News & Views Issue 6, November 2015

INDIA ALLIANCE

Science cannot be divided into what is up to date and what is merely of antiquarian interest; it is to be regarded as the

product of a growth of thought- Peter B. Medawar

As the year draws to a close, our last newsletter issue of 2015 brings to you the latest round up on news of our Fellowship

schemes, updates on our Fellow’s research, public engagement and science communication activities along with some

interesting interviews and outreach initiatives . Our Annual Report of the year 2014-15 can be viewed here.

On the Fellowships front, all our fellowship competitions are presently closed and the submitted applications for Early

Career Fellowships and Senior and Intermediate Fellowships (basic scheme) are under review. Interview for Clinical and

Public Health fellowships, Research Training Fellowships, Margdarshi Fellowships and Senior and Intermediate Fellowships

(basic research scheme) were held in the first week of November in Hyderabad, results of which will be announced

shortly. The 12th two-day Science Communication workshop held in Hyderabad on 14-15 September, was shortly followed

by a one-day sciComm101 workshop at Vinayaka Missions University, Salem, Tamil Nadu on 21 September which was

attended by around 80 PhD students and young researchers. As part of public engagement exercise, our Fellows sent

wonderful entries for our first ‘Research Image Competition’, the results of which can be found in this issue.

In this issue, we feature recently published work of our Fellows, Drs Benu Brata Das, Rakesh K Laishram, Thomas

Pucadyil, Vatsala Thirumalai & R Mahalakshmi. Recognising and echoing the importance of the ‘World Antibiotic

Awareness Week’ that starts today, the feature article “Emergence of a new Resistance” describes the emerging crisis of

Antimicrobial Resistance, one of the biggest threats to global health today. Our Intermediate Fellow at IGIB, New Delhi, Dr

Sheetal Gandotra, shares with us the impact of her current research on Mycobacterium Tuberculosis, role of scientists and

science in India and much more, in the ‘Fellow in the Spotlight’ section. Last but not the least, our Grants Adviser, Dr

Ranjana Sarma reminisces about her early childhood and research days, recounts how India Alliance experience has been

a mixed bag, her love for martial arts and dance, in the ‘IA Staff Corner’ section

My heartfelt gratitude goes out to all the contributors for this issue. A special thanks to Drs Bushra Ateeq and Anjali

Bajpai, for the cover image.

We will continue to bring to you interesting scientific discoveries and discussions in the new year and as always look

forward to your comments and suggestions.

Best wishes,

Dr Sarah Iqbal Public Engagement Officer

EDITORIAL

1.

CONTENTS

3 INDIA ALLIANCE OUTREACH EVENTS

5 INDIA ALLIANCE SCIENCE COMMUNICATION WORKSHOPS

SciComm Hyderabad September 2015, SciComm101 Salem

7 INDIA ALLIANCE PUBLIC ENGAGEMENT CORNER

Research Image Competition for Fellows

8 INDIA ALLIANCE RESEARCH HIGHLIGHTS

Featuring recent research articles by Fellows, Drs Benu Brata Das, Rakesh K

Laishram, Thomas Pucadyil, Vatsala Thirumalai & R Mahalakshmi

11 INDIA ALLIANCE FELLOW IN SPOTLIGHT

Dr Sheetal Gandotra, Intermediate Fellow, IGIB, New Delhi

12 FEATURE ARTICLE

Emergence of a new Resistance

by Dr Sarah Iqbal, Public Engagement officer, India Alliance

15 INDIA ALLIANCE STAFF CORNER

Dr Ranjana Sarma, Grants Adviser, India Alliance

2.

INDIA ALLIANCE

6TH ANNUAL FELLOW’S MEETING

The Wellcome Trust/DBT India Alliance hosted its two-day Annual Fellow’s Meeting on 5-6th November 2015 at Novotel Hotel, Hyderabad. This meeting brought together 100 of its

Fellows from around 50 institutions across India, along with Wellcome Trust officers and about 30 eminent Indian and international scientists from University of Oxford, London School of Hygiene and Tropical Medicine, University of Oxford, University of California, USA, University of North Texas Health Science Center, USA, Johns Hopkins University, USA, University of Leeds, University of Dundee, UK and Institute of Molecular, Cell Biology, Portugal, University College of London, National Institute of Medical Research, UK and MRC National Institute of Medical Research, UK. Two representatives from the African Academy of Sciences also participated in this two-day event to understand the operations of the India Alliance as they prepare for a similar partnership with the Wellcome Trust, UK, in Africa. The scientific research presented at the meeting was on themes ranging from genomics, cancer, neuroscience to

nutrition, stem cell research and many other areas of biomedical research. Apart from the scientific presentations, there were talks and discussions on various facets of scientific

research in India. Dr Simon Kay, International operations, Wellcome Trust, UK, discussed the importance of diversity in science and urged the scientists in the audience to maintain and respect diversity in their workplaces. Renowned Indian scientist, Prof D Balasubramanian (LVPEI, Hyderabad) encouraged the scientists in attendance to talk about their science to the public and explained the significance of this engagement. As part of a public engagement exercise, the two-day event also included a display of research images by the Fellows, which were judged for their visual impact, context and its understandability for a public audience. There were many interactive sessions throughout the two days which showcased and discussed the research funded by the Wellcome Trust/DBT India Alliance.

3.

INDIA ALLIANCE

OUTREACH EVENTS Life Science opportunities in India: A special session at The EMBO Meeting 2015 7 September, 2015 India Alliance along with IndiaBioscience participated in The EMBO meeting 2015 from 5-8 September, 2015 in Birmingham, UK. The Wellcome Trust/DBT India Alliance had also sponsored travel awards for 6 young scientists from India to attend the EMBO meeting. India Alliance and IndiaBioscience had a

booth on all days of the conference. There were questions asked about opportunities in India, how to apply and also to get an overall picture of science in India. In addition to Dr Jameel and Professor Noel Buckley (IA Senior and Intermediate Fellowship committee member & scientist at University of Oxford) representatives from EMBO and DBT were also present. From DBT there was Suman Govil and Meenaskhi Munshi. Participants were also able to interact with invited speakers at the booth. Around 30 people attended the special session on India. The speakers included Drs Shahid Jameel, LS Shashidhara, S Ramaswamy, Suman Govil, Meenakshi Munshi and Anne- Marie Glynn (EMBO).

INDIA ALLIANCE

OUTREACH EVENTS

4.

Young Investigators Meeting (YIM), UK 9 September, 2015 This event was organized at the Deakin Center, Cambridge, UK. Nearly 130 people registered for the event. There was a full day of talks from representatives of Indian Science, funding agencies and industry. The meeting concluded with a talk by Dr Vijayraghavan which was given by video conferencing. After the talks 20-25 graduate students and post-docs presented their work in a poster session. The delegates were highly enthusiastic and there was a great deal of interaction at the event. In addition to talks given by funding agencies, there were also different agencies seated at various tables. Participants were encouraged to approach them for further discussions. The Department of Biotechnology, the Wellcome Trust/DBT India Alliance, EMBO and Euraxess Links UK were some of the funding agencies represented at this event.

National Institutes of Health Research Festival September 17-18, 2015

The India Alliance in collaboration with IndiaBioscience had a stall at the NIH

Career Fair and Exhibition. Thousands of researchers working on various NIH campuses visited the booth. Researchers of both Indian origin and otherwise requested information about life sciences research in India and were particularly interested in the activities of India Alliance. There was a lively discourse about the opportunities and challenges of doing science in India.

Opportunities, challenges and impact of clinical health research in India 4 November 2015 The India Alliance and Krishna Institute of Medical Sciences (KIMS), Secunderabad, jointly organized a one-day symposium on 4th November 2015 at KIMS to discuss opportunities, challenges and impact of clinical and public health research. The symposium was divided into four sessions and concluded with a panel discussion, on themes ranging from genomics, neuroscience, urban health, health economics to funding opportunities and research challenges in

clinical and public health research in India. After the opening address and inauguration by Prof Kakarla Subba Rao, Chairman, KIMS Foundation & Research Centre and Dr Bhaskar Rao, CEO KIMS, eminent geneticist, Prof Arvinda Chakravarti chaired the plenary lecture by renowned Indian scientist Prof D Balasubramanian, LVPEI, Hyderabad. Dr Balasubramanian‟s talk described the opportunities for clinicians in areas of translational and clinical research and innovative methods to deliver healthcare from bench to bedside and vice-a-versa. The plenary lecture was followed by four sessions, where eminent clinician and clinical researchers talked about various clinical research fields. The distinguished line up of speakers comprised of Wellcome Trust/DBT India Alliance Committee members, Dr Aravinda Chakrabarti, Johns Hopkins, USA, Prof David Osrin, University of College, UK, Prof Sukhwinder Shergill, King‟s College London, UK, Prof Kara Hanson, London School of Hygiene and Tropical Medicine, London, UK, Prof Shinjini Bhatnagar, Translational Health Science & Technology Institute, Gurgaon, in addition to various other prominent local clinicians, Dr Aswin Dalal, CDFD, Dr Annie Hasan, Kamineni Institute of Medical Sciences, Dr Amitava Ray, Apollo Multispeciality Hospital and Dr Rakesh Sahay, Osmania Medical College and The sessions were chaired by Dr Sree Bhushan Raju, NIMS, Dr Sita Jayalakshmi, KIMS and Dr Kondagunta Nagaraj, Kamineni Institute of Medical Science, Hyderabad. India Alliance Fellows, Dr Arun Shet, Dr Muralidhara Nagarjuna, Dr Srinivas Marmamula and Dr Rupjyoti Talukadar were also present at the symposium and shared their India Alliance experience and views on clinical research in India. A strong call for more collaboration between basic science researchers and clinicians was made at this symposium.

INDIA ALLIANCE

SCIENCE COMMUNICATION WORKSHOPS

Participants and mentors of SciComm Hyderabad, September 2015

Empowering the communicators in young researchers

The 12th Science Communication workshop was held at the

Daspalla Hotel in Hyderabad from 14-15 September 2015 which

was attended by 34 PhD students, Postdocs, junior Faculty and

Clinicians from 29 different institutions across India such as, IISER

Trivandrum, Central Food Technological Research Institute,

Mysore, Centre for DNA Fingerprinting and Diagnostics,

Hyderabad, Indian Institute of Science, Education and

Research, Kolkata, DAPM RV Dental College and Hospital, IIT

Bombay, Christian Medical College, Vellore, Shiv Nadar

University, Greater Noida, Mysore Medical College and

Research Institute, Mysore, CSIR- Centre for Cellular and

Molecular Biology, Hyderabad, National Centre for Cell Science

(NCCS), Pune, National Institute of Mental Health and

Neurosciences, Bangalore, Indian Institute of Advanced

Research, Gandhinagar, BITS-Pilani, Hyderabad Campus,

ACTREC, Mumbai, Indian Institute of Science Bangalore, Indian

Institute of Chemical Technology Hyderabad, , Institute of

Bioinformatics and Applied Biotechnology (IBAB), Bangalore,

CSIR-Centre for Cellular and Molecular Biology, Hyderabad,

Amity University, New Delhi, Institute Of Medical Sciences,

Banaras Hindu University, All India Institute of Medical Sciences,

New Delhi, Acharya Nagarjuna University, Guntur, University of

Mysore, Defence Institute of Physiology and Allied Sciences

(DIPAS), DRDO, New Delhi, CSIR-Central Drug Research Institute,

School of Life Sciences, Manipal and Pondicherry University.

The first day of the workshop focused on oral presentation

skills and important elements of an effective professional

presentation. This session was conducted by Mrs Sumathy

Haridas, an HR consultant from Bangalore, who gave useful

advice on how to prepare the message of a presentation,

appear confident, speak articulately and engage the

audience. Her session consisted of various hands-on exercises

for the participants that ensured active participation. Following

this session, India Alliance Public Engagement officer, Dr Sarah

Iqbal encouraged the participants to deliberate on the topic of

Public Engagement with Science and in what ways, as scientists

and clinicians, they could take their research to the public and

collaborate with them to get fresher research perspectives. She

also initiated an interesting discussion on what ails productive

communication between the clinicians and basic research

community in India. Grants Adviser, Dr Madhankumar

Anandhakrishnan concluded the first day by giving a brief

overview of the India Alliance Fellowship schemes and

application process. The participants discussed various issues

concerning the workshop, career choices and their current

research with the India Alliance staff and the workshop mentors

over the Networking dinner.

The second day of the workshop covered topics such as,

Ethics in Research, Clinical research, Grant and Manuscript

writing, talks on which were given by Dr Anant Bhan (Yenepoya

University, Mangalore), Dr Anurag Agrawal (IGIB, New Delhi), Dr

Lolitika Mandal (IISER Mohali), Dr Mahak Sharma (IISER Mohali)

and Prof Sandhya Visweswariah (IISc Bangalore). The Mentors

stimulated various discussions on these topics and ensured the

participants were not wary of asking important questions about

research career development, setting up a lab, postdoc

opportunities, clinical research and many more. The highlight of

the workshop for the participants was the research proposal

discussion, where participants received useful feedback and

advice on the structure and content of their proposals from the

mentors.

The enthusiasm and active questioning at the workshop by

the participants reinforced the importance of Science

Communication in nurturing and training the future researchers

of India.

Watch this space for the announcement of the next two-day SciComm workshop and other communication training initiatives

5.

One-day SciComm101 workshop at Vinayaka Missions University

Salem, Tamil Nadu

INDIA ALLIANCE

SCIENCE COMMUNICATION WORKSHOPS

Few of our current Fellows had attended the two-day SciComm Hyderabad workshop before they applied for the IA Fellowships which were eventually awarded to them. Three of them share their thoughts here on how the training helped them to write successful grant applications and their general experience of the workshop.

SciComm Hyderabad 2011 The things that I expected, including a comprehensive overview of Early Career Fellowships, scientific presentation skills, went as expected. Most important aspect of the SciComm for me was the discussion session with the mentor. I was planning to change my research field from cellular immunology to the molecular biology of learning and memory. Based on my short research proposal (which eventually became my ECF proposal) I was grouped with students having somewhat overlapping research interests. The mentor we had during the SciComm workshop was an eminent neuroscientist from India. It was the first time that I had any discussion on merits and shortcomings of my research proposal with the expert in the field. The discussions later proved to be extremely valuable.

Dr Yogesh Dahiya, Early Career Fellow, IISER Mohali

SciComm Hyderabad 2013 The workshop has been a catalyst in honing my grantsmanship skills. It was a very well crafted workshop by the India alliance team. The sessions were engaging and focused. The session on the live recording of presentations proved to be very productive. Interacting with peer scientists was enjoyable; the richness of shared experiences was a great way to learn. Thanks to this opportunity, I was able to successfully apply the learning into accomplishing the award of intermediate fellowship. I highly

recommend to any young public health researcher to attend this workshop for enhancing the skills in scientific communication.

Dr Giridhara R Babu, Intermediate Fellow, Public Health Foundation of India

SciComm Hyderabad 2014

I found the workshop to be extremely useful to improve grant applications. Since I was also applying for the Wellcome Trust/DBT India Alliance ECF, the interactions with mentors on my dummy project were invaluable. These helped me critically evaluate my application and frame it better. In general, the workshop was an extremely well-planned and balanced for instilling presentation and scientific skills. The sessions on body-language and communication were eye-openers and helpful for any competitive grant procedure.

Dr Tavpritesh Sethi, Early Career Fellow, AIIMS, New Delhi

From a SciComm participant to an IA Fellow

India Alliance‟s SciComm101 workshop team reached the

steel city of Salem, Tamil Nadu, on 21 September 2015. The

workshop was held at the Vinayaka Missions University and was

attended by around 80 research scholars and young scientists

of various departments of the university along with participants

from institutions such as, Kongu Engineering College, Perundurai,

JSS College of Pharmacy, Ooty, K.S.R.College of Technology,

Tiruchengode, Velalar College of Engineering & Technology,

Erode, Bharathiyar University, Coimbatore, Mahendra College of

Engineering, Namakkal, Padmavani Arts and Science College

for Women, Salem, Periyar University, Salem, Kerala Agricultural

University, Thrissur, Kerala, Tamil Nadu Agricultural University,

Mahendra Arts and Science College, Salem, Sri Vijay Vidyalaya

College of Arts and Science, J.K.K Nattraja College of

Pharmacy, Government Mohan Kumaramangalam Medical

College, Salem, Vivekananda College of Arts and Science,

Tiruchengode, Sivaraj Siddha Medical College.

In addition to the life sciences streams, the workshop

participants came from varied backgrounds, such as nursing,

biomedical and electrical engineering, architecture, dental

science, chemistry and physics. The attendees particularly

appreciated the interactive nature of the sessions and for the

opportunity of receiving this unique training which is not

available to most of them in their respective institutions.

6.

INDIA ALLIANCE

PUBLIC ENGAGEMENT CORNER

As part of a public engagement exercise, the India Alliance launched its first „Research Image Competition‟ for its Fellows last month. The entries included photographs, microscopy images and illustrations which conveyed a scientific principle and/or a relevant human health perspective. The

images were judged on visual impact, context and their understandability for a public audience. Top three prizes were given to the following images.

7.

INTRICATE ARRANGEMENT OF DIVERSE CELL TYPES IN THE GUT OF A FRUIT FLY

By DR BUSHRA ATEEQ, Intermediate Fel low& DR ANJALI BAJPAI, Ear ly Career Fel low O th e r I mage C r e ato r s : Ms Uma n s h i R a u te l a , P r o f P r a d ip S i n h a

The image shows intricate arrangement of the various

cell types in the mid-gut region of a genetically

modified fruit fly. White/grey colored striated lines

depict gut musculature, rosette shaped white/grey

structures are large copper cells with red nucleus in the

center; small green colored structures are stem cells of

the gut. *This is also the cover image

THE CANCER

By DR SANJAY CHILBULE, Research T ra ining Fel low

Newly formed cancer cells of bone cancer are spreading out

centrifugally from their parent cells which probably may be happening inside the body.

WE CARE, FOR EYE CARE, EVERYWHERE

By DR SRINIVAS MARMAMULA, Research T ra ining Fel low

Vision loss is more commonly in elderly people in rural areas, even more

common among women. This image shows a vision technician assessing

vision in a woman in a village in Telangana as a part of public health

research project undertaken by L V Prasad Eye Institute, India.

Dr Sheetal Gandotra is a Wellcome Trust/DBT Intermediate Fellow at the Institute of Genomics and Integrative Biology (IGIB), New Delhi. Sheetal is using various genetic and cellular tools to understand the survival and infectious mechanisms of Mycobacterium tuberculosis (Mtb). In this interview, she shares with us the impact of her current research, role of scientists and science in India and much more..

INDIA ALLIANCE FELLOW SPOTLIGHT

DR SHEETAL GANDOTRA Intermediate Fellow, IGIB, New Delhi

What are you working on and what impact do you hope it will have?

Tuberculosis disease pathology has had a long standing link

with lipids- be it the virulence imparting lipids of the bacterium

Mycobacterium tuberculosis or the host lipids that accumulate in

the granuloma. We are working on identifying mechanism(s)

whereby the intracellular bacilli alter the host cell‟s lipid storage

depots -the lipid droplets, such that the characteristic lipid loaded

foamy macrophages develop and at the same time the bacilli

make use of fatty acids from the host cell. By addressing the first

question we hope to be able to understand the metabolic link

between the innate immune response and disease pathology.

The second question is fundamental to understanding how lipids

are mobilized from an organelle of the host to the bacilli, across

several membrane barriers. We hope that this will lead to

identifying targets that will limit the ability of bacteria to scavenge

nutrients from the host cell- in essence, we want to bite the hand

that feeds the devil.

What inspired you to become a scientist?

My teachers- Mrs Nandita Narainswamy, Dr Anil Tyagi, Dr Debi

Sarkar, Dr Carl Nathan, and the late Dr Alan Houghton have been

the most instrumental in driving me towards research. Their

undying love for their subjects and their ability to infuse that

excitement through their classes left me with more questions and

encouraged me to ask those questions. Mentoring by researchers

like Dr Sabine Ehrt and Dr Dirk Schnappinger encouraged me to

be fearless in approaching larger questions. I think I am still

learning every day on how to really become a scientist because

that is so much more than simply “doing science”. There is so

much to learn in terms of managing a lab and a team and I think

I grow a little bit with every student that joins my group or

engages me in their questions. In a way, their questions inspire me

further. Last but not the least, the pathogen I work on-

Mycobacterium tuberculosis continues to challenge me and that

really is the basis of what I work on.

How do you think scientists and scientific research can offer solutions to India's problems today?

Science and reasoning is the only way out of the several socio-

economic problems that deeply affect the growth of India. While we

hope that the basic research we carry out in our lab is able to offer

new sustainable solutions to tuberculosis treatment, we do realize that

by inspiring more people in our neighbourhood, in our city, and in the

country, towards logic, reasoning, and high quality research, the

scientific community holds great responsibility in bringing about this

positive change.

How has Wellcome Trust/DBT India Alliance funding helped you and your research?

When I moved back to India, I knew what I wanted to work on but

understood the difficulties and challenges of the questions I was

asking. Applying to the Wellcome Trust/DBT India Alliance in itself was

a means to put these ideas on track and focus on a few of these

questions. The award has allowed me to take on a high risk project

but also cautioned me and advised me through the reviews about

how I should manouver through the challenges. This is equally

important to the generous consumable, equipment, and travel

support that comes with the award. Research in a biosafety

laboratory conditions for a slow growing organism like M. tuberculosis

is not only time consumingbut extremely expensive, with specialized

equipments dedicated for the facility. The generous funding from this

award has helped me establish some of these key aspects of my

research.

What keeps you going everyday?

This really depends on the situation and my surroundings. During my

PhD I started learning Bharatanatyam; I would travel 3 hours from

Manhattan to Queens for a 1 hour class. In the UK, I became an avid

gym fan, and since moving back to India, I think it is the support of

family that keeps me going. I like to paint and experiment with my

creative abilities- be it a wall or a window pane at home. While I get

little time to do such things, the build up to a creative pursuit is equally

important to me.

8.

INDIA ALLIANCE

RESEARCH HIGHLIGHTS

DNA Topoisomerase 1 (Top1) is an essential enzyme for

expediting the release of torsional stress generated during

various DNA transactions. Top1 is expressed much higher in

various tumour cells than the normal cells, therefore,

modulating the Top1 levels could be an important therapeutic

treatment for cancer. Top1 when trapped on the DNA as

Top1-DNA covalent complexes (Top1cc) by anticancer drug

camptothecin (CPT) or its clinical derivatives leads to DNA

double-strand breaks, which results in death of malignant

cancer cells. In our published study, we looked at another

class of compounds known as „hydantoins‟, which have

received much attention in the last decade or so for having

anti-cancer properties. We designed and synthesized a library

comprising of hydantoin and thiohydantoin derivatives and

tested them against human Top1. One of the thiohydantoin

compounds with substituted thiophenyl as the central moiety

exhibited potent inhibition of Top1 through stabilization of

Top1cc as shown by its anti-cancer activity against human

cervical carcinoma (HeLa) and breast carcinoma (MCF-7)

cells. These results suggest that the selected thiohydantoin

may be a suitable lead to develop as potential anti-cancer

compound.

Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity. Majumdar P, Bathula C, Basu SM, Das SK, Agarwal R, Hati S, Singh A, Sen S, Das BB*. 2015; Eur J Med Chem. 102:540-51. Image above: Molecular docking for the anti-cancer compound in a

ternary complex with DNA and human Topoisomerase 1 rationalized the

inhibitory mechanism of the compound (Red). Indicated amino acids

showing the plausible architecture of the active site of Human Top1

interacting with compound. The computational study provides insight to

the structure activity relationship of the compound to gain Top1

inhibitory activity.

Novel anti-cancer compound targeting DNA cutting enzyme, Topoisomerase I DR BENU BRATA DAS, Intermediate Fellow, Indian Association for the Cultivation of Science, Kolkata

Targeting the right messenger RNA Mechanism of poly(A) polymerase specificity

DR RAKESH SINGH LAISHRAM, Intermediate Fellow, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram

Gene expression in humans involves multiple steps: from

messenger RNA (m RNA) synthesis in the nucleus to translation

in the cytoplasm. 3‟-end RNA processing is an essential step in

mRNA synthesis that involves addition of a polyadenosine (A)

tail at the 3‟- untranslated region (UTR) by enzyme called

poly(A) polymerase (PAP). Poly(A) tail is essential for stability

and efficient translation of the mRNA. There are two major

poly(A) polymerases involved in general polyadenylation in

the nucleus - canonical PAPα and Star-PAP. The two PAPs

have distinct niche of target mRNAs and are independent of

each other. Yet, how the two PAPs select their respective

target mRNAs is not understood. Using Star-PAP as an

example, we established the mechanism of PAP specificity

where Star-PAP recognizes a distinct sequence element at the

trailing 3‟–UTR and excludes PAPα from the UTR. There are two

aspects of PAP specificity – recognition of target mRNA and

exclusion of the other PAP, rendering the mRNA to exclusive

control of one PAP. We identified Star-PAP recognition motif

(AUA) on the mRNA target upstream of poly(A) site.

9.

INDIA ALLIANCE

RESEARCH HIGHLIGHTS

Moreover, lack of the polyadenylation factor, CstF-64,

binding prevents PAPα from accessing Star-PAP target

mRNA.

Altering the 3‟-UTR cis-element on Star-PAP target mRNA

switches the regulatory PAP from Star-PAP to PAPα. Both the

PAPs also compete with each other for binding to mRNA

cleavage factor, CPSF but with a preference to Star-PAP

suggesting preferential use of Star-PAP regulated sites. This

specificity regulates alternative polyadenylation and PAP

switch at the 3‟-UTR.

CstF-64 and 3'UTR cis-element determine Star-PAP

specificity for target mRNA selection by excluding PAPα. Kandala DT, Mohan N, A V, Ap S, G R, Laishram RS. 2015 Nucleic Acid Research

Ever wonder how you keep your balance? This is

something that we learn to do as toddlers, and it involves the

coordinated effort of various muscles in the body. An area at

the base of the brain called the cerebellum controls this effort,

and synchronizes our muscles by sending messages in the form

of electrical signals along cells called Purkinje neurons. These

signals consist of steady „tonic‟ activity or short „bursts‟ of

activity. Previous studies in unconscious mammals suggest that

these neurons can spontaneously switch between the two

types of electrical signals.

However, it is not clear whether this switch occurs in awake

animals, or how these nerve activities control muscle

movements. It is technically challenging to record the voltage

of single Purkinje neurons of conscious rodents, so this problem

was avoided by using zebrafish larvae instead. These larvae

are small, transparent and lack a skull, which makes it possible

to record the activity of the cerebellum using tiny glass

electrodes. The experiments show that even when the larvae

are awake, the Purkinje cells produce either spontaneous

bursts or tonic activity and they can readily switch between

the two. The switch is controlled in part by the voltage on the

neurons' surface. A positive voltage is called the „up‟ state,

while a negative voltage is dubbed the „down‟ state. Neurons

in the „up‟ state produced tonic pulses, while neurons in the

„down‟ state produced short bursts of activity with the help of

an ion channel called AMPAR.

Cells called motor neurons in the spinal cord carry the final

command from the nervous system to the muscles. We

recorded the activity of motor neurons and Purkinje neurons

at the same time. This revealed that Purkinje neurons receive

a copy of the motor command that goes to the muscle and

produce short bursts of electrical activity in response. This

effect required AMPAR activity, and was blocked by

molecules that inhibit AMPAR. Furthermore, the timing of these

short bursts with respect to the motor command changes from

one Purkinje neuron to another. Future work will investigate

how the Purkinje neurons receive and process the information

in the motor command.

AMPA receptor mediated synaptic excitation drives state-dependent bursting in Purkinje neurons of zebrafish larvae Mohini Sengupta, Vatsala Thirumalai. eLife Image above: Pseudocolor images of Purkinje neurons in adult zebrafish cerebellum. Image created by Lena Robra and Mohini Sengupta

10.

Unique Nerve Activity in the Cerebellum

DR VATSALA THIRUMALAI, Intermediate Fellow, NCBS, Bangalore

Structural insights into the channels of the mitochondria

DR R MAHALAKSHMI, Intermediate Fellow, IISER Bhopal

Voltage-dependent anion channels, or VDACs, are pore-

forming outer mitochondrial membrane proteins that help

govern cellular homeostasis. These are 19-stranded

transmembrane β-barrel proteins (as shown in the image

above) that shuttle various products of the metabolic process

between the cytoplasm and mitochondria in a cell. Of the

three isoforms (-1, -2 and -3) of VDACs in humans, hVDAC-2 is

more important for cell survival. Current understanding of the

structure-function relationship of anti-apoptotic hVDAC-2 is still

at its inception. It has a unique 11-residue stretch at the N-

terminal helix and an unusually high cysteine content. In this

study, we have examined the role of the N-helix and cysteines

on the structure and function of this important channel. Our

findings highlight the unique and hitherto unknown

interdependent contribution of the N-helix and cysteine

residues to the function, barrel folding and stability of hVDAC-

2. Our work is an important advancement in understanding

hVDAC-2 barrel dynamics and provides insight into factors

that functionally demarcate this protein from the other

VDACs. Our work will help us understand the important role

played by the hVDAC-2 protein in deciding the fate of the

cell. We also demonstrate the evolutionary relevance of the

N-terminal 11-residues of hVDAC-2 in the context of cysteine

conservation.

N-helix and cysteines inter-regulate human mitochondrial VDAC-2 function and biochemistry. Svetlana Rajkumar Maurya and Radhakrishnan Mahalakshmi. The Journal of Biological Chemistry

A high throughput platform to study cell membrane fission DR THOMAS PUCADYIL, Intermediate Fellow, IISER Pune

Cell membrane fission requires the localized application of

curvature stresses to the lipid bilayer in order for a membrane

tube to go from a highly constricted to a cut state. Since

these topological transformations require the bilayer to

deviate from its preferred planar configuration, membrane

fission is an energetically unfavorable process. The GTPase

dynamin represent a group of specialized protein machines

that catalyze membrane fission. Dynamin manages this

process by self-assembling into a helical scaffold that

hydrolyzes GTP to constrict and cut the underlying membrane

tube. How it does it has been a subject of intense controversy.

Membrane fission reactions are carried out in a confined

region of the membrane enclosed within a 10 nm wide, 2-rung

scaffold comprised of ~26 molecules of dynamin. Thus, the

changes in shape of the underlying membrane tube have

been difficult to probe. Our team has now devised a novel

model membrane system comprised of narrow membrane

tubes laid on a non-reactive glass surface, which they call

supported membrane tubes or SMrTs. Membrane tubes

represent an ideal mimic of the necks of clathrin-coated pits,

the physiological substrate upon which dynamin is thought to

act in cells. Since the tubes are stably laid out on a glass

surface, one can now use conventional wide field

microscopic approaches to locally probe changes in

membrane shape during a single dynamin-catalyzed fission

event. Indeed, results from such experiments reveal the

necessity for GTP hydrolysis during dynamin-catalyzed

membrane fission. Dynamin self-assembly into a helical

scaffold constricts the underlying tube but does so to a

moderate extent. GTP hydrolysis is required for further

constricting the underlying tube for it to reach dimensions

necessary for fission.

A high-throughput platform for real-time analysis of membrane fission reactions reveals dynamin function. Srishti Dar, Sukrut Kamerkar and Thomas Pucadyil. Nature Cell Biology.

11.

FEATURE ARTICLE

EMERGENCE OF A NEW RESISTANCE DR SARAH IQBAL, PUBLIC ENGAGEMENT OFFICER, INDIA ALLIANCE

12.

The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the

ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug

make them resistant. Alexander Fleming, Nobel Lecture, 1945, inventor of Penicillin

This year‟s Noble prize in Medicine and Physiology,

applauding the discoveries concerning novel therapies

against infections, is in grim contrast to global health

epidemic of antimicrobial resistance (AMR) that the world is

facing today. AMR has fast become an obstacle in the

prevention and treatment of variety of infections caused by

bugs such as bacteria, parasites, viruses and fungi, which

cause HIV, influenza, malaria, tuberculosis and host of other

infections. Not paying heed to the „words of caution‟ of the

inventor of the first legitimate antibiotic has led us towards a

major public health crisis world-wide, which could become

more severe in the less developed regions, where infections

are rampant and healthcare services abysmal.

AMR can be loosely defined as resistance of the infectious

bugs against the medications used to eliminate them, by

overpowering its toxic effects. A bug or a microbe acquires

resistance through modifications in its genes- an important

illustration of Darwin‟s natural selection. For instance,

antibiotics work through inactivating proteins in the bacteria

thereby shutting down its growth machinery. Any genetic

change in the protein can prevent the antibiotic to do its

work effectively. Alternatively, the genetic modification could

lead to an increased production of the antibiotic‟s target

protein, which makes the drug ineffective in inactivating all of

that protein. Adding to the existing molecular complexities,

the bacterial evolutionary survival mechanisms enable these

microorganisms to literally borrow genes from one another.

This further leads to the spread of resistant genes in the

bacterial population.

Let us zoom out of the bacterial cell and describe the

possible causes that can lead to AMR. If a recommended

drug is not used for the time necessary for eliminating the

infection, it kills a small population of infection-causing

microbes but the remaining population could become

resistant to this medication and keep growing. Additionally,

there is a collateral consequence of using an antimicrobial-

the drug not only removes the infectious microbes but also

some of the healthy ones, which leads to the infectious and

resistant microbes to take over the body. This is the reason

why the doctor strictly instructs us to finish the course of the

prescribed antibiotic even if we feel better after the first few

doses. It has also been observed that low-level of exposure to

certain antibiotics leads to increased incidence of mutations,

non-reproductive gene transfer between bacteria and

consequently a higher likelihood of the bacterial populations

to acquire resistance.

Let us now zoom into one of the biggest centres of this

epidemic with highest users of antibiotics and explore social,

environmental and medical factors which are giving rise to

AMR. Even though the global report by WHO on AMR in 2014

indicates that AMR crisis is present in every region of the

world, its health and economic consequences in a middle

income country such as India could be very damaging and

long-lasting. In nearly every corner of India where one has

access to medicines, antibiotics are given to young children

and adults alike, in an unsupervised and reckless manner.

Easy over-the-counter availability, irresponsible clinical

conduct and strong insistence by patients for antibiotics for

even minor infections, are some of the major factors leading

to high use of this medication in India. For a lot of Indians,

staying home to recover from infections can cost a job and

taking the wrong drug (for e.g, an antibiotic for a viral

infection) can prolong sickness. According to a report by

Center for Disease Dynamics, Economics and Policy, that

surveyed antibiotic use and AMR incidence in 69 countries

including India, suggests that globally 80% of antibiotics are

used outside the hospital where there is very little supervision.

Wellcome Library, London

13.

FEATURE ARTICLE

EMERGENCE OF A NEW RESISTANCE

India was the highest consumer of antibiotics according to a

survey done in 2010, using up to 13 billion Standard Unit (SU)

of antibiotics compared to 7 billion in USA. This unregulated

sale and over-prescription of antibiotics is one of the primary

causes of AMR cases in India. Poor sanitation and

widespread malnutrition in the country only augments the

AMR-related disease burden. Resistance developed due to

nonmedical consumption mainly results from its use as

veterinary medicine, growth-promoters in livestock and in

agriculture. This type of use, however, is not as high in India in

comparison to other countries that are heavy-consumers of

antibiotics, such as China and USA, but can still pose a

serious threat if not monitored and regulated strictly. Another

important route through which antibiotic-resistant microbes

can be acquired is through water, where bacterial cell

populations tend to form a „biofilm‟ on the surface of the

water. A report published in Lancet in 2011, showed drinking-

water and seepage samples collected in Delhi to be

contaminated with bacteria containing antibiotic-resistant

gene (NDM-1), which underscored the need for ensuring

clean water supplies and sewage systems. Pharmaceutical

manufacturing facilities, use of human or animal waste as

fertiliser, pollution of river and coastal sea water pose as

additional „water‟ routes for human exposure to antibiotic-

resistant bacterial populations. But in today‟s fast changing

world, there can be many additional routes- increase in

global travel, trade in wildlife and industrialisation of food

today has also greatly contributed to the spread of AMR

across the globe in both poor and developed countries alike.

Ever since the first class of antibiotics were discovered in the

1940s, in addition to treating common contagions, these life-

saving drugs have been used extensively in the clinic post-

operation to prevent various infections. The last new class of

antibiotic was discovered in the 1980s- there has been a long

gap since then in antibiotic development and the efforts

have not been able to keep pace with the growing list of

resistant strains. For instance, vast majority of strains have

become resistant to the commonly used class of antibiotics

“carbapenems”, also known as doctor‟s last line of defence

for many severe infections. This class is among many others

with declining efficacy that urgently need to be replaced by

new and more effective drugs. However, the current

deliberations in the AMR field suggest, that merely inventing

new drugs will not be sufficient and a more nuanced

approach will have to be adopted in tackling the emerging

trends of this epidemic. Decreasing cost and time of gene-

sequencing technologies has greatly helped in not only

detecting but in increasing our molecular understanding of

the resistant strains. These molecular tools can be employed

in investigating new areas of microbial research and for

developing novel methodologies for drug discovery. There

are also many less explored research areas in AMR, for

example, the role of microbial „biofilm‟ and the gut

microbiome in AMR have largely remained unclear. In

addition to this, the emergence of the resistant gram-

negative bacterial strains such as, Acinetobacter baumannii,

Klebsiella pneumonia, Pseudomonas aeruginosa,

Enterobacter cloacae and E. coli, which are responsible for

life-threatening pneumonias and urinary tract infections

among others, also require immediate attention of the

researchers and the policymakers alike. The inability of

majority of the antibiotics to enter the cell of these strains

and the efficient removal of antibiotics by these cells has

made them one of the most imminent infectious disease

threats that would require innovative approaches for

treatment.

The recent Ebola outbreak taught us many lessons -the

central one being the age-old idiom, it's better to be

prepared for an opportunity and not have one, than to have

an opportunity and not be prepared. The opportunity being

the outbreak, in this case. It was evident that an epidemic as

severe as that caused by the Ebola virus can have an

enormous socio-economic impact in less developed

countries and can consequently set them back decades

with respect to development. Therefore, it is important to

reinforce our public healthcare systems with efficient disease

14.

FEATURE ARTICLE

EMERGENCE OF A NEW RESISTANCE

surveillance, health data management systems, health

laboratories and also develop training programmes for

healthcare personnel to manage such outbreaks. It is also

imperative for the government to foster and fund drug

discovery projects in sync with emerging patterns of infectious

diseases, speed up „ethical‟ clinical trials and provide

affordable drugs for endemic infections by partnering with

Pharmaceutical companies. These public-private sector

partnerships can also serve to be useful breeding grounds for

inventing and commercializing cheap rapid point-of-care

medical devices and diagnostics which can be valuable in

handling these outbreaks. However, the most obvious first step

for the prevention of AMR in India would be to devise policies

for regulating drug sales in combination with encouraging

responsible clinical practice and improve sanitation and

hygiene conditions. Lastly, perhaps the most important

intervention would be to devise and implement community

engagement programmes to improve public understanding of

this looming epidemic and about infectious diseases in general

and steps one should take to prevent future outbreaks. To

conceive and execute such interventions, a cross-disciplinary

methodology will have to be undertaken. which would require

participation from all stakeholders.

The „World Antibiotics Awareness week‟ (16-22 November

2015) that kick starts today will not only make people aware of

drug resistant infections but also serve as a reminder that good

health practice is a collective responsibility of the government,

health care providers, medical practitioners and of the people

and that it is important they join hands for a healthy future.

References: 1. New Scientist https://www.newscientist.com/article/dn28180globalstudyrevealssoaringantibioticresistanceinindia/ 2. Nonmedical Uses of Antibiotics: Time to Restrict Their Use? Richard William Meek, Hrushi Vyas, Laura Jane Violet Piddock. PLOS Biology 3. India moves to tackle antibiotic resistance. Nature 2012 4. WHO Report 2014. Antimicrobial Drug Resistance 5. Centre for Disease Dynamics, Economics and Policy

Click on the image to see the emerging data on Antibiotic Resistance from around the world

What is your background?

I am a Probashi Bangali, having spent all my childhood days in

Hyderabad. I grew up in a DRDO township, surrounded by many

Bengali families and celebrating Durga Puja with a gusto. My

childhood was full of running around the neighborhood and

climbing trees, a decisive sense of freedom. My father worked with

the Defence Metallurgical Research Laboratory as a powder

metallurgist, developing new material for the missiles; while mother

spent a lot of time with children from other parents as a Nursery

school teacher. The atmosphere at home was a fine balance of

research induced chaos and education induced discipline,

enhanced by the playfulness of my sister. I sailed through school as

a top ranker till Bachelor's when life dealt me her lessons. I have a

Bachelor's in technology in Industrial biotechnology from Anna

University, Chennai. I scraped up enough grades to get

recommendations letters towards my PhD application to Universities

in the US. Not having learnt the lessons of life during my time in

Chennai, I marched on towards bigger goals and ended up in the

PhD program at the Biochemistry Department of Montana State

University, USA. I rate the agonies of my graduate studies as the

very best of my adult life till date and hoard each memory close. I

moved to Florida for my first post-doc and then to Karolinska

Institute for my second post-doc. I had the divine luck of having

excellent contemporaries as my colleagues and students. But

home is where the heart (could be stomach for all I care) is and it

was only so long I could stay away from the Durga puja and the

Hyderabadi biriyani. I headed home with my hold-all in September

2013 and these days I spend a lot of creative time negotiating the

city traffic.

How has your India Alliance journey been so far?

I will call it a mixed bag. The team makes everyday fun, the

applicants make every day exciting, the Fellows make the work an

excellent learning experience and the Selection Committee

members give us a feeling of being in touch with the who's who of

bio-medical research. There are days I still wonder what made me

leave research, especially when I read exciting articles in structural

biology. Then something at work reminds me how close I really am

to the ground zero of research happening in India and suddenly it

all makes sense. The most stark thing I have learnt on the job is

that I actually enjoy the element of hospitality management of

this job.

When not busy on the job, what do you enjoy doing?

When not at my job (I wont say I am busy, just at work), I have a

full life. I moved back home when I took up this job to spend time

with my parents who have now retired and my grand black

Labrador retriever. As a family, we have a ton of fun filled

evenings and weekends, with a lot of debates thrown in. I

appreciate my parents' support in making 'my' time possible in my

life, as it constitutes a big chunk. I am a curious person who loves

to learn and my primary hobby is to learn. Combined with my

(mostly) boundless energy, this has led me to pursue several

hobbies over the course of my life. I am a trained martial artist (in

Aikido) and a classical dancer (Bharatnatyam and Kathak). These

arts together help my left and right brain to stay in harmony.

When not being artsy, I am a bi-athlete, either running or

swimming. Also, I am always up for a game of badminton. When

all my energy is spent, I love listening to jugaldandis of strings and

percussion. Ustaad Allah Rakha Khan and Pandit Ravi Shakar's

jugalbandis are my all time, anytime, every time favorite. I also

read voraciously, but my reading is not limited to any genre of

books. My favorite thing to read is the newspaper every morning,

specifically the business section, and the news feed on my

Facebook from

WIRED(http://www.wired.com/category/magazine/)

Who inspires you (living or dead)?

Apart from family members (who are all over achievers),I have a

bunch of lady friends in my life, each of who has fought great

personal battle to be where she is now. That these awesome

women would choose me to be part of their lives, part of the

celebration post all the struggles, inspires me. On a lighter note,

Milind Soman inspires me to attempt the Iron(wo)man by my 50th

birthday

INDIA ALLIANCE STAFF CORNER

DR RANJANA SARMA

Grants Adviser

Dr Ranjana Sarma joined the organisation in September 2013

as a Grants Adviser. Apart from infusing great energy in the

office and narrating numerous amusing stories, Ranjana has

been involved with many activities at IA, from grants work to

SciComm workshops, website and is currently the secretary of

the Research Training Fellowship scheme. In this interview she

reminisces about her childhood and research days, recounts

how India Alliance experience has been a mixed bag, her

love for martial arts and dance, and much more..

16.

Please send your feedback, suggestions and contributions to public.engagement@wellcomedbt.org

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IMAGES IN THIS ISSUE

Image by Dr Thomas Pucadyil, Intermediate Fellow, IISER Pune Montage of a single membrane tube of ~40 nm in diameter

seen under the fluorescence microscope undergoing multiple

cuts in response to dynamin and GTP addition

Image by Dr Sheetal Gandotra, Intermediate Fellow, IGIB,

New Delhi

Mycobacterium tuberculosis infected fibroblast imaged

using a Zeiss Scanning Electron Microscope. The image

reveals the aggressive intracellular growth of the

bacterium followed by necrosis.

16.