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Turning immunity ON and OFF

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Our immune system is a fortress with multiple layers of protection to keep invaders out of the body. But now and then, traitors arise within this fortress, turning the body against itself, causing what are called autoimmune diseases. Does the body have patrols to keep such traitors in check?

Scientists led by Dr. Jan Carette at Stanford University recently identified a new protein, DDX6 that controls the immune system. It makes sure that immune genes are turned OFF in a healthy person and  turned ON when the human body is attacked by microbes. Without this protein, the immune system would be continually active even without infection, turning the body against itself, destroying healthy cells and increasing the risk of developing autoimmune diseases. These findings were published recently in Cell Reports.

Harmful microorganisms trigger the immune cells in our body to release defense proteins called cytokines. Sixty years ago, the first cytokine, “interferon” was discovered. Today interferons are widely used for the treatment of Hepatitis C infection. Taking a closer look at interferons, they set off a cascade of events in infected cells, turning ON hundreds of other immune response genes to attack and kill invading microorganisms. But even after six decades of interferon research, very little is known about what keeps the interferon cascade in check and turned OFF in healthy cells when they are not challenged by foreign invaders.

Researchers in Jan Carette’s group selectively inactivated every gene in the human genome to find genes that turn OFF the interferon cascade. This led to the discovery of DDX6. When DDX6 was deleted, cells started producing large amounts of cytokines and were better at fighting many viruses like Dengue, Venezuelan equine encephalitis and vesicular stomatitis viruses. However, the cells did not know when to stop. The cytokine genes were turned ON even in the absence of infection resulting in a hyperactive, uncontrolled immune system. Hence, while the absence of DDX6 helped the cells fight against viral infection more robustly, it also triggered an inappropriate activation of the immune system.

Overall, the paper highlights the importance of DDX6 as an immune suppressor. This discovery puts many previous unexplained findings into perspective. Earlier scientists had noticed that there were many mutations near the DDX6 gene in people with autoimmune diseases such as rheumatoid arthritis and lupus. From this study, we know that DDX6 keeps the immune genes under control and thus can suppress autoimmune responses. Any mutations near the gene can disrupt its function and cause the body to attack itself. Exploring the link between DDX6 and autoimmunity is important in understanding the emergence of autoimmunity and could help in developing new therapeutics.

Article in spotlight : 

DDX6 Represses Aberrant Activation of InterferonStimulated Genes. Lumb JH et al. Cell Reports 2017 Jul 25;20(4):819-831.

Image source: flickr.com

About the author:

Shwetha Shivaprasad is a postdoctoral fellow in the Department of Microbiology and Immunology at Stanford University. She is a virologist by training and loves to learn something new everyday, expanding her knowledge base and skill set. She is currently in a phase of career exploration and trying her hand at science writing and reviewing. But nevertheless, she is irreversibly drawn towards the charm of a career in academia.

Editors : 

Radhika Raheja, PhD

Sushama Sivakumar, PhD

The human vs mouse conundrum

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Editor’s note : Most researchers endeavor to translate their basic findings into the clinic. While we have successfully cured diseases in mice, our struggle to generate similar positive results in humans continues. Preclinical animal models are poor predictors of successful clinical trials, as they often do not encompass the physiologically relevant features of the disease. Shreyas Jadhav explores this conundrum further by shining the spotlight on an article published in Nature Scientific Reports that highlights the differences between mice and human gene expression profiles in Type 2 diabetes and their impact on translation studies. Ultimately, a thorough understanding of the differences between mice and humans can save time and money to avoid failure in clinical trials. – Radhika Raheja

 Almost 90% of diabetes cases are type 2 diabetes, which is characterized by the inability of the body to properly utilize released insulin or due to impaired insulin secretion from the islets. Since insulin regulates glucose levels in the blood, inadequate amounts of insulin in turn results in a buildup of glucose levels, which consequently affects normal physiology. Insulin release from islet cells is regulated by a complex mechanism involving neurotransmitters and hormones. G-Protein Coupled Receptors (GPCRs) are being pursued as potential therapeutic targets for developing pharmaceuticals to treat diabetes due to their role in insulin release by beta cells. In a recently published report in the journal Nature Scientific Reports, researchers have analyzed the GPCR expression profiles in mouse and human islet cells and made some interesting observations in the differences in their expression profiles and their subsequent impact on clinical translation.

Specifically, they compared the GPCR expression profile by qPCR in two laboratory mouse strains (outbred ICR and inbred C57B/6) and human islet cells and reported some interesting findings. Of the 341 GPCR mRNAs analyzed in mice, 183 GPCR mRNAs were expressed above the cut off limit. Not surprising, there was a strong correlation between the GPCR expression profiles of the two mouse strains. They observed strain specific expression profile wherein 12 GPCRs were expressed solely by the C57 mouse islets and 17 additional GPCRs were exclusive to the ICR mouse islets. Finally, out of the ten most abundantly expressed GPCRs, eight were common to both strains (Calcrl, Cckar, Ffar1, Galr1, Glp1r, Gpr158, Gpr56 and Gprc5c). Of the ten most abundantly expressed mouse GPCRs, only three were commonly expressed between mouse and human islets (GPR56, GLP-1 and FFAR1). Interestingly, GLP-1, the most well characterized islet GPCR was present in both mouse and human islets. Indeed GLP-1 receptor is a target for type 2 diabetes and there are currently at least five FDA approved compounds in the market.

The authors further highlighted the significance of these observed differences in the GPCR expression profiles between human and mice by demonstrating functional relevance. Given that the A3 (ADORA3) receptor is expressed only in mice and not in human islets, the A3 agonist MRS 5698 was able to inhibit glucose induced insulin secretion from mouse islets and had no effect on human islets. Also, since the galanin receptors were highly expressed in mouse islets and not as much in human islets, activation of these receptors inhibited insulin secretion in mice whereas their activation in human islets had no effect. Finally, the Gi coupled sst1 (SSTR1) receptor mRNA which showed high expression level in human islets, inhibited insulin secretion in response to the agonist CH 275. The same agonist failed to show a similar response in mouse islets.

While the majority of our current understanding of the disease mechanisms arises from research in rodent models of diabetes (as shown by the identification of the GLP-1 receptor to develop therapeutics), there exist significant differences in the expression profiles of genes between mice and humans. These differences, unequivocally, will have to be taken into account while establishing procedures to develop therapeutics. Despite the ongoing research efforts to understand the molecular mechanisms underlying the cause of diabetes, definitive treatment strategies remain largely elusive. This, in part, is due to the complex nature of the disorder and the lack of good disease models.

Given that the ultimate goal is to develop pharmaceuticals that will successfully treat humans, there is a need to overcome the limitations posed by rodent models by at least understanding the similarities and differences between specific human and rodent cells in terms of their expression profiles. This paper represents a step in that direction.

Indeed, this scenario is not exclusive to diabetes and extends to other conditions as well, mainly neurodegenerative disorders where we do not have mouse models that mimic the human condition. This certainly poses a challenge in developing therapeutics that can be used to treat patients. While we have to assess strategies to humanize mouse models, iPS cells (including patient derived iPSC’s) could potentially be employed to understand disease mechanisms and as a drug screening platform.

Article in spotlight

Stefan Amisten, Patricio Atanes, Ross Hawkes, Inmaculada Ruz-Maldonado, Bo Liu, Fariborz Parandeh, Min Zhao, Guo Cai Huang, Albert Salehi and Shanta J. Persaud. A comparative analysis of human and mouse islet G-protein coupled receptor expression. Nature Scientific Reports 7, 46600 (2017)

Additional reading

Amisten, S., Salehi, A., Rorsman, P., Jones, P. M. & Persaud, S. J. An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans. Pharmacology & therapeutics 139, 359–391 (2013).

Lalita Prasad-Reddy, Diana Issacs. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs in Context, 4: 212283 (2015)

Aileen JF King. The use of animal models in diabetes research. British Journal of Pharmacology 166, 877-894 (2012)

Sarah Crunkhorn. Human iPSC-derived b-like cells rescue diabetic mice. Nature Reviews Drug Discivery 15, 382-383 (2016)

Image source 

Monica J. Justice, and Paraminder Dhillon Dis. Model. Mech. 2016;9:101-103

About the author

Shreyas Jadhav completed his PhD from the Indian Institute of Technology, Kanpur, India, where he studied the role of mRNA translation in the C.elegans model. During his postdoctoral research at Harvard Medical School (Boston Children’s Hospital and Brigham and Women’s Hospital) and Tufts University, his research focused on applying Molecular and Cellular biology techniques to understanding kidney disease mechanisms, including fibrosis. He is interested in communicating research to a broad audience within the scientific community.

About the editor 

Radhika Raheja completed her PhD from Cornell University and is currently a Postdoctoral fellow at the Brigham and Women’s Hospital. Her research interests have centered around oncology and neuroimmunology. Among other things, she is striving to effectively communicate scientific discoveries to the community.

About the illustrator

Vinita Bharat Ph.D., is currently a postdoctoral research fellow at European Neuroscience Institute, Göttingen, Germany and had been an International Max Planck Research School (IMPRS) student here. Her research area focuses on cellular and molecular neuroscience. Other than enjoying ‘being a scientist’, she has also been working on science education. Presenting science in easy and fun way is what she loves doing through her platform “Fuzzy Synapse” (one can find fuzzy synapse on Facebook, Instagram and Twitter). She is a fun, enthusiastic and curious person, passionate about traveling, loves celebrations and bringing smiles around her.

Microorganisms in Microgravity

in Reporting from the Lab by

With the advancements in science and technology, we are witnessing the golden era of space exploration. However, we have a lot to learn as we embark on this exciting journey. One of the important things is to understand the effects of space environment on human physiology. Space flight might weaken the human immune response, thereby increasing the risk of microbial infections. Space environment might also alter the microbes, making them more harmful. Hence, it is important to conduct studies investigating the effects of space environment on microbes on spaceflights or under laboratory conditions, simulating the microgravity environment observed in space. Addressing this issue, researchers (Tirumalai et al.), at the University of Houston, recently published a study in npj Microgravity, where they grew the bacteria Escherichia coli (E. coli) under microgravity conditions in the laboratory and showed that these microbes undergo both phenotypic and genomic changes.

For this study, the researchers chose a specific strain of E. coli and grew it for thousand generations in low-shear modeled microgravity (LSMMG) environment in the laboratory, which simulates the microgravity condition found in space. This strain was referred to as the 1000-G strain. Interestingly, they found that in the LSMMG environment, the microgravity-adapted 1000-G strain generated more colonies and showed an adaptive growth advantage of 2.46 fold as compared to the unadapted E. coli strain. In order to assess whether the growth advantage exhibited by the 1000-G strain was due to the temporary phenotypic changes brought about by the exposure to the LSMMG environment or due to the permanent genomic changes to adapt to such an environment, the researchers cultured the 1000-G strain under normal gravity conditions for 10-30 generations before shifting it to the microgravity culture conditions and then measured the number of colonies generated. They observed that the 1000-G strain retained 50% of the adaptive growth advantages. This indicated that culture under microgravity conditions resulted in genomic changes in the 1000-G strain, enabling it to grow better than the unadapted strain.

The researchers also sequenced the genome of the 1000-G E. coli strain and found 16 mutations when compared to the normal E. coli strain. The genes that underwent mutations included the ones regulating bacterial attachment to surfaces and stress response. The researchers speculate that these mutations might help the microbes to adapt to the low gravity environment. Despite these genomic changes, the 1000-G E. coli strain did not show any significant change in its sensitivity against a broad range of antibiotics. However, further studies are required to ensure that the mutations observed in the 1000-G strain specifically developed because of the exposure to the microgravity environment.

Although the microgravity conditions in the laboratory provide an excellent system to study the effects of space conditions on microbial properties, the researchers suggest that similar studies performed on the International Space Station will help to confirm these findings. Such studies will help us better understand the effects of the space conditions on the microbes and their subsequent impact on human physiology. Recently, another group showed the ability of cosmic rays to adversely affect the human cells and increase the risk of cancer. While space exploration is indeed a giant leap for mankind, a deeper understanding of the consequences of the space environment on the human body is critical before embarking on long-term space missions.

Journal reference:

Tirumalai MR, Karouia F, Tran Q, Stepanov VG, Bruce RJ, Mark Ott C, Pierson DL, Fox GE. The adaptation of Escherichia coli cells grown in simulated microgravity for an extended period is both phenotypic and genomic. npj Microgravity (2017) 3:15; doi:10.1038/s41526-017-0020-1

Other references:

https://futurism.com/3-bacteria-shown-to-mutate-in-space/

https://www.newscientist.com/article/2133147-floating-in-microgravity-gives-bacteria-permanent-genetic-boost/

https://www.unlv.edu/news/release/study-significant-collateral-damage-cosmic-rays-increases-cancer-risks-mars-astronauts

Featured image source: Pixabay

About the author:

Isha Verma has recently finished her Ph.D. from the Indian Institute of Science, Bangalore. She is currently working as a Research Associate at the same institute. Her research work focusses on the generation of neural cells from stem cells. She also works as a freelance scientific editor and scientific consultant. She loves reading, traveling, and star gazing. She can be reached here.

Edited by: Radhika Raheja

Antisense-ing Alzheimer’s

in Reporting from the Lab by

Enhanced life expectancy has led to a rise in aging associated disorders such as Alzheimer’s disease (AD). Two important pathological hallmarks of AD include the appearance of Beta amyloid plaques and neurofibrillary tangles (NFT) in the brain. The abnormal clustering of beta amyloid protein between neurons forms beta amyloid plaques. NFT’s occur as a result of aggregates formed by Tau, a protein molecule critical for microtubule stability and axonal transport. Both these processes lead to the disruption of neuronal communication subsequently leading to neuronal damage and loss.

While the current treatment options correct the cognitive symptoms of the disease, there is a quest to target specific underlying disease mechanisms. In a fascinating study in Science Translational Medicine, researchers DeVos et al suggest the use of an antisense oligonucleotide (ASO) to decrease the accumulation of the misfolded Tau proteins in the brain as well as to reverse the deposition of Tau in older mice.

In this paper, the authors designed an ASO that can specifically target human tau and reduce its expression. ASOs are synthetic single stranded nucleotides that bind to complementary mRNA or precursor pre-mRNA (transcript that undergoes splicing or other modifications) and consequently inhibit or reduce protein expression or modify protein function. For this study, the researchers used a transgenic PS19 mouse that expresses a mutant P301S human Tau protein responsible for the development of AD in these mice. Upon administration of a synthetic ASO targeting human Tau protein in the brains of these mice, the expression of human Tau protein was significantly reduced. Additionally, in order to determine whether treatment with ASO can be used to prevent the toxic accumulation of Tau proteins, they administered the ASO at 6 months of age and examined the levels of Tau protein in the brain at 9 months of age. Interestingly, treated mice showed significantly reduced Tau levels, suggesting the ability of the ASO to prevent Tau-associated pathology, as the mice got older. The researchers further demonstrated that NFT accumulation observed in 9 month old mice can be reversed upon ASO treatment, underscoring the therapeutic ability of these ASOs. AD progression is brought about by the propagation of Tau proteins within the brain. This ability of pathologic Tau to misfold naïve Tau was also reduced upon treatment with ASO. Ultimately, treatment with the ASO increased survival of these mice without causing any decline in their ability to complete a functional task such as building a nest, which is used as a common measure of cognition, social behavior and motor capabilities in mice.

These in vivo preclinical studies were further supported by studies in non-human primates, Cynomolgus monkeys. As Tau proteins are naturally occurring within the nervous system, the researchers showed that ASO treatment reduces the endogenous Tau levels in the brain and spinal cord of these monkeys. Further, the levels of Tau within the cerebrospinal fluid (CSF) can be used as a surrogate marker of treatment efficacy as the levels of Tau in the CSF correlated directly with reduction in protein level within the brain of ASO-treated monkeys.

A major limitation in the treatment of current Tau pathologies is the inability to reverse the damage that has already occurred by these aggregates. In this regard, one of the most remarkable features of this study is the ability of the human Tau ASO to not just prevent but also reverse the Tau pathologies observed in the PS19 mouse. The advancement to clinical trials requires further studies to establish its efficacy in clearing Tau aggregates without affecting general cognitive functions in humans. In the current study, ASO was administered by the surgical placement of an osmotic pump in the brain of mice. However, it is critical to identify feasible and safe mechanisms of delivery of ASOs to the central nervous system of patients. This has been an ongoing area of research for several neurological disorders.

ASOs have been studied extensively as therapeutic molecules for various disorders especially devastating neurodegenerative diseases such as Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS). A recent breakthrough in the ASO therapeutic field came about with the FDA approval of Biogen and Ionis pharmaceuticals’ Nusinersen, an ASO to treat SMA, a debilitating disease affecting children. An ASO (BIIB067) that disrupts the production of misfolded proteins produced by the mutant SOD1 gene in ALS is also in clinical trials. In partnership with Roche, Ionis is also conducting clinical trials with an ASO (ASO-HTT-Rx) which can reduce the levels of Huntingtin protein in Huntington’s disease.

AD is in dire need of a significant drug molecule that targets specific pathogenic activity and not just the symptoms of the disease. Unfortunately, promising candidates that prevent the formation of Beta amyloid plaques, such as Pfizer and Johnson & Jonhsons’ bapineuzumab, Eli Lilly’s solanezumab and Merck’s verubecestat have failed clinical trials. Despite these setbacks, companies continue to investigate novel therapies to fight this disease. Preclinical studies in this paper with an ASO that reduces Tau protein levels can transform Alzheimer’s therapeutic landscape.

Journal article:

DeVos SL et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy, Science Translational Medicine. DOI:10.1126/scitranslmed.aag0481

Additional newsfeed:

http://www.thescientist.com/?articles.view/

http://www.sciencemag.org/news

https://www.alz.org/research/science/

https://www.eurekalert.org/pub_releases/

https://www.newscientist.com/article/2119254

Photo source: 

www.alzheimersreadingroom.com

Edited by Isha Verma 

About the author 

Radhika completed her PhD from Cornell University and is currently a Postdoctoral fellow at the Brigham and Women’s Hospital. Her research interests have centered around oncology and neuroimmunology. Among other things, she is striving to effectively communicate scientific discoveries to the community.

 

 

 

 

 

 

Dare to Share – The dilemma surrounding data sharing

in Reporting from the Lab by
  • DataShareing_Opensource_Ritu300417.png?fit=2918%2C3283

Preview note: As the scientific community slides into the era of towering collaborative and multidisciplinary projects it is now impossible to ignore the importance of Open source and Free data sharing. However, the community is gravely divided on this ground. As we progress in our discussion, we figure out that both the pros and cons are justified and deserve open minded considerations. Inspired by a heated online debate on the official Facebook page of Career and Support Group on 29th March 2017, Rohit decided to reasonably curate the views under one roof. This is a very enticing article, especially for the early stage researchers who often find themselves in the dilemma of ‘To be shared or not to be’ Rituparna Chakrabarti


Data sharing is an integral part of collaborative scientific research and is often encouraged within the scientific community. National Science Foundation has emphasized the importance of sustainable data sharing and management in the progress of science and engineering, and has proposed policies in its favor. The New England Journal of Medicine has published a number of articles and editorials highlighting the importance and new developments in data sharing, especially in clinical sciences. Therefore, generally speaking, while there may be multiple aspects and finer details attached to the individual arguments, it is accepted that data sharing has a positive impact on scientific research and is encouraged1. There is, however, a part of the data sharing conversation that is often experienced firsthand by fresh PhDs, post-doctoral fellows and other young scientists and researchers.

 

As young researchers attempt to embark upon new career opportunities, they must reply upon the limited research experience they have accumulated thus far. It is natural they want to use this experience to sell their skills and knowledge to the prospective employer during their job interview. It is also expected that sometimes the prospective employer would want to learn more about the candidate’s past research and evaluate them based on their work. This may involve seeking relevant data, research methodologies and innovations involved in that research. If the said research has already been published (or has been accepted to be published) then the subsequent process would be fairly straightforward and the candidate will triumphantly share the past research. If, however, the research is yet unpublished and/or is under peer-review process then data sharing can be tricky. The Principal Investigator (PI) heading the research might not be too keen on sharing it outside the lab until it is published. Scientific research is a competitive domain and it is a valid concern for such a PI who might be at a risk of getting scooped because the data may end up in the hands of a competitor. And the push and impact of publishing novel research on the career of a scientist is not unknown. But what must then the young researchers do? They are not allowed to share the research they have worked hard on thus far even if they want to. A prospective employer will want to evaluate the candidate’s research skills and such a discussion might require discussing unpublished work. Everyone involved appears to be justified in their stance.

 

There are some suggestions2, ranging from having better interpersonal communication to changing mindsets in the field that may allow young researchers to circumvent this issue. At the outset it is essential to establish the fact that all data and other research content generated in an academic setting belongs to the hosting university or institute, and therefore, the employees may not be at complete liberty to disseminate this content without prior permission of the university. But this doesn’t mean that the research may not be discussed at all (unless some form of a non-disclosure agreement is involved) with a third party. In such a situation, researchers seeking for employment outside the university may choose to have prior discussion with the prospective employer and ask to share only the published research details (preferably pre-approved by the PI/university), which might demonstrate their competence and research acumen. But this may not always be easy. Talking about the dilemma of how much research one should share when interviewing at a company while working at another, Derek Lowe has noted,“ No published work worth talking about, no patent applications, no nothing. I actually did go out and give an interview seminar under those conditions once, and it was an unpleasant experience. I had to talk about ancient stuff from my post-doc, and it was a real challenge convincing people that I knew what was going on in a drug company. I don’t recommend trying it.” If the unpublished data must be discussed, it can be done as a part of more general problem to solution to impact discussion i.e. without communicating any specific details, presenting any slides and only mentioning the data verbally– the interviewee must be clear about what can and cannot be discussed, because once the idea is out there anyone may be able to claim rights to it if it is not already published or patented. Data sharing under these circumstances does present a unique challenge. As an innovative solution, the PI and the prospective employer may discuss a publication strategy beforehand that may benefit all parties involved. This approach is more likely to succeed if the candidate takes the initiative to establish such a communication channel and be open about the prospects – high risk, high reward.

 

Needless to say that this problem may not arise at all if the research in question is already published on a preprint platform such as arXiv or bioRxiv.While the jury is still out on the pros and cons of the preprint strategy, it is undeniable that it has been gaining in popularity due to its open source nature and ease of submission. In spite of the benefits, this option may be more favorable to researchers publishing in physics, mathematics and informatics related fields (primarily on arXiv), than to those publishing in life sciences (primarily on bioRxiv) and chemistry related fields. This argument is supported by the statistics as they currently stand. Launched in November 2013, bioRxiv had received ~3100 submissions till January 2016 (as per ; ~114 submissions/month). On the other hand, arXiv was launched in August 1991 and has received ~1.2 million submissions to date* (~4050 submissions/month). The reason it took some 23 years for a life science-centric preprint server to be launched might have had to do with both culture and content in the life sciences research. As it may be clear by now, publishing one’s research on a preprint server is not the end of the road. Most researchers eventually want to publish the same (or an improved version of) research in a high impact peer-reviewed academic journal. Policy on publishing the manuscripts that have been published elsewhere, including on preprint servers, differs by journal. Even though researchers would like to publish on a preprint server (for all the reasons discussed above), they are wary of the fact that they will likely not be able to ultimately publish the same research in high-impact journals like NEJM or AACR. The problem is more acute in life science journals while most physics and mathematics journals accept research previously published on preprint servers.

 

But things seem to looking up in the preprint world in general. bioRxiv is far younger than arXiv, but the trend in the rate of submissions has been steadily increasing since their inception which means that more and more researchers are opting for this route. On that note, it is now possible to directly submit bioRxiv preprints to leading academic journals. Encouraged by the success of preprint approach and its potential in pacing the speed of scientific discoveries Chan Zukerberg Initiative has decided to provide a funding of $3 billion over 10 years to bioRxiv.  What’s more, American Chemical Society has decided to launch a preprint server for chemists. These developments point to the preprint approach becoming the leading approach to share research data before it is published in a peer-reviewed journal. Therefore, in absence of extraordinary circumstances, if the PI can be persuaded to publish the research to a preprint server, the candidate may avoid the difficulties around data sharing. It is, therefore, important to foster a productive, amicable and strong professional relationship with the PI.

 

Even with the increase in the sheer amount of data, data sharing today is easier than ever. The question is how much are we willing to share and how much are we allowed to share. For young researchers and graduates transitioning into new research positions these questions can be the difference between success and failure. These suggestions aim to provide a template and facilitate decision making for these very researchers. Eventually, a more collaborative effort and understanding by all the stakeholders is required.

 

 

1Further reading on the importance of Data sharing:

https://www2.usgs.gov/datamanagement/share/guidance.php

http://blogs.nature.com/methagora/2013/07/importance-of-data-sharing.html

https://www.nature.com/nbt/journal/v25/n4/full/nbt0407-398.html

 

2Certain suggestions are adapted from a recent discussion on the official Career and Support Group Facebook page, which inspired this post. The contribution of the members to this discussion is acknowledged and appreciated.

 

*At the time of publishing of this article

Acknowledgements: Somdatta Karak (Editing), Rituparna Chakrabarti (Featured image).

 

About the author: Rohit Arora obtained his PhD from ENS in France. Post-Phd he worked as a postdoc in France in collaboration with a major pharmaceutical company. He is currently a postdoc at Beth Israel Deaconess Medical Center. His research focus includes understanding biological structure-function relationships and developing novel tools to make sense out of “big data” in biology. He enjoys reading about his newfound interest in the history of mathematics, geometry, and philosophy. He can be reached on Twitter @RealRohitArora (sure, you try and come up with a better handle for name this common)

This work by ClubSciWri is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Bad complements ?

in Reporting from the Lab by

Recently, we observed “Rare Disease day” to raise awareness of the rare diseases that afflict millions of people in the United States. While the definition of rare diseases varies in every country, in the United States a rare disease is one that affects less than 200,000 people at a given time. Scientists worldwide have made tremendous progress to identify and understand the clinical manifestations and pathogenesis of these diseases leading to several treatment options and saving many lives. In a recent article by Pandey et al in the journal Nature, scientists unraveled a critical role played by the body’s immune system in Gaucher disease, thereby prompting a potential treatment option.

Gaucher disease is an inherited disorder characterized by a mutation in the gene Gba1 that leads to a deficiency in the enzyme glucocerebrosidase.(GCase). This enzyme is present in the lysosome, the digestive system of the cell, that contains numerous enzymes necessary for the break down of complex molecules. GCAse, in particular, is required for the breakdown of a fatty acid compound, glucosylceramide (GC) into simpler components that can be recycled and utilized for other cellular processes. Consequently, a deficiency of this enzyme leads to the accumulation of GC within the lysosomes in the immune cells of the spleen, bone marrow and liver leading to chronic inflammation. The reason for this tissue inflammation remains elusive.

Enzyme replacement therapy (ERT) is effective in compensating for the enzyme deficiency associated with Gaucher disease. Genzyme’s Cerezyme (imiglucerase) was the first approved ERT treatment. Alternatively, substrate reduction therapy (SRT) prevents the formation of GC itself thereby reducing its accumulation. Two oral drugs, Actelion pharmaceutical’s Zavesca (miglustat ) and Genzyme’s Cerdelga (eliglustat) are commonly used for SRT. However, neither of them address the inflammation associated with the disease. The study by Pandey et al identifies a novel target that can help overcome some of the limitations of the current treatment and potentially benefit patients.

In a mouse model of Gaucher disease, Gba19V/-, Pandey et al found elevated levels of C5a in the immune cells of the spleen, liver and lung in these mice compared to normal mice. This was accompanied by an increased expression of C5aR1 in these cells. C5a is part of the complement immune system that plays an important role in inflammation and homeostasis. It is a cleavage product of C5 and is produced upon activation of macrophages and circulating monocytes, cells of the innate immune system that play a critical role in protecting the body by generating effective immune responses. C5a binds to the receptor C5aR1 on the surface of some innate immune cells that perpetuates the inflammatory response by activating another type of immune cells, namely T cells. Strikingly, double-deficient mice lacking GCase and the C5aR1 receptor (Gba19V/- C5aR1-/-) showed little to no GC accumulation and a significantly reduced inflammatory response with an improved survival. Another interesting feature of these double-deficient mice was the decreased expression of the enzyme glucosyl ceramide synthase (GCS), an enzyme that is required for the synthesis of GC. The treatment of Gba19V/- mice , with an antagonist compound that blocks C5aR (C5aRA) also resulted in decreased GC accumulation and reduced inflammation.

This study suggests that targeting  C5aR1 or C5 itself can potentially ameliorate inflammation and GC accumulation. There are two options available pharmaceutically to test this proposition in preclinical models. Alexion pharmaceuticals’ Soliris (eculizumab) is an anti-C5 monoclonal antibody that binds C5 and prevents its cleavage into C5a. It is currently approved for the treatment of a rare disorder, paroxysomal nocturnal hemoglobinuria. Another option is to target the C5a receptor (C5aR1) using antagonists such as Avacopan (CCX168) developed by Chemocentryx which is currently in clinical trials for the treatment of inflammatory disorders that affect the kidney.

Another interesting implication of these studies arises from the observation that Gaucher disease is closely associated with the neurodegenerative disorder, Parkinson’s disease (PD). Studies indicate that GCase and alpha- synuclein, the protein whose dysfunction is a major phenomenon in PD, have a reciprocal relationship and several ongoing investigations are focused on parsing apart this connection. This study published by Pandey et al opens up an area of investigation to determine the interplay between the complement system and inflammation in the brain that can perhaps explain the correlation between these diseases.

There are over 50 lysosomal storage disorders (LSDs) that are rare, inherited and commonly driven by enzyme deficiencies leading to unwanted accumulation of materials in the body. This study provides a promising therapeutic strategy not only for Gaucher disease but also for other LSDs associated with chronic inflammation.

Journal article :

Manoj K. Pandey et al, Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease, Nature (2017). DOI: 10.1038/nature21368

Additional newsfeed :

https://gaucherdiseasenews.com/2017/03/02/

study-says-

suppression-of-protein-

could-lead-to-new-gaucher-therapies/

http://www.alzforum.org/papers/complement-drives-

glucosylceramide-accumulation-and-tissue-inflammation-

gaucher-disease

https://www.sciencedaily.com/releases/

2017/02/

170222131459.htm

http://healthmedicinet.com/nature-study-suggests-new-therapy-

for-gaucher-disease/

Photo source : Stocktrek images

 Edited by Isha Verma

About the author 

Radhika completed her PhD from Cornell University and is currently a Postdoctoral fellow at the Brigham and Women’s Hospital. Her research interests have centered around oncology and neuroimmunology. Among other things, she is striving to effectively communicate scientific discoveries to the community.

 

 

Identifying the lemurs

in Biodiversity and Environment/Reporting from the Lab by

In the last century, we lost many of our magnificent animal species including the Honshu wolf, California grizzly bear, Tasmanian tiger, Barbary lion, Caribbean monk seal, Arabian ostrich, and Japanese sea lion. Additionally, many other species are facing the risk of extinction. Among them are the lemurs – you might remember them as the cute fuzzy creatures from the movie Madagascar. Lemurs are a unique group of primate endemic to Madagascar Island in Africa and are considered to be the most threatened mammalian species on Earth. According to the International Union for Conservation of Nature (IUCN) red list of threatened species, out of the 111 lemur species, 24 are critically endangered, 49 are endangered and 20 are vulnerable. This highlights the urgent need to develop conservation strategies for these animals.

In order to do so, it is important to acquire knowledge of behavior, ecology, and evolution of various lemur species, including data on life history, fitness, longevity, and reproductive patterns. Such data can be acquired through long-term studies of known sets of lemurs. However, long-term studies are limited by the difficulties in tracking the known individuals over extended periods of time. The most commonly used method of lemur identification is by capturing and tagging them with unique identifiers. However, this method is expensive, can cause harm to the animals and is not suitable for large scale studies. Alternatively, the researchers rely on the variations in the appearances of lemurs, such as the differences in body size and shape, to identify them. But this is highly subjective and prone to errors and also requires substantial training of the researchers. Addressing these problems, scientists (Crouse et al.) recently published a study in BMC Zoology, where they modified the human facial recognition technology to develop a highly accurate computer-assisted lemur facial recognition system termed as LemurFaceID. This system uses the variations in the facial patterns of the lemurs for their identification based on the photographs.

For the prototype development, the researchers generated a dataset of 462 photographs of 80 red-bellied lemurs (Eulemur rubriventer) mostly from the individuals in Madagascar. Additionally, to increase the size of the lemur photo gallery, another database was generated that contained the images of lemurs belonging to other species. Each image in the database was subjected to multiple pre-processing steps and further normalizations were performed to reduce the effects of the ambient illumination and lemur’s facial hair on the accuracy of LemurFaceID. The corrected image was subjected to feature extraction using multi-scale local binary pattern (MLBP) method. The final feature vector was constructed based on the linear discriminant analysis (LDA), which helped to minimize the variations between the photographs of the same individual. To perform the face matching, the lemur dataset was divided into (i) a training set which was used to train the LemurFaceID system and (ii) a testing set which was used to test the accuracy of this system. Further, in the test set, two-thirds of the images of each individual were used as a gallery in the system database, while the remaining one-third of the images were used as queries. Each query consisted of one or more images which were identified against the gallery database.

The researchers conducted the face recognition experiments in two different modes. The open-set mode was based on the assumption that during the experiments, queries might be encountered that may not match with any of the images in the gallery. This corresponds to the conditions in the wild, where one might encounter novel lemur individuals which were not spotted before and are consequently absent from the dataset. On the other hand, experiments in the closed-set mode were performed with the assumption that all the query lemurs were present in the gallery. This simulates the condition in the captive lemur colonies where all the individuals are already identified. Across a 100 trials performed in the closed-set mode, LemurFaceID identified lemurs with an accuracy of about 93.3% for a 1-image query and 98.7% for a 2-image query. However, the results with the open-set mode were less accurate suggesting a need to further improve the technique perhaps by increasing the size of the lemur database. In the future, the researchers plan to test the system in the field to compare its accuracy with that of the trained and untrained field observers.

The LemurFaceID provides a novel tool that will greatly facilitate the long-term research of known lemur populations and will help to develop informed strategies for lemur conservation. As lemurs also face the threat of being live-captured to be kept as pets, this technique can be developed into a tool to identify the captive lemurs and report their sightings. IUCN has started the lemur conservation program under the auspices of Save Our Species (SOS) initiative and has been trying to tackle various threats faced by lemurs. LemurFaceID can boost the IUCN’s efforts to conserve the lemur populations. In the future, face recognition tools similar to LemurFaceID can be developed for other animals that show similar variations in facial and skin patterns, such as bears and red pandas. Such innovative approaches, combined with advanced technology, have the potential to create better solutions for conserving our biodiversity.

Journal reference:

Crouse D, Jacobs RL, Richardson Z, Klum S, Jain A, Baden AL, Tecot SR. LemurFaceID: a face recognition system to facilitate individual identification of lemurs. BMC Zoology. 2017, 2:2. DOI: 10.1186/s40850-016-0011-9.

Other references:

http://www.sciencenewsline.com/news/2017021701450007.html

http://www.livescience.com/57995-lemur-facial-recognition-software.html

https://phys.org/news/2017-02-facial-recognition-lemurs.html

http://www.seeker.com/facial-recognition-tech-could-help-save-endangered-lemurs-2268739486.html

http://stateschronicle.com/save-endangered-lemurs-18714.html

https://www.iucn.org/news/species/201610/major-donation-boosts-efforts-save-madagascar%E2%80%99s-lemur-species-extinction

Featured image source: Pixabay

About the author:

Isha Verma is currently pursuing her PhD in Stem cell research from the Indian Institute of Science, Bangalore. She loves reading and traveling.

Edited by: Radhika Raheja

For the love of sleep

in Reporting from the Lab by

After a long and tiring day, we all love to go to our beds and get lost in the sweet world of sleep. Sleep provides us a break from the outside world and rejuvenates our bodies and minds. It is essential for our physical and mental well-being. Research has shown that sleep serves many important purposes including energy conservation, replenishment of cellular supplies, waste clearance, memory processing, and learning. However, sleep is still a mysterious biological phenomenon as we do not completely understand its mechanisms and functions.

Researchers have specifically linked sleep to the normal functioning of the brain through the synaptic homeostasis hypothesis (SHY). According to this hypothesis, a core function of sleep is to restore the strength of the synapses, the structures that allow the neurons in our brains to communicate with each other. SHY states that the learning occurs during the wake, when we are under the influence of signals from the environment, through the process of synaptic potentiation which leads to an increase in the strength of synapses. On the other hand, while we are asleep, synaptic depression takes place in our brains, resulting in the decrease in the strength of the synapses. Hence, sleep helps in the renormalization of the synaptic strength. The strengthening and weakening of synapses, termed as synaptic scaling, occur regularly across the wake/sleep cycle and is crucial for the integration of new information in our brains.

In a recent study published in Science, scientists (Vivo et al.) at the University of Wisconsin-Madison provided the morphological evidence of synaptic scaling occurring in the mouse brain across the wake/sleep cycle. To study this phenomenon, the researchers isolated the brains from three groups of mice. The first group of mice got proper sleep, whereas the mice in the other two groups were forcefully kept awake or stayed awake on their own. The researchers then used a technique called block-face scanning electron microscopy to image the synapses in two different regions of the isolated brains. Based on these images, they calculated the axon-spine interface (ASI) i.e., the surface area of direct contact between the axonal bouton and dendritic spine head, which serve as the transmitting and receiving ends of the neuron, respectively. The ASI was used as the parameter to assess the strength of the synaptic connections.

Researchers made the interesting observation that the ASI decreased by about 18% in the first group of mice that got sufficient sleep as compared to the other two groups that were awake, indicating a downscaling in the synaptic connections during sleep. However, downscaling was not observed uniformly across all the synapses but was limited to small and medium synapses, which represented about 80% of the total synapses. The remaining 20% of the synapses, which were larger, did not undergo a decrease in ASI. In addition, while downscaling was observed in the spines which were structurally unstable and contained endosomes which facilitated the structural changes by recycling of cellular material, it did not occur in the spines that lacked the endosomes. Also, the decrease in ASI during sleep was observed to be minimal in the dendritic spines with high synaptic density. The researchers suggest that the synapses that are large or do not contain endosomes or have high synaptic density might be associated with committed and stable memory circuits and hence, they escape the process of downscaling during sleep.

Although it might not be possible to replicate this study in humans, the researchers suggest that synaptic scaling during wake/sleep cycle also occurs in our brains. Taken together, this study provides a definite evidence for the SHY and establishes that while wake results in an increase in synaptic strength, an important function of sleep is to selectively reduce the synaptic strength to bring it back to the normal levels. In simpler terms, sleep provides a useful mechanism of “smart forgetting”. When we are asleep, our brains can comprehensively analyze all the memories made during wake and keep the ones that are important, while discarding the ones that are irrelevant. Another group of researchers has confirmed the results of this study by identifying the gene involved in synaptic downscaling during sleep.

This study highlights the importance of sleep for the proper functioning of our brains. A good night’s sleep enhances our reasoning and problem-solving skills and helps us to concentrate and memorize. So, next time whenever you are feeling confused, unable to make a decision, just try to sleep on it. And hopefully, when you wake up, your brain will be able to think much more clearly!

Journal reference:

de Vivo L, Bellesi M, Marshall W, Bushong EA, Ellisman MH, Tononi G, Cirelli C. Ultrastructural evidence for synaptic scaling across the wake/sleep cycle. Science. 2017 Feb 3;355(6324):507-510. doi: 10.1126/science.aah5982.

Other references:

http://science.sciencemag.org/content/355/6324/511.long

http://www.cell.com/neuron/abstract/S0896-6273(13)01186-0

https://www.theguardian.com/science/neurophilosophy/2017/feb/03/sleep-may-help-us-to-forget-by-rebalancing-brain-synapses

https://www.sciencedaily.com/releases/2017/02/170202141913.htm

http://www.learningscientists.org/blog/2017/2/23-1

https://www.psychologytoday.com/blog/memory-medic/201702/sleep-perhaps-learn

Featured image source: Pixabay

About the author:

Isha Verma is currently pursuing her PhD in Stem cell research from the Indian Institute of Science, Bangalore. She loves reading and traveling.

 

Got fat ? Let’s migrate !

in Reporting from the Lab by

Targeted cancer therapy, for the most part, focuses on restricting the uncontrolled growth of a tumor. While these treatment strategies have been successful during the early stages of cancer, there is a constant need to identify treatment options for tumors that have undergone metastasis i.e. the tumor cells have dispersed from their primary site and localized to other organs of the body. In a recent study published by Nature, Pascual et al have shed some major insights into the process of metastasis and identified a fatty acid receptor, CD36 as a potential target to impair metastasis.

The researchers  generated tumors in mice by injecting them with oral carcinoma cell lines and patient-derived cells. These cells were stained with a fluorescent label dye, which diminishes with every dividing cancer cell. They were able to identify slow dividing dye-retaining cells as well as rapidly dividing dye-negative cells in the tumors that developed. A transcriptome analysis, to identify differences in the gene signature of these two populations, showed an enhancement of genes involved in metastasis and lipid metabolism in the slow dividing dye-retaining cells. CD36, a cell surface receptor and a crucial component for lipid uptake and metabolism, was one of the top implicated genes in their data analysis. Cell surface receptors communicate with specific molecules in the extracellular environment and transmit signals within the cell, which consequently dictates cellular processes.

How does CD36 affect metastasis? Interestingly, loss of CD36 in mice reduced the ability of tumors to penetrate to other organs by 80-100% while it did not affect primary tumor formation. Consistent with its requirement for metastasis, antibodies that block the CD36 receptor significantly inhibited metastasis in mice without affecting the size of the tumor. Furthermore, the expression of the cell surface receptor, CD36 was greatly increased when mice were fed with a high-fat diet. In a series of subsequent experiments, the authors concluded that the metastatic potential of tumors is increased with a high fat diet in a CD36 dependent manner.

There are several aspects of this study that are interesting.

This work shifts the paradigm of cancer metastasis theories where tumor cells are believed to undergo a transition from an adhering epithelial cell to a migratory mesenchymal cell (EMT) to invade distant sites. These CD36 expressing cells did not exhibit a mesenchymal gene signature. While further experimentation is required to link CD36 and EMT, it is conceivable that these processes are independent of each other to facilitate metastasis. A detailed mechanism of how CD36 initiates and regulates metastasis remains to be determined.

A high fat diet, which included palmitic acid (an essential component of palm oil) enhanced metastasis in a CD36-dependent manner in these mice. Palm oil is a key ingredient in several food products including Nutella. A press release early last year claimed that the breakdown products of palm oil are potentially carcinogenic, therefore correlating Nutella consumption with cancer risk. While these correlative studies require further scrutiny, validation, and support by causation studies in humans, it is imperative to understand the impact of an EXCLUSIVE high-fat diet on health.

The constantly evolving landscape of cancer research has witnessed the discovery of promising molecules to combat the most aggressive forms of the disease. A majority of these molecules are immuno-oncological targets that enhance the anti-tumor immune response and prevent tumor spreading. In 2016, the FDA approved two drugs, Bristol Myers-Squibb’s Opdivo for metastatic head and neck squamous carcinoma and Genentech’s Tecentriq for metastatic non-small cell lung carcinoma. Both these drugs regulate the immune checkpoint PD-1 and PDL-1 respectively. Some other drugs in the pipeline include Bristol-Myers Squibb and ASLAN pharmaceuticals’ ASLAN002, an inhibitor of the receptor tyrosine kinase, RON. RON regulates immune surveillance and its activation enhances tumor metastasis. Innate Pharma‘s, anti-CD73 blocks the enzyme, CD73 whose function contributes to the generation of an immunosuppressed and pro-angiogenic tumor microenvironment. What makes the fatty acid receptor CD36 unique, so far, is that it exclusively affects metastasis without affecting primary tumor formation. While its cross talk with the immune system remains to be investigated, CD36 represents a novel class of potential anti-metastatic targets that requires further validation. Targeting CD36 by itself, or perhaps in combination with the other aforementioned drugs, might have the potential to treat some of the most aggressive forms of tumor and subsequently have a positive impact on patient lives.

Journal article:

http://www.nature.com/nature/journal/

v541/n7635/full/

nature20791.html

Additional newsfeed :

http://www.nature.com/nature/journal/

v541/n7635/

nature20791/metrics/news

https://www.worldwidecancerresearch.org/blog-post/

new-research-links-major-component-of-palm-oil-to-cancer-spread/

https://www.sciencedaily.com/releases/

2016/12/161207132117.htm

http://healthmedicinet.com/i/preventing-cancer-spread-

mouse-study-points-to-fat/

https://www.centerwatch.com/drug-information/fda-approved-drugs/

therapeutic-area/12/oncology

http://www.aslanpharma.com/drug/aslan002/

http://www.innate-pharma.com/en/pipeline/

first-class-anti-cd73-checkpoint-inhibitor-program

Photo source: Shutterstock

Edited by Abhinav Dey.

About the author 

Radhika completed her PhD from Cornell University and is currently a Postdoctoral fellow at the Brigham and Women’s Hospital. Her research interests have centered around oncology and neuroimmunology. Among other things, she is striving to effectively communicate scientific discoveries to the community.

 

 

 

 

Turning back the hands of time

in Reporting from the Lab by

Aging is one of the most complex biological processes and the prime driver for many human diseases. For a long time, it was considered to be a unidirectional process. However, in the year 2006, Nobel Prize winning scientist Yamanaka proved that mature differentiated cells of the body, such as skin cells, can be converted to undifferentiated embryonic-like cells by the process of cellular reprogramming. This can be achieved by the expression of Yamanaka factors, which include four genes namely Oct4, Sox2, Klf4 and c-Myc (OSKM). These factors result in epigenetic changes in the cells, i.e. heritable changes in the cellular gene expression without any change in the DNA sequence. The reprogrammed cells are termed as induced pluripotent stem cell (iPSCs). iPSCs have unlimited self-renewal ability and under suitable conditions, they can give rise to all the differentiated cell types found in the body.

Interestingly, the process of cellular reprogramming has been shown to improve various age-related phenotypes in cells under in vitro or laboratory culture conditions. However, an important question that remains to be answered is whether we can use the reprogramming method to slow or reverse the process of aging without converting the cells to iPSCs. Also, one of the major concerns is that when the process of cellular reprogramming is performed in vivo i.e. at the organismal level, it results in tumor development and high mortality rates. Addressing these issues, scientists (Ocampo et al.), at the Salk Institute for Biological Sciences, recently published their findings in the journal Cell, where they developed an in vivo partial reprogramming method that can reverse the signs of aging without the risk of tumor formation.

The researchers initially tested their method under in vitro conditions. For this purpose, they used skin cells isolated from the mouse model of premature aging and induced short-term expression of Yamanaka factors for 2-4 days. It is important to note that for the complete reprogramming of mature cells to generate iPSCs, these factors are typically expressed for 2-3 weeks. Partial reprogramming, induced by short-term expression of Yamanaka factors, did not alter the identity of skin cells. However, researchers made the interesting observation that this method reduced the generation of double-strand breaks in DNA and production of reactive oxygen species and also lowered the expression of various genes involved in ageing-associated pathways. Further experiments revealed that epigenetic remodeling of the cells, during the process of partial reprogramming, is the main driver for improving these hallmarks of aging.

When applied in the aging mouse model, in vivo partial reprogramming resulted in an increase in the average lifespan of animals from 18 weeks to 24 weeks. These mice rescued the development of cardiovascular alterations and showed normal proliferation rates in multiple organs. The researchers also tested the applicability of this method in physiologically aged mice. Partial induction of OSKM in 12-month-old mice resulted in better pancreatic function and enhanced muscle regeneration.

In vivo partial reprogramming might not be possible in humans because of the requirement of genetic engineering technique for the expression of Yamanaka factors. However, researchers showed that partial reprogramming of aged human cells under in vitro conditions resulted in improvement in a few of the hallmarks associated with aging. Although further experiments are necessary for its validation, if successful, this technique will provide a unique platform to tackle age-related disorders, such as Alzheimer’s and diabetes, in humans. Epigenetic-modifying drugs, that can mimic the process of partial reprogramming, can be developed to ameliorate various effects of aging.

In conclusion, while the results from this study are very encouraging, it is important to keep in mind that we have not discovered the Philosopher’s stone and it might not be possible to stop the process of aging completely. However, in the future, various strategies can be developed to control age-associated diseases, resulting in healthier living and increased longevity. Until then, we can be hopeful to turn back the hands of time at least at the cellular level!

Journal reference:

Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T, Vazquez-Ferrer E, Donoso D, Roman JL, Xu J, Rodriguez Esteban C, Nuñez G, Nuñez Delicado E, Campistol JM, Guillen I, Guillen P and Izpisua Belmonte JC. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell. 2016 Dec 15; 167(7):1719-1733.e12. doi: 10.1016/j.cell.2016.11.052.

Other references:

http://www.cell.com/cell/fulltext/S0092-8674(16)31662-2

http://www.sciencedirect.com/science/article/pii/S1471491416300533

https://www.sciencedaily.com/releases/2016/12/161215143541.htm

http://www.salk.edu/news-release/turning-back-time-salk-scientists-reverse-signs-aging/

https://www.sciencenews.org/article/proteins-reprogram-cells-can-turn-back-mices-aging-clock

https://www.regmednet.com/users/24433-naamah-maundrell/posts/14169-forever-young-reversing-the-hallmarks-of-aging

About the authors:

Isha Verma is currently pursuing her PhD in Stem cell research from the Indian Institute of Science, Bangalore. She loves reading and traveling.

Radhika Raheja completed her PhD from Cornell University and is currently a Postdoctoral fellow at the Brigham and Women’s Hospital. Her research interests have centered around oncology and neuroimmunology. Among other things, she is striving to effectively communicate scientific discoveries to the community.

About the illustrator:

Ipsa Jain is a Ph.D. student at IISc. She wants to gather and spread interestingness. She prefers painting and drawing over writing.

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