Tuesday, August 21, 2012

Xerox the available gene if the other important fellow is not available

Hello people,

   Welcome back readers for yet another episode of interesting microbiology. As always am back here to discuss some cool microbiology, some science and blah bla bla. Lately i have been listening to some interesting talks in ibioseminars and learning some interesting facts. The content is really appealing and i advice you to check it out.

Fig 1: Big bang Theory (Wikipedia)
    Science is ever changing. Older hypothesis or theories are challenged with better technologies and newer explanations are given grounds. Theories that were once considered path breaking are remodeled to break more paths. This applies to any branch of science. If can sum it up "Theories are best only until a newer one appears". Who doesn't know about the big bang? The origin of universe!!! And if i say the theory is now challenged! Well, thats what is in forefront news now. James Quach, the lead author of a new paper is the challenger. (Read more about it here)

    Another work that caught my brief attention is a work on hantavirus. Hantavirus is a negative sense RNA virus of the Bunyaviridae family. The virus is known to be pathogenic in humans and the infection is basically a zoonosis, mean to say acquired from animals. Rodents are the important source. The infection mainly leads to Hantavirus pulmonary syndrome (HPS) or Hemorrhagic fever with Renal syndrome (HFRS) (Source). Type I interferon (IFN) is known to be inhibitory against the Hantaviral replication. Obviously, the virus has evolved strategies to bypass this. How this is achieved is largely unknown. The paper published in Advances in Virology by Valery Matthys and Erich R. Mackow (Link), address this issue. The viral RNA is sensed by the MAVS system (See my previous post on MAVS). The pathway finally results in activation of a protein STING (Stimulator of interferon genes). For a detailed literature on STING go here. Gn proteins cytoplasmic tail (Gn-T) is proposed to be intefering with STING-TBK1-TRAF3. The fig 2 shown below shows the action.

Fig 2: Potential model of hantavirus Gn-T disruption of STING-TBK1-IRF3 complex formation
    The next story has to do with "Rift valley fever virus". Just as the above this also is a negative sense RNA virus of the Bunyaviridae. RVF causes zoonotic infection typically transmitted by mosquito bite (Aedes or culex). The paper titled "Curcumin Inhibits Rift Valley Fever Virus Replication in Human Cells" shows the potential of curcumin, a compound found in turmeric to inhibit RVF replication. The paper identifies that IKK complex in NF-kB pathway is important for viral replication and by down-regulating it they can impair the viral replication. The fig 3 illustrates the role of IKK complex formed from 3 subunits One thing that this implies to me is somehow the virus needs NFkB activation for its survival in contrast to the hantavirus that i talked about above.

Fig 3: NF-kB pathway (Source)
Photo 1: Aarthi Narayanan

     The down regulation of IKK complex was achieved using circumin. Curcumin partially exerts its inhibitory influence on RVFV replication by interfering with IKK-β2 mediated phosphorylation of the viral protein. The effect was shown against the MP-12 strain (lab strain) and the virulent ZH501 strain. “Curcumin is, by its very nature, broad spectrum,” Narayanan says. “However, in the published article, we provide evidence that curcumin may interfere with how the virus manipulates the human cell to stop the cell from responding to the infection.”. Co investigator Kylene Kehn-Hall adds “We are very excited about this work, as curcumin not only dramatically inhibits RVFV replication in cell culture but also demonstrates efficacy against RVFV in a mouse model.” (Source).

     One paper that needs to be discussed in a slight detail is by Tolu Oni etal. But first some background information for this paper.

   Mycobacterium tuberculosis is a common respiratory pathogen in many parts of the world. TB as nicknamed for tuberculosis, can often be very challenging to diagnose. Most of the diagnostic lab rely on a simple AFB staining technique (Not even fluorescence method), with low sensitivity to diagnose TB. The tests is sometimes accompanied by a simple mantoux test. Newer diagnostic methods are slowly making its way to diagnostics. For a concise list of newer diagnostic method in detection of TB check out my ppt below.

       Latent tuberculosis Infection (LTBI), is a difficult to diagnose situation. Often a lab was left with an option of mantoux test which cannot distinguish between a latent and past TB infection. The method was then replaced with interferon-gamma release assays (IGRA). Interferon Gamma Release Assays are theoretically a class of assays for viral and infectious diseases that measure the CMI (Cell mediated immunity) in infected individuals through the levels of interferon gamma released. In the event of infection, T cells from the individual will be senstized (via MHC proteins) to the antigens presented by cells of the infecting organism. T cells will thus be able to bind to foreign infecting cells, releasing interferon-gamma (Reference). Please note that mantoux test and IGRA, both detect CMI.

Fig 4: Mantoux test (Source)
      Now the question is what is the difference in terms of detection if both assays detect the same profile. The answer lies in the fact that, for TST (Tuberculin skin test) or mantoux test the complex mixture of different antigens used are not specific for M. tuberculosis. Hence a local immunologic activity at the site of the antigen deposition does not differentiate between an existing immune response elicited by bacille Calmette-Guérin (BCG) vaccination, past infection or cross reacting mycobacterium. IGRA is a newer generation assay, and is designed to be more specific. The assay uses specific M. tuberculosis antigens like early secretory antigenic target-6 (ESAT-6), culture filtrate protein 10 (CFP-10), and the TB7.7 antigens. This avoids false positives with previous vaccinations. And by the way, IFN-γ is produced by different cells of the immune system: CD4 T-cells, CD8 Tcells and NK cells. For more information on IGRA refer here. Quantiferon-Gold in-tube assay (QFT-IT) or T-spot are the commercially available IGRA.      Now let me give you a situation. What if you do a IGRA for detecting TB in HIv infected patient? Just think about it before you read on. Its a immunocompromised situation and the assay depends on sound immunity. And mind you TB infection is more common in HIV infected patients at least as far as i know. The paper states that the performance of QFT-IT is Immuno-dependent and T spot is not. (I don't know the explanation in this case).

Table 1: Interpretation of QFT (Source: ECDC guidance for IGRA)
     "The aim of this study was to evaluate predictors of indeterminate gamma interferon (IFN- ) responses, particularly in HIV infected persons". In this paper the main finding was confirming an association between low CD4 counts in HIV-coinfected persons and higher odds of indeterminate IFN- results. A previous BCG exposure also accounted for some of the intermediate results. My interpretation of this paper is that if I'm going to use this assay then, i will preferable retest the intermediate results or declare it as negative. I urge the readers to read this paper for more information as it is open access. Another paper that i want to discuss here is that by Nels C. Elde and others on poxvirus. Poxviruses are DNA viruses, the most famous members among them include small pox and vaccinia. For readers interested in reading some history and eradication of Small pox please go here. Coming to the point of paper, DNA viruses mutate slowly in comparison to RNA viruses. Yet, they are equally comparable to how they adapt and evolve to challenges in a cell. A theory in evolution referred as Red queen Hypothesis states, "In reference to an evolutionary system, continuing adaptation is needed in order for a species to maintain its relative fitnessamongst the systems being co-evolved with" (Taken from Wikipedia).

Fig 5: Protein kinase R activation in defense (Source)
     One of the cellular defending strategy on sensing a ds-RNA is to activate Protein Kinase R (PKR; see fig on the left). This PKR phosphorylates the translation initiation factor eIF2a to inhibit protein production This interferes with viral replication.

     I need to take a step back here. I was talking about dsDNA virus and now am telling that sensing RNA is important in defense. If you seem to miss the point, the dsRNA is found as an intermediate in the life cycle of poxvirus.

      Coming back to the point. If the host evolves to produce a resistance as per the red queen hypothesis the virus should also evolve a bypass strategy. So what does the virus have? In case of vaccinia 2 antagonists seems to be important- K3L and E3L. They simply inhibit the PKR form activation.

     The researchers now tried to answer the question "How the poxvirus can mutate quickly with a DNA genome, that is specified to have a lower mutation rate". To understand this they passaged the vaccinia virus  nullified for E3L from Copenhagen strain thus creating an artificial selection pressure on K3L to inhibit PKR. The mutant virus (E3L-), replicated poorly for first few rounds in comparison to its wild counterpart. The method was to inoculate new batch of HeLa cells from previous growth. By 6th round of replication they were able to see a 10 fold increase in each subsequent passage. In short, the virus was getting better and better. Now thats what is capability. You put too much pressure, yet the virus emerges successful. Boy, thats impressive.

      Looking for answers to this phenomenon in genome of the virus what they found is truly smashing. They found only two non-synonymous and one synonymous polymorphism in the genomes of passage 10 virus replicates at a frequency higher than 1%. Mean to say mutation was low. They had also carried out southern blot of viral DNA at various points of passage and found that the copy number of K3L was increasing slowly. Here's the explanation. the increased number can sustain increased fitness and so better replication. Despite the fact that K3L is weak antagonist of PKR the mere concentration overcame the problem of not having the better counterpart E3L. And yes they also did a bunch of experiments to prove that K3L was involved here.

     A specific mutation was noted in high K3L containing viruses. (Note that, all viruses that had gained fitness didn't possess this change). There was a codon change- H47R. Mean to say, Histidine changed at amino acid number 47 to Arginine. Though the paper doesn't address if the specific change has produced any specific action, the authors did comment that somehow it produced a gain of function. My impression was that possibly the specific site had increased some kind of slippery replication to cause increased copy numbers (I don't know if thats the case, but thats a possibly worthy explanation from my side).
Fig 6: Propose mechanism for rapid evolution (Source)
      Nels C. Elde, the lead author of this paper commented "Our studies show that increasing K3L copy number leads to increased expression of K3L and enhanced viral replication, providing an immediate evolutionary advantage for those viruses that can quickly expand their genome.” and “Our observations reveal that, while poxviruses do undergo gene mutation, their first response to a new, hostile host environment can be rapid gene expansion. We also found evidence that the virus genome can contract after acquiring an adaptive mutation, thus alleviating the potential trade-off of having a larger genome, while leaving a beneficial mutation in place.” (Source)

      This is not a new phenomenon. various bacteria simply increase their products, such as efflux proteins that can throw the drug out of bacterial cell. so if u increase drug concentration, the enemy increases his efflux.

      All said, i have a take on this paper other than what the author proposes. The first take for me if a virus can simply increase gene copies to overcome inhibition, this is a difficult situation. If we are to make drugs that are inhibitory in action, this strategy can easily overcome the pharmacological defense. The virus can simply increase its product. But my doubt is how much. I mean after all its a virus how much copy number can it increase? The genome needs to be accommodated after all. So i just do some wild math here. If the virus can increase its gene by even a 10% which can be packed in, then the drug dose is required to sustain this is somewhere in 100 times. At that concentration any antiviral is toxic or non usable. So we don' stand a chance at least theoretically.

Tolu Oni, Hannah P. Gideon, Nonzwakazi Bangani Relebohile Tsekela, Ronnett Seldon, Kathryn Wood, Katalin A. Wilkinson, Rene T. Goliath, Tom H. M. Ottenhoff and Robert J. Wilkinson (2012). Risk Factors Associated with Indeterminate Gamma Interferon Responses in the Assessment of Latent Tuberculosis Infection in a High-Incidence Environment Clinical and vaccine immunology, 19 (8), 1243-1247 DOI: 10.1128/CVI.00166-12

Nels C. Elde, Stephanie J. Child, Michael T. Eickbush, Jacob O. Kitzman, Kelsey S. Rogers, Jay Shendure, Adam P. Geballe, & Harmit S. Malik (2012). Poxviruses Deploy Genomic Accordions to Adapt Rapidly against Host Antiviral Defenses Cell Host & Microbe, 150 (4), 831-841 DOI: 10.1016/j.cell.2012.05.049

Further reading:
  1. Rutherford M, Alisjahbana B, Maharani W, Sampurno H, van Crevel R, et al. (2010) Sensitivity of the Quantiferon-Gold In-Tube Assay in Sputum Smear Positive TB Cases in Indonesia. PLoS ONE 5(8): e12020. doi:10.1371/journal.pone.0012020. Link
  2. H Ludwig etal. Double-stranded RNA-binding protein E3 controls translation of viral intermediate RNA, marking an essential step in the life cycle of modified vaccinia virus Ankara. J Gen Virol May 2006 vol. 87 no. 5 1145-1155. Link
  3. M V Davies, H W Chang, B L Jacobs, and R J Kaufman. The E3L and K3L vaccinia virus gene products stimulate translation through inhibition of the double-stranded RNA-dependent protein kinase by different mechanisms. J Virol. 1993 March; 67(3): 1688–1692. Link

Wednesday, August 15, 2012

This week in research

Good to see people back,

        Last week i signed of with just a few news. Subsequently there was lot of microbiology that came up. I should have written blog late last week cause so many paper caught my attention. And an announcement. I recently launched my website- "Microboids" (A rather funny name, but will do it for me). I have brought all my digital materials under this one hood. If you haven't checked it out yet, have a look at it. (Oh no, this is not any advertisement, but kind of self promotion!!).

Photo 1: Caenorhabditis briggsae
       So, let see what is been making the news. The first catchy material for me, has to do with Caenorhabditis briggsae nematode. They are model animals for studying evolution of animal, their development and behavior. The study by Clark KA etal published in PloS, has found some selfish DNA in the mitochondrion, affecting the life span of the organism. Denver (co-author) said, "Selfish DNA is not supposed to be found in animals. But it could turn out to be fairly important as a new genetic model to study the type of mitochondrial decay that is associated with human aging." (Source). Need to excurse a bit here. I don't understand the use of "Selfish DNA" quite well here. As per wikipedia "Selfish DNA refers to those sequences of DNA which, in their purest form, have two distinct properties: The DNA sequence spreads by forming additional copies of itself within the genome; and it makes no specific contribution to the reproductive success of its host organism". I thought the transposons and retrotransposons are selfish DNA. They are present in abundance in human genome (Reference here and here). The interesting point is that this study is expected to shed some light into the process of aging.

      I have another equally interesting news form nematode, which has a different story to tell. The story is form another PLoS journal- PLoS pathogens by Robbie Rae etal. Its a fact that the life span of an organism is increased when its reproductive system is removed (I really didn't know that till i had read this paper. I guess sex reduces life span!!!). The mechanism is largely unknown. By using Pristionchus pacificus (a species related to C. elegans), the genetic expression pattern (Using Microarray technique) which may show reasons for increased longevity was studied. They propose that the resistance is due to expression of genes involved in insulin signaling, nuclear pore complexes, ribosomal translation and lipid production. This is the first study to show a significant link between reproductive system, lifespan and innate immunity.

Photo 2: N Fujii
     Rarely i have come across a week, where a paper hasn't been published on HIV. This leaves me wondering. If i had to write a review on HIV and publish it as a book, the very next day of print, it would be declared as outdated. HIV mode of entry to cell requires the use of a CD4 receptor and a co-receptor which is either CXCR4 or CCR5 as per standard models. (I mean to say there are other entry mechanisms which we have realized to operate). CCR5 blockers such as Maraviroc is available, but CXCR4 antagonists are not in market. In 2005, Nobutaka Fujii (Photo Shown to right) proposed a cyclic penta-peptide to be used as an antagonist for CXCR4. The Figure 1 below illustrates the pentapeptide.

Fig 1: Pentapeptide against CXCR4 (Source)
       The new paper by Demmer etal, came up with a better peptide simply by shifting the arginine side chain they could improve the pharmacological properties. I haven't got my hands on to this article in full. I just  could have a look at this image (Shown below).

Fig 2: Frozen Peptoid Boosts CXCR4 Affinity and Anti-HIV Activity (Source)

     I have two reviews in addition to all this that is worth a careful reading. The first is in PLoS pathogens by Zeldovich VB and Bakardjiev titled "Host Defense and Tolerance: Unique Challenges in the Placenta". This review focusses on how the immunity has to deal with a paradox situation laying down the armor of immunity for the sake of growing fetus (Link). The 2nd review is by Christophe Vanpouille etal titled "Microbicides: still a long road to success." (Link).

    I have an interesting short story to talk about here, Though not related to medical field in any way this was so interesting when i first heard about it. But then i came across this video (below) that explains everything i want to tell.

Video 1: Cordyceps: attack of the killer fungi (From Youtube)

   Inspired by zombie above i thought i will make a brief mention of the human zombie protein. I mean prions. For a background information on prion disorders please refer to my previous posts here.

   I want to give an additional set of background information here. The first question that is asked in the field of prion biology is "Are they genetic or environmental". I must admit, they are the only kind that is both. They can be genetic (Such as FFI or Familial Fatal Insomnia and many subtypes of CJD) or acquired as infection (Classical example is kuru). You can read some of the details in my notes section here. The infection is thought to be acquired mainly by ingestion (Not always). So from GIT or through blood somehow the proteins set a journey to the central nervous system. Meantime, they are known to colonize lymph nodes. It is now well agreed that that the prions migrate from lymph nodes to Peripheral nervous system and then subsequently to Central nervous system

Fig 3: The spread of prions throughout the body
    Extraneural prion accumulation is thought to occur primarily within stromal cells within follicular dendritic cells (FDCs). B cell-derived tumor necrosis factor (TNF) and Lymphotoxins are believed to keep the FDC in game. The receptor for these include a LTβR and TNFR1. 
     The tumor necrosis factor α receptor (TNFR1) on suitable stimulation activates downstream effectors that include the mitogen-activated protein kinase kinase 7 (MKK7)/c-Jun-NH2-kinase (JNK)/ activator protein 1 (AP1) cascade. The LTβR decides the regulation of inflammatory response actions.

     Quoting from the journal "A number of studies have implicated FDCs in the germinal centers of secondary lymphoid organs as the primary reservoirs of prions prior to neuroinvasion, Yet the ability of TNFR1 null cells to accumulate prions with a minimal loss of infectivity compared to wild type presents an apparent paradox, since FDC maintenance depends on TNFR1 signaling". So that was the question this paper tried to answer. And the answer they found was interesting. The TNFR1 was not important at all in this context. The main player was LTβR signaling. It also coincides with entry of prions into lymphoid organs through High endothelial venules (HEV) and replicate in presence of mature dendritic cells.

Tracy O’Connor, Nathalie Frei, Jana Sponarova, Petra Schwarz, Mathias Heikenwalder, & Adriano Aguzzi (2012). Lymphotoxin, but Not TNF, Is Required for Prion Invasion of Lymph Nodes PLoS pathogens

Demmer, O., Frank, A. O., Hagn, F., Schottelius, M., Marinelli, L., Cosconati, S., Brack-Werner, R., Kremb, S., Wester, H.-J. and Kessler, H. (2012). A Conformationally Frozen Peptoid Boosts CXCR4 Affinity and Anti-HIV Activity Angewandte Chemie International Edition DOI: 10.1002/anie.201202090

Monday, August 06, 2012

Tit Bits of the week

Welcome back all,

    As i look at the calendar, after a chillax weekend and lazying around i was thinking of what do i write about this monday. Nothing had caught my attention that needs to be blogged. Ofcourse that doesnt mean microbiology was celebrating a holiday last week. It just means that i didn't get a paper that had caught me up so much that i wanted to write about it. Anyways, there still was some headlines of microbes floating around that i thought i will make a note of here. And maybe i will stumble upon something that i can talk about.

Photo 1: Curiosity rover (Image taken from here)
    Oh and by the way, the NASA project curiosity has successfully landed. What's interesting about it for a microbiologist? The "Curiosity" vehicle is meticulously designed and equipped to look for signatures of life. And maybe we find some microbes sitting on another planet and minding its own business there. And if things turn out so, we could be more serious of some "Astromicrobiology / Cosmomicrobiology" (Too complicated words). Thats interesting to me cause we probably would be talking more microbiology in the context of some panspermia theories. (Read more here).

    You must have heard about the German patient story, who controlled his HIV status with a stem cell transplant (Link). Following this a landmark paper by Wilen CB etal (Link) showed that by chopping of specific genes using a zinc finger nuclease, we could probably engineer some resistance to cells against HIV. The same whole issue of transplanting stem cells has come up again. Two men with HIV infections no more  show retropositivity in their blood cells following bone marrow transplantation (Link). This whole issue is now interesting to me. What we can do is catch hold of a donor who has stem cells resistant to HIV probably get it to replicate in laboratory and pack as vials and give transplants to HIV patients. Boom!! (Am just speculating the future possibilities. If someone finds himself such a possible donor, he better patent his cells!!!). I have a better feel of this issue. IF we could possibly find a commercial method to engineer the cells from patient himself and then transplant him back (Read Wlien CB paper i mentioned above) we are really a step nearer to shutting down the HIV menace. Interesting enough.

Fig 1: Endonuclease domain of influenza
     Influenza virus have been in news for a long time now. But this is bit different. The influenza virus is in itself a outlier of the fact that unlike other RNA viruses, they replicate in nucleus. An explanation is so. Influenza being a negative sense RNA genome. For this it first needs to produce a positive sense mRNA in order to produce necessary enzymes. The feasibility to do this exists in nucleus. In the host nucleus, the virus carries out its primary transcription through a special mechanism known as "Cap snatching". The host mRNA is stolen and broken down into small fragments of 10-20 bases length. This is done with the help of an endonuclease. This activity is embedded in the viral RdRp (RNA-dependent RNA polymerase). The generated fragments is used a a primer to kick start building new cRNA from which all required materials can be built. (For more information click here). This is pure elegancy which is not completely understood. The researchers elucidated the 3D structure of the polymerase and observe interactions by several different small molecule inhibitors that can attack its active site. As Stephen Cusack says "Based on this detailed structural information we can now design new synthetic chemicals which bind even more tightly to the endonuclease active site and thus will potentially be more potent inhibitors of influenza virus replication" and "We can even try to build in anti-drug resistance by making sure the inhibitors only contact those amino acids that the virus cannot mutate since they are essential for the normal activity of the polymerase. The figure 1 (shown above  right, shows secondary structure of the endonuclease domain of the influenza virus polymerase; ß-sheets in yellow and α-helices in blue. The active site lysine 134 and the amino acid side chains that ligand the two metal ions (represented as green spheres) in the active site are indicated. (Source).) Read paper here and here.

     Every disease that we know of has a multifactorial etiology. Often if not always, a part is played by microbes that we interact with daily. Diseases that have been thought to be completely innate are now found to been triggered at least in part by microbes. Multiple sclerosis and many other auto immune disorder has been speculated to be due to gut microbiome. Mind you, I'm not specifying a organism but a collection of microbes- "The Microbiome". Read more here. The idea is that immune system is trained and kept at healthy conditions most often by our normal flora. Change in flora and change in immune response. This at times have even lead me to ask a question. Is our immune system deciding which microbe should stay or microbe is deciding what immune system should stay. Thats why our body should interact well with the filthy microbiome out there in environment, to stay healthy. (Read my previous post Microbiophobia). Why am i talking about all this? for 2 reasons. 1st awareness and 2nd, to break the news.

Photo 2: Gestational Diabetes (Source)

   The news that am talking about above is that of a relation between pregnancy, diabetes and gastro-microbiome. Gestational diabetes is not so uncommon phenomenon. This is attributed to a resistance to insulin, which increases in all mothers during pregnancy. of this about 2-5% develop a temporary diabetes. In majority of scenraio's there is no external symptoms and is detected only by screening. Only rarely do the classic symptoms of diabetes appear, e.g excessive thirst, frequent urination and tiredness. The fetus probably has a parasitic role in gestation period. The physiological reprogramming of sensitivity to insulin in mothers is thought to be placenta mediated. The fetus can then gain the extra glucose not taken up by mother. (Am not sure if this is the case. But thats how i see it.

Fig 2: Potential mechanisms for insulin resistance in skeletal muscle during late pregnancy in human gestational diabetes  (Source: Linda etal; Link)

      Apologies for such a long digression to tell you a single line news. And the news is "Pregnancy alters microbiota of gut". There are some important findings that i latched onto. First is the diversity of gut bacteria declined between the first and third trimesters, but the abundance of certain types, such as the Proteobacteria and Actinobacteria, increased. This according to me should be co related to the known fact that in early pregnancy, insulin secretion increases, while insulin sensitivity is unchanged, decreased, or may even increase. In late gestation, maternal adipose tissue decline, while postprandial FFA levels increase and insulin-mediated glucose disposal worsens. This correlates with the findings of the study, that third-trimester microbiota resembles that of people at risk of diabetes. David Relman commented “That is pretty suggestive that the microbiome is at least contributing to the change, or maybe driving it”. Ley makes a statement “The body might be using the microbes as a tool" and "You alter the microbiota, and they give you the changes in metabolism that you want”. If she hadn't said it, that would be exactly the same statement that i would have made here. (Source). For more information on link between diabetes and microbes go here and here.

     As i said already, am not discussing a paper in full today. So, Signing off for now. Be sure to check my post in my other blog on luminescence and its application in laboratory science.

Rebecca M. DuBois etal (2012). Structural and Biochemical Basis for Development of Influenza Virus Inhibitors Targeting the PA Endonuclease PLoS pathogens

Thursday, August 02, 2012

Copy- paste: Oh I Infringed

Good to see everyone back

     First an apology for late post this week. I was too busy creating my own website Microboids, to link all my digital matter under a single self owned domain. And now this blog is under the Microboids category.

    "No matter how much we have improved on technology, and how good we microbiologists and pharmacy are, we are beaten to the core when it comes to microbes. And the viruses? We are many a times fighting a loosing battle..." said one of my friend (Name not revealed here). For a time i guess that is so true. We design new drugs and therapy through painstaking extraordinary research. After spending billions the companies build a marketable drug. And then? The microbe becomes resistant in a few month. Swap, just like that. But then we haven't lost everything. We really have conquered some. Its up to you microbiologists testify yourself in or against the debatable question, and i will leave it to you.

Photo 1: Rabid animal (Source)
     So what do i have in the news section? (I just named it so, for a convincing appeal of it). A drug called Vorinostat had previously made some news (I had written about this. Please check the post; Flush the hidden HIV out). I'm simply amazed at the time it had taken to come out in a journal. The article is in Nature (Link). The story is covered up in science news and in nature podcast 26 July 2012, termed "Smoking out HIV". A second news comes from the ability of we humans to direct one enemy of ours to another enemy. Sounds crazy right? Am talking about the paper that uses proteins implicated in Alzheimers disease to treat multiple sclerosis. OOh... Am impresses at this. The paper can be found here. I just am loving the way you people are shocked. So let me give you one more. There is almost no debate on if the rabies is fatal. There are just 2 cases i know of that escaped from rabies death sentence being infected without vaccination. In what is more famously known as The Milwaukee protocol or Wisconsin protocol this was thought to be achievable (Source), but is just horrible (Source) to treat a rabies infected person without vaccination. But now it seems that all people infected with rabies didn't die. Reality; many didn't even possibly know they had dealt with rabies virus. So goes my interpretation. Find more details here.

   Today i have a deviation from the usual paper or fundamental microbiology/immunology discussion. And i want to make a justification, before i move on. Basics and some fundamental rules always have a higher priority for discussion. I did want to write about many other cool microbiology out there. But, there's something more fundamental that i wanted to present here, which merits a discussion platform at least here. There are 2 actually- Plagiarism and the debate about access to publication.

    What is plagiarism? Most people simply put plagiarism as stealing from others ideas without endorsing proper credit to the original author. As a background information, i want to give you some brief idea about Intellectual property rights. If you want to know more about, Ethics which is broader version of this please refer to my notes section (Link).

    Intellectual property refers to a copyright and usage rights of an original work created by an individual or group. Based on the degree of usage and permissibility of usage the intellectual property may be roughly classified into 3 types
  1. Copyright works
  2. Patented works
  3. GPL (General public license)

    Copyright is a form of intellectual property protection granted under  law to the creators of original works of authorship. In context to India, the Copyright Act, 1957 came into effect from January 1958. This Act has been amended five times since then, i.e., in 1983, 1984, 1992, 1994 and 1999, with the amendment of 1994 being the most substantial. Prior to the Act of 1957, the Law of Copyrights in the country was governed by the Copyright Act of 1914. This Act was essentially the extension of the British Copyright Act, 1911 to India. (Copyright office, Gov of India)

    All the laws of copyright, in any country allows the author to deliver certain exclusive rights such as the right to copy in part or full, publish and use the work for further development without any hindrance. Further the copyright is usually conferred for a life time or a set number of years depending on legal system of the region and type of material. The copyright is represented by ©. Any violation of the copyright will be considered as illegal and referred as "Copyright infringement" or more commonly known as piracy. Copyright infringement occur when someone other than the copyright holder copies the work itself or the idea of work.

Exceptions to Copyright Infringements

     Exceptions to the copyright infringement rules, which allow one to reproduce another's work without obtaining a license or assignment of rights:

1.  Fair Use or Educational use:

     This is a doctrine which permits the reproduction of copyrighted material for a limited purpose of teaching, reviewing, literary criticism and the like. In publication of research works, many ideas may be derived from various sources. The ideas maybe copied, however they are required to mention the source of information and quote the original author. Such a work is not considered as piracy.

2. Public Domain

    This refers to works which are released by GPL or the ones for which a time period of copyright protection is no more valid.

3. Non-Copyrightable Works

    Copyright infringement cannot occur when someone uses material that cannot be protected by copyright, such as facts or ideas which is in common use (For e.g: The phrase "Sugar is sweet" is an universal idea. Nobody can copyright that).


      Patent refers to exclusive right granted by a government to an inventor to manufacture, use, or sell an invention for a certain number of years sufficient enough to make a justifiable profit. In most of the countries this is 20 years. This is in exchange for the public disclosure of an invention. A patent is not an exclusive right but rather, it’s a power authorized by the governing body to exclude others from using the invention. The patented methods may be used by educational institutes for non profitable research and education, without permission to do so from the owner of patent. The owner of the patent is also allowed to sell his work in part or full to others for which a document should be provided. If a method was invented by a scientist working for an institution and the work is a part of his routine assigned profession then, the inventor is not the owner of patent. Rather, the patent rights are given to the institution itself.

    This rule differs in various countries according to the legal codes. Breaking the code of practice of patent is called as Patent infringement. An exception exists by that the Government may use any patented invention without permission of the patentee, but the patentee is entitled to obtain compensation for the use by or for the Government.

General public license

     The concept of general public license or public use license is new in the field of medicine. The principle is that the credit of invention of material or ideas is given to the original author; but they can be legally copied, used, published, or even mended. A great example of GPL is that of Linux Operating system in computer science and Open access publishing in various journals.

Fig 1: Illustration of copyright law (Source)
So what is the benefits and risks of different types?

    In copyright and patents, the technology that is projected is not easily accessible. The development of a competitive technology requires fresh research and start from the lowest level. The GPL overcomes this hurdle, as the technology can be further developed from the current status without any legal obligations. This saves lot of resources which can be used for upgrading science. Also open access allows more ideas to flow and rapid improvement. The disadvantage is however that the original inventor may not make financial profit from his work. Owing to the fact that, the GPL is for common use, there is no issue of infringement unless you have cited.

Photo 2: Prime Minister Victor Ponta (Source)   
      *The decision of to what type of intellectual property the owner of work decides to use is the exclusive right of the author. No governing body can question or force the author to choose a specific type of IPR. To a limited extent this also depends on the type and nature of the work. The publication in journals therefore uses a copyright form which agrees upon the type of IPR the work will be classified into. Only after the authors consent is a paper published. Why do i have sudden interest in plagiarism? Well, i thought i need to talk about this after reading the story of  Romanian prime minister accused of copyright infringement. The story can be found here in nature news.

       The most important and almost a commonly asked question is "If i have created some material (say some publication), do i need to cite that for my subsequent article". The simplest answer for the issue would be "no". Why? Cause its your material. Your own intellectual property. None can question that. But let me warn you, the issue is not as simple as it presents to you.

     Consider a work has been created by you, such as a illustrative figure. (Let the copyright you used be of any type). If you have published this on a journal you would, as per the policies of journal, its no more entirely yours anymore. Of course, you would still retain the usage right at will provided that u cite. If on the other way you have nothing such as this, you may choose not to. But there would be an additional advantage in citing your own source. First, it shows you have imprinted this earlier and made a significant work on this. Second (more importantly), its likely that someone who wish to use the material may want more information which could be tracked through your citation and hence more hits for your work.

     There is a super advantage of attributing proper credit to the original author. Other than that you are free from plagiarism, if there is a mistake in the argument or statement made, the burden of defending it is more on the original author than the one who borrowed the argument. Do you need anything more than that?

   The second issue thats connected with this (But not completely) is that of access to publication. Let me start from scratch. Where does the money to do science come from for the scientists? From Government which is fueled by tax (Exceptions exist). And the tax is payed by the country men. So if public wants to know the result of a experiment they need to read from a journal. Simple. But if the publisher doesn't allow access to material till you have made a payment!! You pay for work to be done and you pay again to know what's done with your money!!! "Thats absurd" is my reaction.

   So the Federal Research Public Access Act (FRPAA) bill was passed (Link). This act required that the literature of work using public money should be made available to public irrespective of which journal you publish.  A group of 81 scholarly journal publishers opposed this bill (Source). Elsevier a massive publishing group with supposedly heavy charges for literature access, launched a great opposition to this bill. This created an outrage among the scientists. They decided to boycott the Elsevier publications. Several scientists signed a understanding that they wouldn't publish their work with Elsevier nor would be a peer reviewer for that (Source). Boy, Thats a massive blow to the company operating for years together.

   So now you see the importance of open access publishing. But i want to make a point here. These are just business models. Some journals choose to charge the reader (restricted access), some charge the writer (In most of the Open access), to bear for the charges of maintaing the journal. There is a 3rd model that is gaining popularity. Its a subtype of open access where the writers are not charged or charged very low in comparison to high publication charges in most of the open access journals. Here the journal is just not doing business i guess (I just laugh at this. I actually don't have a clear idea on how this model works).

   The advantages of publishing in an open access would include that you give public access to literature in return for the money they provided you for the work, and keep the glory. 2nd wider range of readership increases chances that you will be cited (adds to glory) and your work will see higher scientific advancement faster.

Zaenker KS. (2012). The emperor of all academic and cultural maladies in scientific writing: Plagiarism and auto-plagiarism. Inflammation & Allergy-Drug Targets , 2012 Feb 2. DOI: 10.2174/187152812798889367

Further Reading
  1. World Intellectual Property organization website, WIPO
  2. Daniel.lende. American Anthropological Association Takes Public Stand against Open Access. (Link)
  3. Meredith Schwartz.Elsevier Backs Off RWA Support; Still Opposes Mandated Open Access (Link)