BIOINFORMATICS REVIEW- FEBRUARY 2017

FEBRUARY 2017 VOL 3 ISSUE 2

“Science is organized knowledge.

Wisdom is organized life.�

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Immanuel Kant

Perspective: Small molecules as players in targeted therapies

Survival guide: How to overcome lab politics and not become a lab rat

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Contents

February 2017

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Topics Editorial....

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03 Bioinformatics News Perspective: Small molecules as players in targeted therapies 07

04 Tips & Tricks Survival guide: How to overcome lab politics and not become a lab rat 10

FOUNDER TARIQ ABDULLAH EDITORIAL EXECUTIVE EDITOR TARIQ ABDULLAH FOUNDING EDITOR MUNIBA FAIZA SECTION EDITORS FOZAIL AHMAD ALTAF ABDUL KALAM MANISH KUMAR MISHRA SANJAY KUMAR NABAJIT DAS

REPRINTS AND PERMISSIONS You must have permission before reproducing any material from Bioinformatics Review. Send E-mail requests to info@bioinformaticsreview.com. Please include contact detail in your message.

BACK ISSUE Bioinformatics Review back issues can be downloaded in digital format from bioinformaticsreview.com at $5 per issue. Back issue in print format cost $2 for India delivery and $11 for international delivery, subject to availability. Pre-payment is required CONTACT PHONE +91. 991 1942-428 / 852 7572-667 MAIL Editorial: 101 FF Main Road Zakir Nagar, Okhla New Delhi IN 110025 STAFF ADDRESS To contact any of the Bioinformatics Review staff member, simply format the address as firstname@bioinformaticsreview.com PUBLICATION INFORMATION Volume 1, Number 1, Bioinformatics Reviewâ„¢ is published monthly for one year (12 issues) by Social and Educational Welfare Association (SEWA)trust (Registered under Trust Act 1882). Copyright 2015 Sewa Trust. All rights reserved. Bioinformatics Review is a trademark of Idea Quotient Labs and used under license by SEWA trust. Published in India

EDITORIAL

Bioinformatics Review (BiR): Bridging Between The Two Worlds Informatics and Biology are two sciences which are as different from each other as possible. One runs on the core concept of variation and another on strict reasoning. But still, these two have combined in a most natural way under the realm of “Bioinformatics”. For a biologist today it’s difficult to imagine a world without all biological databases and further no branch to decipher the huge enigma that it brings. Bioinformatics Review (BiR) journal is a platform to discover the latest happenings in this melting pot of two varied fields.

Dr. Roopam Sharma

Honorary Editor

The era of “omics” kick-started with the drafting of Human Genome Project (HGP) in 2003. Since then, a number of technological advancements especially, NGS has been generating mind-boggling data for the knowledge banks. Latest inventions like single-cell transcriptomics or metagenomics of most unusual habitats show how the evolution of technological advancements is directly resulting in breakthroughs in biological sciences.

Among various areas of biology which has benefited from these advancements is Pathology. In fact, deciphering the molecular and genetic basis of diseases in humans was the guiding force behind human genome sequencing Project. Bioinformatics has led to an impressive increase in recognition of possible pathogenic factors in varied systems, so much so that new techniques are being devised to increase the speed to actually test these factors in the wet lab. If we consider computationally, smaller but ever-changing genomes and transcriptomes of these pathogens, make them a much suitable candidate to test out many hypotheses for Bioinformatics studies. Effector Bioinformatics involves building custom pipelines for distinct species based on characteristics of effectors and size of the genome involved. These can be based on

Letters and responses: info@bioinformaticsreview.com

Homology or feature extraction or both, e.g. discovery of RXLR motifs in Oomycete effectors allowed many more effectors to be identified. This collaboration of two sciences for plant pathology has led to the development of many general use platforms like Broad-Fungal Genome Initiative, EuPathDB, PhytoPath and so on, but there is much need of developing specified resources like PHIbase for specific areas like effector biology. The use of machinelearning techniques like artificial neural network approach (which is actually based on biological neural networks) really shows how the two branches are so distinct yet so intertwined. All in all, it’s a brave new world where artificial communication is not only stimulating but also helping us understand the communication (between host and pathogen) going within the realm of life.

EDITORIAL

In this issue, BiR focusses on reviews related to some of the very basic techniques which have been used in computational biology and its applications in various biological studies. We look forward to continued support from our readers and contributors. For suggestions and feedback, do write to us at info@bioinformaticsreview.com

BIOINFORMATICS NEWS

Perspective: Small molecules as players in targeted therapies Image Credit: Stock photos

“In this insight report, the author discusses the prospect offered by small molecules for the development of targeted therapies. The author also talks about monoclonal antibodies and antibody recognition in a human body and why carbohydrate antigen targeting appears to be a promising playground in near future.� s the Centers for Disease Control and Prevention points out, breast cancer in the USA, and Not counting some kinds of skin cancer, is the most common cancer in women, irrespective of race or ethnicity. The second most common cause of death from cancer among white, black, Asian/Pacific Islander, and American Indian/Alaska Native women.

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the technique, nowadays, is highly endorsed by the American Association for Cancer Research and is seen as a radical improvement over traditional.

Sill in 2015, 224,147 women and 2,125 men in the United States were diagnosed with breast cancer and 41,150 women and 405 men in the United States died from breast cancer.

The only way to prevent and cure cancer is through innovative research.

The way our group thought of doing it is by designing small molecules as in targeted therapies. The concept and

Targeted therapies or rational drug design is normally based on the knowledge of the three-dimensional spatial arrangement of the protein molecular complex and structural analyses of receptors/targets provide us with an effective tool for the development of disease therapeutics.

The general notion about targeted therapies is that they are expected to be more effective than current treatments and do not so much impact normal cells. Several therapies based on mechanisms that target critical checkpoints in signaling pathways, progression from normal to tumorigenic cells are gaining more

traction. In the last couple of decades, the US Food and Drug Administration (FDA) has approved more than a dozen monoclonal antibodies (mAbs) to treat certain types of cancers.

Clinical trials of newer mAbs are now being done on many types of cancer.

While many pharma giants compete with each other for their first-in-line immunotherapeutic products, patient safety and health should be monitored for a longer term to determine how each of these drugs far in progressing survival rates over conventional methods like chemotherapy.

Nevertheless, mAb-based immunotherapy together with molecular innovation and potent target discovery are here to stay for the next generation of diagnostics and Bioinformatics Review | 7

personalized medicine. In my previous life as a structural bioinformatician, I was investigating antibodies reactive to tumor-associated carbohydrate antigens that play a major role in many metastatic cancers. Neocarbohydrate antigens are chemical aberrations found on the cell surface of many tumors like breast, lung, prostate etc. Our findings change the older notion of antibody recognition in our body. Antibodies reactive against these neoantigens follow a different developmental pathway.

They mostly proceed via the Thymus cell independent pathway in contrast to the what we find in immunology textbooks. For antibodies against Thymus cell-dependent antigens, the acquisition of high reactivity to antigens is known to proceed via antigen-driven evolution based on somatic hypermutation (mutational changes in the somatic cells of our body) [1].

We have shown here that mother antibody cells or the germline Lewis Y reactive B cells yield higher affinity clones as a result of a somatic diversification. The B cells or the B lymphocytes are responsible for antigenic recognition. The germline antibody (precursor antibody) is preformed to recognize salient structural fragments of the carbohydrate antigens. Accumulating discrete mutations in their structure

as part of diversification has only recently been addressed. This mutational process yields high probability clones that accommodate better fine structures of the antigen fragments. This reflects a strategy different from the classical theory of antibody maturation. This study highlighted the occurrence of thymusindependent antibody related to a single precursor family which is a first of its kind. Thus, as our knowledge about the structural details of antibody-antigen interaction broadens, we may be able to design better antibodies, as well as design improved antibody-based vaccines through more refined reverseengineering concepts based on the knowledge of antibody structural plasticity and specificity, paving the path towards improved immunotherapy for cancer patients.

As an obvious next step towards developing a small molecule therapeutic, I was involved in the development of a peptide referred to as p109/P6 that function as an antigenic mimic of the Lewis Y (carbohydrate antigen) as p109/P6 binds to an anti- Lewis Y antibody.

Molecular modeling indicates that the peptide sequence should contain certain amino acid types like Arginine, Tyrosine, Tryptophan, and Serine that are found to interact with saccharide units. I

have exploited these structural rules to predict the kinds of structural conformation these peptides will adopt as carbohydrate mimics. This is a key concept utilized to design immunogenic agents to induce an anti-carbohydrate cross-reactive response that can overcome the problem of low titer values when carbohydrate antibodies bind to these pathogens. The peptide clearly combines the advantages of antibodies and small molecules that induce inhibition of cell adhesion and cell aggregation [2] presumably through interactions with cellular receptors, at the same time being proapoptotic in nature when targeted against carbohydrate antigens [3]. The unique advantage in targeting carbohydrate antigens by mimetic peptides is that multiple proteins and lipids on cancer cells can simultaneously be modified with a singular carbohydrate structure.

Thus, targeting carbohydrate antigens broadens the spectrum of antigens recognized by the immune system.

References 1.

Saha S, Pashov A, Siegel ER, Murali R, KieberEmmons T. Defining the recognition elements of Lewis Y-reactive antibodies. PLoS One. 2014;9(8):e104208.

2.

Glinsky VV, Huflejt ME, Glinsky GV, Deutscher SL, Quinn TP. Effects of ThomsenFriedenreich antigen-specific peptide P-30 on beta-galactoside-mediated homotypic

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aggregation and adhesion to the endothelium of MDA-MB-435 human breast carcinoma cells. Cancer research. 2000;60(10):2584-8.

3.

Kieber-Emmons T, Luo P, Qiu J, Chang TY, O I, Blaszczyk-Thurin M, et al. Vaccination with carbohydrate peptide mimotopes promotes anti-tumor responses. Nat Biotechnol.

1999;17(7):660-5.

Disclaimer: The views in this article are that of the author’s alone and not necessarily endorsed by GlaxoSmithKline(GSK)Plc.

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TIPS & TRICKS

Survival guide: How to overcome lab politics and not become a lab rat Image Credit: Google images

“Lab politics can be nasty, and those who don't want to get involved are almost certainly the easiest target.� f you find yourself in a laboratory full of people with scientific temperament, it can be exciting, awesome and hilarious. You may experience a real life "big bang theory" episode and witness all the characters around you.

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However, for the uninitiated, a large number of labs are a flourishing ground of rivalry and war grounds reiterating the fact on its inhabitant that they live in a maze.

Lab politics can be nasty, and those who don't want to get involved are almost certainly the easiest target.

Here are a few tips based on my experience in labs on how to survive lab politics and prevent yourself from getting into situations uncalled for.

1. Communicate Backbiting and misinformation is the nuclear weapon of every mole.

They pass on a false information about you leading to complexities. It ranges from simple misinformation about you being absent or drunk during work hours when you are not, to some complicated statements attributed to you. You can deal with this situation through regular communication. with your peers. Every one of them.

Especially if you sense that your guide

is growing weary of you. communicate as clearly as possible and if you sense a misinformation, make it a priority to point it out without targeting the person acting as a mole. This will be such a blow.....oops!

2. Be Humble

Back in graduation days, I was made a leader for a group project, I worked harder than everybody suddenly to realize that it was only me that was working for the whole duration. So I became proud which reflected in my behavior. Seeing this, two girls approached the guide with some story, which I am still unaware of. The guide,

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who happens to be a lady, immediately removed me from the project & my name from manuscript after it completed. The results were published without my name, the first author being that girl who was not even fully aware of the topic. Moral? even if you are doing everything, be humble or you risk being a lab rat.

3. Divert to productivity

When somebody else is the target, it is relatively easy for you to just ignore what is happening but remaining silent is such situations will lead to exponential increase in it and you never know when the dial points at you. You may try shifting focus to an interesting observation, experiment or paper.

This way, you show them that what these guys are talking about is not worth the time.

4. Don't be evil

If someone is doing something a certain way and you know they are wrong, just point it to them. Don't go to your guide to complain. If complain too much it is perceived as a negative trait. If you have problems, try to resolve it on your own rather than asking someone to

do it for you. If you can't do it yourself, try to get help rather than ordering. Nobody owes you anything so be humble.

Although I have tried to accommodate as much as I could, do you think I have missed something? would like to add something to the story? go ahead and comment below.

5. Don't over-promise You may become a target without even saying a word! yes! it happens.

The world is full of hatred for achievers. So if you have a lot in your kitty, don't keep flaunting it. don't promise that you will do this and that.

Just keep doing things one by one. So they won't even notice that you were running your own race and they were not even the participants.

6. Don't get discouraged If you are surrounded by 'lab politicians' and they criticize your work and working habits, then don't get discouraged, because they would be trying to distract you from your work.

In fact, it is a good sign, great success comes with criticism. Don't believe what they say because 'politicians' never want anyone else's account to be filled, just say thanks to them with a smile and keep going in your direction.

These are the tips that I have learned by working at labs in the University of Delhi, Indian Institute of Science Education & Research - Kolkata, Jamia Millia Islamia & Jawaharlal Nehru University.

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