selle

May Issue Image: Hi-C Chromatin Interaction Networks Predict Co-expression in the Mouse Cortex.
Image Credit: Ms. Annelies te Selle

The recently developed method of convex clustering preserves the visual appeal of hierarchical clustering while ameliorating its propensity to make false inferences in the presence of outliers and noise. Despite the advantages of convex clustering, there are still obstacles that stand in its way of becoming a practical tool in bioinformatics: current algorithms are computationally intensive, and there is minimal guidance available on how to choose penalty weights. To address these issues, Gary K. Chen and colleagues describe a fast new algorithm and a corresponding software implementation, CONVEXCLUSTER (freely available at http://www.genetics.ucla.edu/software/).


Modelling Circulating Tumour Cells for Personalised Survival Prediction in Metastatic Breast Cancer

Breast cancer survival is strongly correlated with genetic markers that are associated with increased resistance and invading skills of cancer cells, but it is poorly correlated with the amount of circulating tumour cells. To improve the understanding of the dynamic progression of the disease, Annalisa Occhipinti and colleagues develop a multi-compartment model which mimics the dynamics of tumoural cells in the mammary duct, in the circulatory system and in the bone.


Synaptic Restructuring Across the Sleep-Wake Cycle

Synaptic patterns are downscaled during sleep without LTP, but undergo restructuring after sleep-dependent LTP. Credit: Blanco et al.

Sleep is important for long-lasting memories. One existing theory posits that sleep weakens synapses, leading to the forgetting of all but the strongest memories. An alternative theory proposes that sleep promotes both weakening and strengthening of different connections, the latter through a process known as long-term potentiation (LTP). Sidarta Ribeiro and colleagues measure the levels of a protein related to LTP during the sleep cycle of rats, and use these data to build models of sleep-dependent synaptic plasticity. The results indicate that the current competing theories are not mutually exclusive; rather, each constitutes an important stage of memory consolidation.



Category: Cancer, Cell biology, Community, Computational biology, Neuroscience, PLOS Computational Biology, Uncategorized | Tagged , , , | 1 Comment

Deep Reads: John Bryant reflects on a book that inspired his research

The fourth of our Deep Reads blog posts is written by John Bryant,  a Professor Emeritus of Cell and Molecular Biology at the University of Exeter, UK. In addition to his deep interest in plant DNA, John has been involved actively in Bioethics for the past 20 years. He retains a passion for the natural world in general and is very active in communicating science and bioethics to a wider public.

A colleague and I were talking about the books we had kept since our undergraduate days. As we compared our lists, both of which were relatively short, we were delighted to find one book in common: Towards an Understanding of the Mechanism of Heredity by H.L.K. Whitehouse. My colleague and I were each fortunate enough, in our respective undergraduate years at Cambridge, to ‘sit at the feet’ of the author, Harold Whitehouse, or ‘Flash’ as we affectionately called him. Needless to say, Harold was not in any way ‘Flash Harry’, rather the opposite in fact. In my third year as a student, Whitehouse gave a series of lectures on genetics that really were inspirational! They were models of clarity and of organisation. Each lecture told a story; stories that dealt with classical views of inheritance, Mendelian genetics, chromosome theory, views on the nature of genes, the functioning of DNA and so on. Evidence was discussed and evaluated, and conclusions were reached. We were brought right up-to-date.


DNA. Image from Pixabay CC BY.

In my time at university, we learnt that the lectures were based on a book (or was it the other way round?) that was soon to be published. Towards an Understanding of the Mechanism of Heredity was published after I graduated, but I can genuinely say that its contents and associated lectures pushed my career in a particular direction. I think especially of the chapters on DNA as genetic material, the genetic code, the nature of genes and operons and above all on the replication of DNA. I was, in addition to being thrilled by developments in molecular genetics, very interested in and committed to plant biochemistry. Indeed, I had already started to sound out Thomas ap Rees (who has been a major role model throughout my academic life) with a view to doing a PhD with him. But the combination of plant biochemistry and molecular genetics meant that for me, only one option was possible: I had to work with nucleic acids. Tom ap Rees was primarily known for his work on metabolic regulation which, without a doubt, would have been the direction I would have taken, had it not been for Harold Whitehouse’s lectures and book. As it happened, Tom allowed me to go where I wanted to go and I started a research career in which a major focus has been the biochemistry of plant DNA replication and its place in the cell division cycle.

But back to Towards an Understanding of the Mechanism of Heredity. As mentioned earlier, it was not published in time for me to read as an undergraduate, even though we had been exposed to its contents in lectures. PhD grants do not have much leeway for buying books and thus it was not until the second edition was published (just four years after the first) that I splashed out some of my postdoc salary to get my own copy. It is indeed a wonderful text. Look at the modesty and understatement of the title: Towards an Understanding … This contrasted greatly with the brashness and confidence of much of the molecular biology community. The book is highly readable, clear and well-organised, with each chapter devoted to a specific theme (or in Whitehouse’s terminology, theory) in genetics, dealing with the evidence and the conclusions with admirable clarity. It was a great help to me in my early years as a university teacher, with much of my teaching being at the interface between biochemistry and genetics. It is still a very good read, even though, inevitably in this field, much of it is now out-of-date.

Inspired by Towards an Understanding of the Mechanism of Heredity, my research interests led me to investigate plant DNA polymerases and other enzymes involved in plant DNA replication in my own research group. Indeed, for several years, mine was one of only four groups across the world working on these enzymes. This reinforced my interest in cell division and led me, together with Dr Dennis Francis, to set up the Cell Cycle group within the Society for Experimental Biology. The success of that group was celebrated in three days of good science at the 2013 Annual Main Meeting of the Society¹. In the meantime, working on DNA, the stuff of genes, eventually led me back to genes themselves, in looking at the regulation of genes encoding proteins involved in the initiation of DNA replication. And, just like Harold Whitehouse in his writings and lectures, I think we are approaching an understanding of these things².


Image credit: Miki Yoshihito, Flickr CC BY


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 20th July, 2015 and we’ll be in touch if yours is chosen.


1 See, for example http://jxb.oxfordjournals.org/content/early/2014/02/02/jxb.ert469.full.pdf?keytype=ref&ijkey=lzrXOMWCzlazdzl

2 This understanding of science as ‘an approach to the truth’, verisimilitude, is one of the main ideas discussed by the science philosopher Michael Polyani whose work I have come to appreciate

Category: Blog, Books, Genetics, Molecular biology, Plant biology, PLOS Genetics | Tagged , , , , | 1 Comment

FASEB Conference on Genetic Recombination and Genome Rearrangements: Michael Lichten

As part of its mission to encourage engagement within the genetics community, PLOS Genetics is sponsoring a number of conferences and meetings this year. In order to raise awareness about these conferences and the researchers who attend them we are featuring a number of these conferences on Biologue.

PLOS Genetics is sponsoring the FASEB Science Research Conference on Genetic Recombination and Genome Rearrangements, to be held in Steamboat Springs, CO on July 19-24, 2015. We asked Michael Lichten, Associate Editor at PLOS Genetics, about what he is looking forward to in the upcoming meeting.

I’m Michael Lichten, Associate Editor at PLOS Genetics, PLOS Biology and PLOS ONE, and a principal investigator at the National Cancer Institute in Bethesda, MD. Co-organizer Tanya Paull (University of Texas, Austin, TX) and I are organizing the FASEB Science Research Conference on Genetic Recombination and Genome Rearrangements, to be held in Steamboat Springs, CO on July 19-24, 2015. This conference is the 16th in a conference series that for the past 30 years has been presenting cutting-edge, unpublished research on the mechanisms that maintain integrity of the genome and that ensure its faithful transmission from one generation to the next.  It’s also been a great venue for a different kind of transmission; a place where young researchers and those who are more established in the field can get together in a relaxed, informal setting to get to know one another and to exchange ideas.

Fish Creek Falls, near Steamboat Springs. One of the places where meeting participants have been known to meet informally for scientific discussions. (Image credit: Michael Lichten)

Fish Creek Falls, near Steamboat Springs. One of the places where meeting participants have been known to meet informally for scientific discussions. Image credit: Michael Lichten

The 2015 conference program includes eight plenary sessions that address a wide range of topics, including the structure and biochemistry of recombination proteins, molecular mechanisms of recombination and repair, the relationship between recombination and replication, networks that regulate recombination and repair, the chromatin and nuclear contexts in which recombination occurs, and the impact of recombination on genome stability. A similarly broad range of approaches will be included, from single-molecule analyses, structural studies, in vitro and in vivo biochemistry, live-cell imaging, to whole-genome analysis of mutations and genome rearrangements.

One of the great things about this and other FASEB conferences is the opportunity they offer to researchers at all career stages to meet and discuss science. In the 2015 meeting, we’ve included several features to promote this. Every participant will have the opportunity to present in either a platform talk or a poster session, and this year we’ve expanded the number of platform talks, so that more than one in five talks will be selected from abstracts. In addition, if space permits, we’re planning to have all posters up for the duration of the meeting, so that there will be extra time for informal discussions, in addition to formal poster sessions. There’s also a networking session (called “Meet the Experts”), scheduled for lunch and early afternoon on the second day, so that graduate students and postdocs can meet with speakers for informal discussions—but there’s also plenty of free time for even more informal conversations.

The FASEB conference on Genetic Recombination and Genome Rearrangements has always been one of my favorite meetings, because of its relatively small size (<200), pleasant environment, and high-level science. If you are interested in attending, please visit the conference website (http://www.faseb.org/SRC-Gene/Home.aspx) for more information.

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How it Works: the PLOS Computational Biology April Issue

Here are some highlights from April’s PLOS Computational Biology


Image Credit: Daniel Bendor

Image Credit: Daniel Bendor

How We Hear Time within Sound

How does our auditory system represent time within a sound? Daniel Bendor investigates how temporal acoustic patterns can be represented by neural activity within auditory cortex, a major hub within the brain for the perception of sound. Using a computational model, the author finds that stimulus-locked responses are generated when sound-evoked excitation is combined with strong, delayed inhibition.



How Actions Influence Decision-Making

The modern view of how we make perceptual decisions is of a process of accumulating sensory evidence until reaching a threshold level of certainty. However, this evidence accumulation model neglects the contribution of action and motor processes to the choice that is made. Nathan Lepora and Giovanni Pezzulo present an explanation of how actions, encompassing behavioral strategies such as preparation and commitment, can bias decision-making processes in ways that optimize the ecological choices of animals behaving in natural environments.


How Individual Cells Contribute to the Tumor Environment

Image Credit: Wells et al.

Image Credit: Wells et al.

Over the course of tumor growth, cancer cells interact with normal cells via processes that are difficult to elucidate through experimental observation, particularly at the early stages of tumor formation. To address this, Joshua Leonard and colleagues develop a computational model of a nascent metastatic tumor (capturing salient features of known tumor-immune interactions) that faithfully recapitulates key features of existing experimental observations.


That’s how, for now..

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Restoring vision with a new optogenetic tool

Photoreceptor degeneration, and eventual blindness, affect millions worldwide. Image credit: flickr user Jenn Turner.

Photoreceptor degeneration, and eventual blindness, affect millions worldwide. Image credit: flickr user Jenn Turner.

Millions of people worldwide suffer from progressive degeneration of the eye’s photoreceptors (the light-sensing cells), leading ultimately to blindness. A recent therapeutic approach for restoring vision in blind retinas involves introducing light-sensing proteins into surviving retinal cells that normally cannot sense light, turning them into “replacement photoreceptors”. This so-called “optogenetic” method, however, has several limitations, because traditional light-sensitive proteins require extremely high light intensities, which can be harmful, and use a mechanism alien to the cells.


In a new PLOS Biology paper, Michiel van Wyk, Sonja Kleinlogel and their colleagues bring this promising technology closer to medical application by engineering a new light-sensing protein that is compatible with the cells’ own signalling mechanism but retains all the advantages of traditional optogenetic proteins: fast responsiveness and resistance to light damage (“bleaching”).


Design of Opto-mGluR6. Image credit: doi: 10.1371/journal.pbio.1002143

Design of Opto-mGluR6. Image credit: doi:10.1371/journal.pbio.1002143

This new protein, termed Opto-mGluR6, is a chimeric protein that consists of two “local” retinal proteins: the light-sensing domains of the retinal photopigment melanopsin and the signaling domain of the metabotropic glutamate receptor 6 (mGluR6). mGluR6 is a protein found in retinal ON-bipolar cells that is naturally activated by the neurotransmitter glutamate released from the photoreceptors, thereby amplifying the incoming signal.


Because ON-bipolar cells naturally receive direct input from the photoreceptors, turning the native chemically activated receptor mGluR6 into a light-activated receptor means that signaling mechanisms in the ON-bipolar cells are preserved, conferring high light-sensitivity and fast “normal” responsiveness. And using the extracellular domain of melanopsin as a “light antenna” provides resistance to bleaching: No matter how hard the protein is hit by light, the response of Opto-mGluR6 never attenuates.


To demonstrate the therapeutic potential of this new tool, the authors show that mice suffering from retinitis pigmentosa – a genetic form of retinal degeneration characterized by night blindness and progressive loss of peripheral vision – can be treated to regain daylight vision.


This new optogenetic approach could potentially be applied to the treatment of any kind of photoreceptor degeneration, including age-related macular degeneration.  Plus, the engineering of the bleach-resistant chimeric Opto-mGluR6 opens up broader possibilities for the treatment of other conditions: The mGluR6 receptor belongs to a large family of diverse signaling proteins called G-protein-coupled transmembrane receptors, which are implicated in a wide range of human disorders and are consequently prime targets for biomedical research and pharmaceutical interventions.

Category: Biology, Blog, Disease, Neuroscience, PLOS Biology | 3 Comments

Stressed to Death: Overcoming Drug Resistance in Malaria Parasites

Artemisinin (public domain, via Wikimedia Commons)

Artemisinin (public domain, via Wikimedia Commons)

In recent decades the burden of malaria has greatly decreased. This is the result of both successful public health initiatives and widespread use of antimalarial therapeutics. Artemisinins are a family of drugs that have been incredibly effective against Plasmodium falciparum – the parasite that causes most cases of malaria – and are the foundation of antimalarial treatment worldwide. Unfortunately, strains of P. falciparum that are resistant to artemisinins have emerged and are spreading in South East Asia.


Containing and eliminating resistant parasites before they spread is critically important, and in a new research article published in PLOS Biology by Con Dogovski, Stanley C. Xie, Nectarios Klonis, and Leann Tilley at the University of Melbourne, working with colleagues from Thailand, Singapore and the USA, have identified two ways to overcome artemisinin resistance. They also develop a model, which can be used in clinical settings to predict whether a parasite has become resistant to artemisinins, providing a powerful tool to improve detection and treatment of malaria.


Plasmodium falciparum gametocyte among human blood cells

Plasmodium falciparum gametocyte surrounded by human blood cells (image credit: CDC).

Their research begins with determining how artemisinins kill P. falciparum. They found that normal parasites, when treated with artemisinins, exhibit the signs of cellular stress. When cells are stressed (and these can be any type of cell, from single-celled yeast, to parasites, to the cells that comprise your body), their proteins are often damaged. Stressed cells halt the production of new proteins and break down the damaged proteins, in a process known as the stress response. In the presence of a little stress, the stress response is able to prevent the cell from being inundated with damaged proteins, but in the face of a lot of stress, the stress response will be overwhelmed and the cells will die. What Dogovski, Xie, and colleagues found was that drug-resistant parasites resistant had a better stress response than sensitive parasites, which allowed them to tolerate and survive the stress-inducing artemisinin treatment.


The researchers identified two means to overcome the drug-resistant parasites’ increased stress tolerance. First, they blocked the way that cells degrade damaged proteins. Damaged proteins are broken down by a complex known as the proteasome. By treating drug-resistant parasites with artemisinins and a proteasome inhibitor they were able to stress the parasite and prevent its ability to protect itself from damaged proteins. Artemisinins and proteasome inhibitors, which are used in some cancer therapies, acted synergistically to kill the resistant parasites.


The second way they found to defeat drug resistance was to simply extend artemisinin treatment. Artemisinin treatment is usually only three days long, but the work presented in this article suggests that extending the treatment to 4 days, or splitting the doses, is effective at overcoming resistance. This concurs with research that recently found in an area with prevalent artemisinin-resistance that extending treatment to 6 days from 3 days was 97.7% effective at treating infections.


The WHO, in their Global Plan for Artemisinin Resistance Containment, states that “There is a finite window of opportunity to contain artemisinin resistance. If the current foci of artemisinin-resistant parasites are not contained or eliminated, the costs, both human and financial, could be great”. The research of Professor Tilley and colleagues makes an important step towards preventing the spread of drug resistance by identifying treatments that can kill resistant parasites.



Dogovski, C., Xie, S., Burgio, G., Bridgford, J., Mok, S., McCaw, J., Chotivanich, K., Kenny, S., Gnädig, N., Straimer, J., Bozdech, Z., Fidock, D., Simpson, J., Dondorp, A., Foote, S., Klonis, N., & Tilley, L. (2015). Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance PLOS Biology, 13 (4) DOI: 10.1371/journal.pbio.1002132

Category: Biology, Cell biology, Disease, Infectious disease, Microbiology, PLOS Biology, Research | 2 Comments

Help us choose the PLOS Comp Biol Tenth Anniversary T-shirt!

In June 2015 PLOS Computational Biology will be ten years old, and as part of our celebrations, we’d like you to help us pick the image for our official tenth anniversary t-shirt from these past PLOS CB designs:


T-shirt 1




























What’s your favourite? Click the survey link below to submit your vote:


Or simply tweet us (@PLOSCB) or email us (ploscompbiol@plos.org) with the letter of your favourite design by Monday 4th May. Get voting!

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Category: Uncategorized | 1 Comment