Special Volume on Special Volume Government of India of Government Ministry of Science & Technology, Ministry Science & Technology, of An agent for sustainable sustainable for agent An 30 Years of Department of Biotechnology, of Department of 30 Years socio-economic transformation transformation socio-economic

Biotechnology An agent for sustainable socio-economic transformation Supported by Media Partner Partner Media Special Volume on Special Volume Government of India of Government Biotechnology An agent for sustainable sustainable for agent An Ministry of Science & Technology, Ministry Science & Technology, of socio-economic transformation transformation socio-economic 30 Years of Department of Biotechnology, of Department of 30 Years Ministry of Science & Technology Government of India

Global Biotechnology Summit Celebrating Biotechnology: Destination India 5th - 6th Feb, 2016 at Vigyan Bhawan, New www.dbtindia.gov.in Biotechnology: An agent for sustainable socio-economic transformation

Biotechnology: An agent for sustainable socio-economic transformation

Adventurous Thirty

One of the key government departments of India www.nature.com/natureindia credited with heralding the era of adventure and entrepreneurship in the country’s science – the Department of Biotechnology (DBT) – is 3A, 5th Floor, DLF Corporate Park, M G Road Phase-3 Gurgaon 122002, Haryana, India entering its youthful years. Thirty, as they say, is Ph: +91 124 3079600/+91-124-3079657 the new twenty. In these three eventful decades, DBT’s achievements have been many, in terms EDITORIAL of the science it has enabled, the policies it Editor: Subhra Priyadarshini has introduced, as well as the linkages it has established across disciplines and countries. Copy Editor: Twarita Chakraborty DBT’s many forays into biological sciences Art and design: Ajay Kumar Bhatt education and its societal contributions have Cover image © PhotoDisc/Getty Images also bolstered its position as a formidable science-faring body in the country – as a PUBLISHING confident young global icon who looks to NPG India the future, armed with a dynamic policy biodiversity to big data. The future of science framework, the spirit of adventure and ample and science-led entrepreneurship lies in an ADVERTISING & SPONSORSHIP room for self-criticism. interdisciplinary, global approach; in frugal Advertising & Sponsorship Manager - India innovations; in providing local solutions to the Sonia Sharma, M: +91 9650969959 Nature India is happy to be associated with DBT world’s problems. DBT, which has been playing [email protected] at this historic time of transition, a time when the catalyst in all these areas successfully, now India’s science is making waves globally. This SUBSCRIPTIONS & REPRINTS has an enviable 30-year benefit of hindsight to special volume marking DBT’s 30 years features reflect upon and open newer doors to newer Sonia Sharma: +91-124-3079657, M: +91 9650969959, commentaries from leading names in biological [email protected] challenges. sciences in India and across the world. The NATURE JOURNAL QUERIES milestones of DBT have been highlighted in As media partner, Nature India, a showcase of India’s science, is proud to collaborate with DBT Manager, Sales Support, NPG: Jacob Thomas a commentary ‘The changing face of biological +91-124-3079646, M: +91 9818171996 sciences in India’ and a short note ‘Three in its newest mission of disseminating science [email protected] decades of biotech solutions’ by two of the many better. It would be a mission well accomplished visionary past leaders of the department. DBT’s if the youth of this country gets back to thinking present chief outlines the vision for the future in that ‘science is cool’. an interview titled ‘As India’s economy grows, we Connect with us on will have more support for science’. The articles compiled in this issue range from facebook.com/npgindia @NatureInd looking at the state of basic biotech research in the health sector (, TB, allied microbes and stem cells) to green medicine Subhra Priyadarshini and frugal medical innovations; from biosafety © 2016 Nature Publishing Group Editor of India’s laboratories to the looming debate over genetically modified crops; and from

Nature India Special Issues are sponsored supplements that aim to stimulate interest and debate around a subject of interest to the sponsor, while satisfying the NPG editorial values and our readers’ expectations. Most of our special issues focus on affairs pertaining to science and research in India and at the same time are of significance to the global scientific community. The Nature India Special Issues are available freely for download at http://www.natureasia.com/en/nindia/. Copyright © 2016 Nature Publishing Group

I As India’s economy grows, we will have more support for science Krishnaswamy VijayRaghavan, Secretary of the Department of Biotechnology (DBT), speaks to Archita Bhatta, Chief Editor of DBT Communication Cell about DBT’s journey over the last 30 years and the path ahead.

Q. At 30, what particularly looks at being inclusive about carrying social according to you are science interactions and builds up a new era right from the the most significant foundations of basic interdisciplinary biology to institutional achievements of DBT? building and interactions with the society. So there is a lot more to do now but the strength of DBT allows it to embark A. The simple way to answer on these new ventures. that is if you ask what would have happened if DBT did Q. How did this evolve over the years? not exist. In genetics this is A. When people look at the so called success of institutions, called the law of functions they assume that putting in place robust structure and test. By that test DBT has done resources is sufficient, but people often forget that it is the core extraordinarily well. It has culture of the organisation which is most important. The DBT built foundations in life sciences and biotechnology education, was extraordinarily fortunate to have as its starting leadership extraordinarily good individuals, extraordinary institutions team Dr S. Ramachandran who came from the industry but and extraordinary interactions with society and industry. also brought a team from the Department of Science and In terms of life sciences education, it has done really well in Technology. Dr Manju Sharma, particularly, and others who pushing extraordinarily good masters and PhD programmes, worked to develop an institutional structure, trained people doctoral and post-doctoral fellowship programmes and built not only to do specific things but also to think and be daring a base of people who are really well-trained in life sciences, in whatever they do within the government system. It has been and genetics. Many of these people have an extraordinary effort and thinking out of the box is now the gone on to become institutional leaders. DBT has not only core culture of DBT along with a culture of helping each other. supported the development of fully aided institutions but Our major challenge is to keep in mind that we have to also aided institutions, supported institutions outside its have a spirit of adventure and not to assume that we are own core network in universities and research institutions the way we are because it’s natural. Preserving this culture in the private sector. These institutions have resulted in the is very important while changing our processes in the new development of quality people who have gone on to build world, as is being adventurous to grasp new things. I would a solid vaccine industry in the country, a thriving generics particularly like to mention Dr Ramachandran, Dr Manju industry and a bubbling biotech entrepreneurship system. Sharma, Dr Bhatia and the foundation that these people In terms of specifics, I think we must see that India is laid. Following Dr Manju Sharma’s long tenure, Dr M. recognised as being at a high level in life sciences and K.Bhan made an amazing effort to consolidate and build new biotechnology research today and that is in no small measure structures, new systems, new institutions and particularly because of DBT. new interaction with industry and society. So I think we have However, we must also look at what is called the gain of a huge responsibility going on from here. functions in genetics. Supposing we were to expand DBT Q. From responsibilities to adventure, how do into areas where it is not present now, would it have a positive you see DBT’s journey forward? impact? The answer is yes. DBT will have a tremendous impact if it now expands its human resources training into A. It is very important for us to keep in mind that the interdisciplinary areas, brings in engineering and medicine, government cannot do everything. However, wrong

II Interview

intervention by the government can easily prevent good should be done in a responsible, sustainable manner. Industry things from happening. So it’s very important for us as is not about money alone. It’s about sustainability and profit government not to prevent good things from happening. in the context of responsible science and technology for Therefore,when we develop policies we must make sure that the benefit of people. The other aspect is that it is not the they are enabling and not so complex that they can’t take us government’s job to transform a few billion dollar industry through the regulatory path. And this is doable only if we to a 100 billion dollar industry. These are a set of goals which keep our constituency in mind. Besides this, the government give a sort of direction about what the government should can do two things. The first is to ensure that the foundation not do and what it can catalyse. of high quality science and technology is in place. This needs Catalytically, what it can do is the following: let’s take an a huge focus on training programme targetted towards all example. We have a situation where knowledge from DNA sections of society. This is a big challenge with small resources. sequencing of microbes, plants and human beings are But it is doable with public and private resources. The second becoming widely and relatively easily accessible. But this is to provide core infrastructure of high quality at the largest does not become knowledge until it is processed to make number of places in a context development method. So, if we sense. It is a tremendous possibility for industries, which are can proactively train quality people, provide resources and intellectually/knowledge driven, to be able to collect data, have an enabling environment, the whole world is ours. whether it is from genome sequencing,RNA sequencing or Q. How has the 30-year experience helped in mass spectrometry and analyse it in separate contexts. This is formulation of the new National Biotechnology not a call centre problem, it is a much higher level of computer Development Strategy? science. It also requires scientists from multiple scientific disciplines, particularly with domain knowledge. So if you A. The experience is very valuable – firstly because you are looking at microbial diversity and genetic sequencing learn from it and you know how you can manage the system you need to have microbiologists, soil experts, gut experts and do interesting things despite all the constraints. But and computer scientists working together. These kinds of experience, particularly if you are modestly successful, is structures, both in academia as well as in industry, provide dangerous because it can make you comfortable doing the a huge new opportunity. These new kinds of investments same things. So the new strategy is unusual because it builds can catalyse our modest investments and bring about huge on the positive aspects of our learning. It went through an changes as well. extraordinarily good consultation process both nationally and internationally to try and be disruptive and to do new Q. DBT has already done a lot to improve the things in new generations. But the problem with these human resource in biotech, but the interest in strategies is that while we can outline our general directions, biotech is still not as desired. Is there any change when we sail in uncharted territory we don’t know what will in human resource strategy that you envisage? happen unless we get into the sea. Therefore the strategy also has a huge level of flexibility. It says we will do certain kinds A. The frank situation in life science is that parents prefer their of things in new emerging technologies but it is not wedded kids to go into business management,finance, engineering with a specific detailed path. It gives you a broad outline and or medicine. In a situation where these areas are perceived we will have to work out ways in which we can attack our to provide jobs, we need to be able to attract quality people problems and that flexibility is what this strategy is all about. to research, academic positions, entrepreneurship or other kinds of job which require quality understanding of science Q. The strategy talks about boosting the industry in general and biotechnology in particular. So, the challenge to a 100 billion dollar industry. How does DBT is that people are not sufficiently keen on pursuing this field. plan to do that? There are two different things we can do. One is at the broad A. It is very interesting that while the strategy is a nice, big fat society level, and the other is a more focused DBT-oriented document,everyone catches this number as if that is the goal. effort. That is because, people love to have matrix. We must keep At the broad society level, the excitement, the thrill of science in mind two aspects of this 100 billion dollar figure. First, needs to be communicated better. We are communicating it and most importantly, whatever the number ends up being it little better than we used to, but not doing that sufficiently.

III Interview

One of the crucial necessities is to improve the quality of for example telescopes and super colliders. Similarly, science education in schools. This is not confined to the in life sciences we need to put to use our international DBT’s perspective alone. We need to discuss it in a broader interactions not just to build infrastructure and machines, way. The second thing DBT can do is given that people go but also to take on big global challenges such as vaccines into medicine and engineering and physics and chemistry as against emerging diseases, discoveries of drugs for tropical a choice in addition to biology, we need to take our human diseases and so on. These may not be seen as physical resource programme to a level that gives opportunity to entities but are very important. people, not only in biology but also in other areas, to work on life sciences questions. If we can get that in place, we will Q. Are there any 30-year gifts or promises you attract quality people into biology. hold for the nation?

Q. Are there any new areas you plan to focus A. Well, there are two kinds of promises. One we make as DBT and the other as scientists. As the economy improves we funding on? will make sure that we get more and more support for science. A. Yes, our research now has been a bit compartmentalised. We need to improve our internal processes constantly and be We fund our institutions for big programmes and have a responsible to the people. The feedback, particularly critical competitive grants programme. Research globally requires feedback, is very important. Similarly as scientists and as the interactions of many different kinds of people today. individuals we must also be more ambitious. We should While foundational support is necessary and must grow, in move out of constantly pointing where others are wrong, addition, group funding of different kinds of people working to a situation where we are self-critical – where we can do together will trigger their interaction. This needs to be better, where we can be more efficient, more ambitious. We pushed. So we are going to have programmes which support have to define basic problems which the rest of the world funding of interactions between institutions and people. We finds fascinating, look at applications that will transform our need resources for this and I expect we will be able to get society. These are challenges we need to take up as scientists. them. Q. What are the expectations you have as DBT Q. Do you see any change in international from the government and from the people? collaborations at this point? A. DBT is part of the government. The real expectation A. I think there is no question that this will happen in a would be, 30 years from now or even 10 years from now,we very big way. There are two major aspects which we need should see directions where India leads the world. We to change in this new era. One I already eluded to, and should be demanding the kinds of problems we can solve. that is how we must be interdisciplinary and interactive We should be demanding the kinds of questions we are with a much larger section of the scientific society through trying to answer. And we must dare to try and grasp more human resource programmes. But for that to be done directions currently beyond our reach. Only then, we will speedily, the only way out is to work interactively. Science, go in those directions effectively. like disease,health and humanity, knows no boundaries. We will have to work internationally to make sure that our A country like India with its human and intellectual resources discoveries and knowledge are used for the entire planet and should be reaching out and taking the lead despite its many big similarly discoveries and knowledge from elsewhere come problems. And as the Prime Minister said, and several people in. If this has to happen specifically in our programmes, have been saying, we have billion problems but we also have then our international programmes must impact on the a billion minds. Therefore, we should actually look at solving human resource programme in a big way. Also look at the problems for the world and not just look at our immediate huge global resources that have taken decades to build, minor issues.

IV Contents

COMMENTARY • The changing face of biological sciences in India...... 1 Manju Sharma • Three decades of biotech solutions...... 6 M K Bhan • Basic biotech research in the health sector in India: What has academia done?...... 7 G. Padmanaban • The birth of DBT...... 11 Inder Verma • Fighting the malaria scourge...... 13 Virander S. Chauhan • Stem cell research: Beyond the headlines...... 18 D. Balasubramanian & Alka Sharma • India cannot afford to miss the biological revolution...... 22 Krishna M. Ella • Genetically engineered crops: The path ahead...... 25 Jitender Giri & Akhilesh Kumar Tyagi • Forensic science: Why India is rooting for its DNA identification Act...... 29 Jayaraman Gowrishankar & Madhusudan R. Nandineni • Bugs, food and intelligence quotients: The complex biology of malnutrition and its consequences...... 32 Gagandeep Kang • Green medicine: The next big thing?...... 36 Ram Vishwakarma • Frugal medical innovations: Vision 1010 for maladies of India...... 40 Prashant Jha & Balram Bhargava • The TB battle: How well are we fighting the bug?...... 42 Jaya Sivaswami Tyagi • Big data for a big country: Mind the gap...... 45 Binay Panda • Biosafe laboratories: A luxury in resource-constrained regions...... 48 Dhinakar Raj Gopal, Aravindh Babu R. Parthiban & Mohanasubramanian Bhaskaran

V Biotechnology: An agent for sustainable socio-economic transformation

• The biodiversity-biotechnology nexus: Where do we stand?...... 53 Uma Ramakrishnan • India holds the key for solutions in global health...... 56 Trevor Mundel

DBT INSTITUTION PROFILES • National Institute of Immunology, New Delhi...... 59 • National Centre for Cell Science, Pune...... 61 • Centre for DNA Fingerprinting and Diagnostics, Hyderabad...... 63 • National Brain Research Centre, Manesar, Haryana...... 65 • National Institute of Plant Genome Research, New Delhi...... 67 • Institute of Bioresources and Sustainable Development, Imphal, Manipur...... 69 • Institute of Life Sciences, Bhubaneswar...... 71 • Translational Health Science & Technology Institute, Faridabad...... 73 • Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram...... 75 • National Institute of Biomedical Genomics, Kalyani, West Bengal...... 77 • Regional Centre for Biotechnology, Faridabad...... 78 • National Agri-Food Biotechnology Institute and Bio-Processing Unit, Mohali, Punjab...... 80 • Institute for Stem Cell Biology and Regenerative Medicine, Bangalore...... 82 • National Institute of Animal Biotechnology, Hyderabad...... 84 • Biotech Science Clusters...... 86

PUBLIC SECTOR UNDERTAKINGS • Biotechnology Industry Research Assistance Council, New Delhi...... 87 • Bharat Immunologicals and Biologicals Corporation Limited (BIBCOL)...... 89

VI ADVERTORIAL

PIONEERING BIOTECH INNOVATION

Department of Biotechnology (DBT) under the pursuing research in the specialized areas of Building research infrastructure Ministry of Science and Technology, set up in agriculture and allied sciences, healthcare, “Centres of excellence and innovation” have 1986, has given a new impetus to developments animal sciences, environment and industry. been a great focus at DBT’s institutes and reputed in modern biology and biotechnology. The More than 80 technologies have been developed R&D organizations have improved research DBT, over the past 30 years, has matched every and many have been commercialized through faculty capability through enhanced research inflection in its journey to grow from a nascent technology transfer. and infra- structure, facilitating the acquisition sector to a sunrise industry, making significant of new skills and experience. Twenty Five centres achievements in the growth and application of excellence (CoEs) have been established till of biotechnology in the areas of agriculture, RGCB, Trivandrum www.rgcb.res.in THSTI, Faridabad date in the sectors of agriculture, medical, basic www.thsti.res.in healthcare, animal sciences, environment and NCCS, Pune www.nccs.res.in developmental biology, bio-informatics and industry. NIPGR, New Delhi www.nipgr.res.in molecular biology. DBT-Boost to University

ILS, Bhubaneswar www.ils.res.in Interdisciplinary Departments of Life Sciences The result framework document for for Education and Research (DBT-BUILDER) is a NBRC, Manesar performance monitoring and evaluation www.nbrc.ac.in IBSD, Imphal programme for advanced education and research system has rated the Department of www.ibsd-imphal.nic.in for the up gradation/reengineering/remodeling/ Biotechnology as very good. CDFD, Hyderabad www.cdfd.org creation of Life Science departments in central NIAB, Hyderabad www.niab.org.in and state universities. The objective is to promote

Scope, role and function NII, New Delhi www.nii.res.in Interdisciplinary research and technology NIBMG, Kalyani It has been a long journey for the DBT - to shift www.nibmg.ac.in development at university level. INSTEMBengaluru RCB, Faridabad www.instem.res.in www.rcb.res.in NABI, Mohali its focus from policy formulation to programme www.nabi.res.in The DBT has contributed significantly to development, helping the scientific community biotechnology research in the 11th plan. More at large, especially researchers, students and than 150 patents have been filed through academic institutions. It has expanded its basket Public Sector Undertakings R&D-sponsored projects and with institutional to support biotechnology-based industries to support; 63 patents have been granted and 650 The DBT has two PSUs namely BIBCOL and boost the country’s bio-economy. publications released. BIRAC. Bharat Immunologicals and Biologicals The DBT focused on the creation of institutional Corporation Limited (BIBCOL), a leading Biotech Clusters infrastructure, human resource development biotechnology company based in Uttar Pradesh, in biotechnology and bio-informatics to bridge currently manufactures and produces a range Department has taken an initiative to establish the gap between biotech research in basic and of pharmaceutical products such as oral polio multi-institutional regional clusters to ensure applied aspects. vaccines, zinc tablets and diarrhoea management synergistic connectivity between partner The DBT was given a visionary role in developing kits. Its mission is to save millions of children institutions within cluster and with other India’s infrastructure in the biotechnology from avoidable disability through polio stakeholders in the city; build and maintain sector, with emphasis on setting up dedicated vaccination. Biotechnology Industry Research common infrastructural resources for institutions. The NII was the first Autonomous Assistance Council (BIRAC) is a not-for-profit research, translation, product innovation and Institute of DBT set up in 1986. From 1994 Section 8, Schedule B, Public Sector Enterprise, validation; to enable the creation of cluster- to 2004, it set up seven autonomous institutes set up by Department of Biotechnology (DBT), wide resources, including human capacity, - CDFD, ILS, NCCS, NBRC, NIPGR, RGCB Government of India as an Interface Agency to physical and technological infrastructure for and IBSD. The scope was further expanded strengthen and empower the emerging Biotech regulation sensitization, translational platform, during the 10th and 11th plan; the number enterprise to undertake strategic research and product validation, infrastructure and systems, has since increased to 14 with the addition of innovation, addressing nationally relevant entrepreneurial and community connectivity and new institutes, namely NIBMG, RCB, TSHTI, product development needs. 300 Start us and global engagement necessary and appropriate for NIAB, InStem, NABI and IGGEB. These SME’s have been supported. cluster energy; and to promote entrepreneurship institutes have state- of-the-art facilities for and techno-business. ADVERTORIAL

Under this initiative, the Bangalore Life Sciences Research Programmes Cluster for Multiscale Basic and Applied Under the aegis of the DBT, the National Bio- Research in Biological Sciences (B-Life) has Resources Development Board (NBDB) was been established in January, 2015 with the established with a mission to evolve a broad overall objectives to develop structural biology policy framework for research and development infrastructure to complement existing biocluster for sustain- able utilisation of bio-resources strengths from molecules to ecosystems; NCR and an effective plan of action for economic Biotech Science Cluster is also being established prosperity of the nation through accelerated to provide strategic support to national and R&D, using modern tools of biosciences. regional research organizations in creation and Its efforts in bio-fuel research have focussed integration of scientific, technical & business on developing second-generation bio-fuel related frameworks to accelerate and translate technologies that can be commercialized. It has discoveries and pass on validation and transfer of established three bio-energy centres in India product technologies to enterprises. with Indian Oil Corporation, ICGEB and Centre effective vaccines, marker assisted breeding to crop improvement and sustainable agricultural Education and Training of Energy Bio-science, which lays emphasis on the exploration of marine fungus, algal strains development and microbial bio-prospecting and DBT has taken multiple initiatives in teaching for ethanol and lipid production. engineering. and training by supporting undergraduate, The DBT has given a strong impetus to genomic The DBT has strategically developed multiple post-graduate and re- search programmes in research in India with international partnership. international partnerships with countries such as applied and basic life sciences. Under the post- Its efforts on the development of transgenic rice, Switzerland, Nor- way, Canada, Sweden, the UK, graduate teaching programme, 71 universities varieties for salinity/drought tolerance, fortified Germany, Finland, Denmark, Japan, Australia, with 1,150 students are trained every year. Under wheat varieties with iron/zinc, development EU and the US under joint project funding the undergraduate Star College programme, of virus-resistant tomatoes, genes that affect initiatives in agriculture, medical and human the emphasis is on nurturing excellence in immunity in cattle and genome sequencing of vaccine development. science education. As such, 92 colleges have various fish have have all had field trials with The department is also laying special emphasis on been supported under the Star College scheme. optimistic results. the north-eastern region by setting up the North- Training programmes for the undergraduate and Eastern Region- Biotechnology Programme post-graduate facul- ties have also been initiated The Indo-US Vaccine Action Programme (VAP) has supported innovative vaccine Management Cell (NER-BPMC) through to upgrade the skills of teachers, and mid-career development for 25 years and developed the Biotech Consortium India Limited (BCIL) in scientists for research laboratories. On the ROTAVAC diarrhoea vaccine for diarrhoeal the past five years. It is promoting biotechnology pattern of experiential learning and with the aim infection among children. Under the Indo-US activities in the region in close cooperation of introducing the concept of finishing school, vaccine programme, low-cost vaccines against with government agencies, ministries and the biotech industrial training programme malaria and TB are also being developed. Grand departments at the Central and state levels, along (BITP) has been implemented. This is planned Challenge Programme in the areas of healthcare, with universities and research institutions for for six months for fresh BE, B Tech, M.Sc and sanitation and agriculture have been launched development and implementation of various M Tech students, and can accommodate 800 for accelerated development of affordable and programmes. candidates every year.

M.Sc/M.V.Sc/M.Tech IN BIOTECHNOLOGY POST M.Sc INDUSTRY ATTACHMENT DBT JUNIOR RESEARCH FELLOWSHIP(DBT-JRT) DBT POST DOCTORAL FELLOWSHIP YOUNG ENTREPRENEURSHIP SCHEME (YES) DBT SPEARHEADED…… BIOTECHNOLOGY OVEREAS ASSOCIATESHIP SHORT TERM TRAINING COURSES TATA INNOVATION FELLOWSHIP 5 national S & T mission programmes that aim finding solutions to national challenges TECHNICIAN TRAINING PROGRAMMES TEACHERS TRAINING PROGRAMMES STAR COLLEGES Grand Challenge Programmes-vaccines, molecular breeding of crops, microbial prospecting, INNOVATIVE YOUNG BIOTECHNOLOGIST AWARDS (IYBA) reinventing toilet, agriculture & nutrition

Nationwide Biotechnology Information System 3 bioenergy centers for biofuel research Network (BTISnet) has been established with Rotavac - Indigenous 1USD rotavirus vaccine for diarrheal infections developed under PPP of 168 centres which include Centres of Excellence multiple public and private organizations and launched in 2013 in India (CoEs), Distributed Information Centres (DIC) and sub-DIC and Bioinformatics Information Basic infrastructure and trained manpower for bioinformatics Facilities (BIF) for biology and biotechnology Biosafety guidelines and establishment of 3 tier biosafety review system teaching. Teaching programmes in MSc, M Tech and PhD in bio-informatics and computational National Biotechnology Development Strategy 2007 biology supported by BTISnet centres are under International partnerships with multiple countries for biotech R&D- US, UK, Japan, Sweden, way, in addition to advance post- graduate Germany, Denmark, EU, Finland, Canada, Norway etc. diploma courses. Biotechnology: An agent for sustainable socio-economic transformation

The changing face of biological sciences in India

Manju Sharma1

The year 2007 was considered National Botanical Research Institute (NBRI), the Central annus mirabilis for biology, Institute of Medicinal and Aromatic Plants (CIMAP); genes and inheritance. It was the Central Drug Research Institute (CDRI), and the clear that the 21st century Indian Toxicological Research Institute (ITRC), Lucknow will see biology dominating doing research on some aspects of molecular biology and among the areas of science. biotechnology. Regional Research Laboratories and some Spectacular advances have Universities such as Jawaharlal Nehru University (JNU), taken place world over in New Delhi; MS University, Baroda; Madurai Kamaraj this field after the landmark University (MKU), Madurai; and Pune University were discovery of the double helix also conducting research in the field. However, it was structure in 1953. It is always with the establishment of the National Biotechnology interesting to go back in time when the double helix Board (NBTB) in 1982 that the field really got the much structure was announced by Francis Crick and James needed impetus. The NBTB had a new funding model with Watson. They said it was a night to celebrate. Raising their UGC and other departments joining in, and the focus glasses in the Eagle pub near the campus of Cambridge was on infrastructure development, human resources and University in England. Euphoric, Crick, 36 and Watson, support to R&D at some centres. With NBTB efforts, 24 drank to what they had just accomplished. Over the within 3-4 years, a good beginning was made and the hubbub in the crowded pub, Crick’s voice boomed, “We scientists became more interested in taking up research in have discovered the secret of life”. several advanced areas of molecular biology. In the words of Leon Jaroff: Finally“ discerning the double Taking note of these developments, the government helix structure of deoxyribonucleic acid (DNA), the giant decided to set up the Department of Biotechnology (DBT), molecule of hereditary had cleared the way for a great in 1986, in the Ministry of Science and Technology. To leap forward in human understanding of the process of life.” begin with, DBT had taken up some mission projects (Nature 2003) Since then, biologists have not looked back for animal biotechnology, plant molecular biology, and continued to explore the secrets of life. The science of tissue culture and bioinformatics. There was major thrust genomics, the technological fete to complete the human on human resource development. A premier research genome project and many new areas of molecular biology institute for immunological research, i.e. the National of plants, animals and microbes blossomed. It was at Institute of Immunology (NII) had already started but this time that India with advice from a large number became a very important centre of research subsequently. of experts decided to focus attention on biotechnology, A National Facility for Animal Tissue and Cell Culture just like other areas of science such as space, atomic (NFATCC) was created in Pune. The first Secretary energy and electronics. It was realised that biotechnology of the Department S. Ramachandran sowed the seeds of is an area of science closest to humankind and can mission mode programmes and some R&D funding along contribute towards food, nutrition, health, environment, with bioinformatics and human resource development. energy, industry and livelihood security. There were a Later leaders of DBT have all made sustained efforts number of CSIR laboratories, namely, the Centre for to promote the growth of this field in India. Between Cellular and Molecular Biology (CCMB), Hyderabad; the 1996 and 2004, several new initiatives were taken and Indian Institute of Chemical Biology (IICB), Kolkata; the autonomous institutions in special areas of research

1Former secretary, Department of Biotechnology, New Delhi, India.

1 Biotechnology: An agent for sustainable socio-economic transformation

were set up. The NII was strengthened and in addition to by DBT as an autonomous institute in September 2007. vaccine research, many other areas were started. Similarly, The mission of this institute is to integrate the fields the NFATCC was made into a full-fledged Institute for of medicine, science, engineering and technology into cell biology research – NCCS, Pune. The Centres for translational knowledge and making the resulting Plant Molecular Biology (CPMBs) had started plant and biomedical innovations accessible to public health, to agri-biology work and one of the Centers at the JNU was improve the health of the most disadvantaged people in upgraded. A new institution, the National Institute of India and throughout the world. Plant Genome Research (NIPGR), was established. This In November 2008, DBT set up a Regional Centre for institute is a premier research body today undertaking Biotechnology (RCB) at Faridabad as an autonomous plant genomics research with a focus on rice, tomato, institute. The mandate of the Centre is to provide a platform chick pea and potato. The genetic modification of potato for biotechnology education, training and research at the by and his team was a landmark research where interface of multiple disciplines. improved protein content and productivity was developed At Manipur in the North Eastern Region, taking note of using the grain amaranths gene. In other centers of CPMB, the enormity of bioresources, the Institute for Bioresources there was a new direction, both in agriculture and plant and Sustainable Development (IBSD) was established. The biotechnology and the scientists were looking at some Institute of Life Sciences (ILS), Bhubaneswar had not taken nationally important crops. Molecular genetics has now off at all as it did not receive adequate financial support been practiced for 60 years and transgenics have spread all from the state. At the instance of the State government, it over the world in the last 30 years. was taken over by DBT as a centrally supported institute During this period, the National Brain Research Centre in the region. All the facilities were created and today it (NBRC) was established to undertake advanced research has become a major research regional organisation for in this most important and relevant area of brain. The molecular biology with focus on cancer, infectious diseases Institute at Manesar is one of the finest research facilities and developmental biology. Two micro propagation tissue for brain research in this country. The scientists at CCMB, culture parks were established at TERI, New Delhi, and Hyderabad were already working on DNA Fingerprinting NCL, Pune for providing high quality planting material and to use DNA techniques for forensic purposes. A Centre for plantations in different regions of the country. for DNA Fingerprinting and Diagnostics (CDFD) was Realising that biotechnology research is capital and skill developed. The Centre works very closely today with the intensive, 70 Departments of Biotechnology in different central Ministry of Home Affairs and other departments Universities were created to generate human resources to provide scientifically accurate evidence for crimes. in the areas of plant, animal, medical, environmental The Institute for Stem Cell Science and Regenerative and general molecular courses. Distributed Information Medicine (inStem) has been established at Bangalore Centres (DICs) and Sub-DICs in bioinformatics became by DBT in July 2008 as an autonomous institute of the the bred and butter for modern biology research. The Department. This institute has six research themes i.e. DBT decided to set up many Centers of Excellence and stem cells and regeneration, cardiovascular biology and units in the Indian Institute of Science (IISc), Bangalore; disease, chemical biology and therapeutics, signaling LV Prasad Eye Institute, Hyderabad; CCMB, Hyderabad; and cancer, molecular and materials engineering and All India Institute of Medical Sciences (AIIMS), New neurodevelopmental synaptopathies. A CMC-DBT Delhi; Sanjay Gandhi Post Graduate Institute of Medical Center for Stem Cell Research (CSCR), CMC, Vellore is Sciences (SGPGIMS), Lucknow and Post Graduate a translational unit of this institute to carry out clinical Institute of Medical Education and Research (PGIMER), research. Chandigarh. Special facilities were created for confocal Translational Health Science and Technology Institute, microscope, proteomes, advanced animal houses, current Faridabad (THSTI), Faridabad has been established Good Manufacturing Practices (cGMP) facilities and

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National Mouse Research Resource Facility. DBT had National guidelines for stem cell research have been considered the spread of biotechnology network all over formulated by DBT jointly with Indian Council for the country, avoiding regional imbalances and as a result Medical Research (ICMR). the R&D culture in modern biology had spread very fast. Biotechnology for societal benefit, rural development for Several international collaborations with United States, women and also for helping victims of natural disasters UK, Switzerland, France, Germany, SAARC countries, were special programmes launched by DBT. G-15 countries, United Nations and UNESCO gave the required pace to the progress of biotechnology. A special Advisory structures such as the Scientific Advisory structure the National Bioresources Development Board Committee (SAC-DBT) and SAC-Overseas with experts (NBDB) was established and it produced a scientific from abroad, and several task forces helped the scientists database in collaboration with the Department of Space evaluate, identify, support and monitor the programmes. A for the bioresources of the country using satellite images. vision document with a mandate of attaining new heights in biotechnology research, shaping biotechnology into a Vaccines, diagnostics, therapeutics, alternative sources of premier precision tool of the future for creation of wealth medicine, bioprospecting of bioresources and genomics, and ensuring social justice, especially for the welfare of the particularly joining hands with International Rice poor, was also created. Genome Project were the flagship programmes of the DBT. While taking up R&D on the frontiers of modern A unique institution established by DST and further biology, the industrial aspects were not ignored and in the nurtured by DBT was the International Centre for present scenario, the Biotechnology Industry Research Genetic Engineering and Biotechnology (ICGEB). An Assistance Council (BIRAC), a Public Sector Undertaking international treaty was signed between India and United setup by DBT has become a prime mover of the biotech Nations. This institute has done excellent research in the industry for product development, commercialization areas of plants, vaccines, basic research and immunology. and patenting. BIRAC has helped create and nurture Since 1982, there have been major changes in the the start-up ecosystem and promote industry-academia development and application of biotechnology in the collaborations for innovation research. country. A large number of skilled human resources The DBT has implemented Biodesign programme as a has been created with expertise in cutting edge areas of med-tech innovation flagship programme jointly with biotechnology useful in academia, research and industrial AIIMS, New Delhi and IIT-Delhi in collaboration with endeavours. The trained students are being utilised in the Stanford University, USA and other international several large industries and small and medium enterprises. partners. The aim is to train the next generation of medical A diverse infrastructure base of modern biology will enable technology innovators in India. This programme has been the younger generation to carry forward such advanced successful in encouraging medical device innovation, research. The DBT also offers scholarships for both national promoting entrepreneurship in medical device sector and international training and several awards to encourage by formation of startups, indigenous manufacturing of and motivate young scientists. The National Biotechnology medical devices and dissemination of innovations at Award given to young scientists has motivated a large national and global level. number of young scientists in the country for pursuing cutting edge research in biology. Research on stem cells and regenerative medicine is being promoted and supported by the Department since The government has been very supportive towards this area 2001. The strategy includes: basic research, early and since the inception of the Department of Biotechnology. late translational research, public-private partnership, However, now it is time to consolidate and focus in the networking, policy/guidelines. So far, a number of areas that produce tangible results in terms of products, programmes have been implemented on various aspects new processes, technologies and contribute to the national of embryonic, adult and induced pluripotent stem cells. economy. Industrial biotechnology has shown tremendous

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Past and present DBT autonomous institutes Institute Established 1. National Institute of Immunology (NII), New Delhi June, 1991 2. International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi 1982 3. National Facility for Animal Tissue and Cell Culture (NFATCC), Pune 1988 4. National Centre for Cell Sciences (NCCS), Pune 1996 5. Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad March, 1996 6. National Institute of Plant Genome Research (NIPGR), New Delhi July, 1998 7. National Brain Research Centre (NBRC), New Delhi June, 1999 8. Institute of Bioresources and Sustainable Development (IBSD), Imphal April, 2001 9. Institute of Life Sciences (ILS), Bhubaneshwar August, 2002 (Taken over by DBT) 10. Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananathapuram February, 2007 11. Translational Health Science and Technology Institute (THSTI), Faridabad September, 2007 12. Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore July, 2008 13. Regional Centre for Biotechnology (RCB), Faridabad November, 2008 14. National Institute of Bio Medical Genomics (NIBMG), Kalyani February, 2009 15. National Agri-Food Biotechnology Institute (NABI), Mohali November, 2009 16. National Institute of Agricultural Botany (NIAB), Hyderabad March, 2010 National biocomputational facilities 1. Jawaharlal Nehru University, New Delhi 2. Bose Institute, Kolkata 3. Madurai Kamaraj University, Madurai 4. Indian Institute of Science, Bangalore 5. Centre for Cellular and Molecular Biology, Hyderabad 6. University of Pune 7. Indian Institute of Technology, Delhi (Source: DBT)

progress, especially after setting up of BIRAC. Yet India strengthening and more business from both public and has to see some concrete products and technologies which private sectors. will benefit the country. The biotechnology parks were The National Capital Region (NCR) Biotech Science Cluster started with a view to generating and utilising skilled and Bangalore Life Sciences Cluster have been established human resource for revenue generation. However, these recently at NCR, Delhi and Bangalore, respectively by parks, spread all over the country, are still dependent DBT to provide strategic support to national and regional on central and state grants. More industry has to come research organisations in creation and integration of forward to support biotechnology commercialisation. In scientific, technical & business related frameworks to this context, in 1990, DBT established the Biotechnology accelerate and translate discoveries and pass on validation Consortium India Ltd. (BCIL), a unique organisation for and transfer of product technologies to enterprises. bridging the gap between academia and research. BCIL has played a pivotal role in technology transfer, consultancy, DBT in the initial stages has developed robust biosafety project formulations, training of human resources dealing and regulatory procedures as Institutional Biosafety with IPR related matters. This would also need further Committee (IBSC), Review Committee on Genetic

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Manipulation (RCGM), and Genetic Engineering the focus keeps shifting from genetic engineering, stem cell Appraisal Committee (GEAC), under the Ministry of research, genomics, structural biology, system biology and Environment and Forests. It worked quiet well, but it is developmental biology but that is the normal way in which time that a Biotechnology Regulartory Authority is also science has progressed globally. It is now time, especially established to promote clearances and use and application keeping in view the large population on planet earth, of genetic technologies. diminishing natural resources due to over exploitation, DNA Identification Bill and Regional Centre for climate change and aspirations of the younger generation Biotechnology Bill have also been formulated by the that the country gears up with tools of modern biology DBT for consideration and approval by the government. to meet the challenges posed before the scientists in all Biosafety, undoubtedly, is most critical, but the procedures these areas. India has the necessary infrastructure, skilled as enunciated in the present regulatory system and by the human resources, biodiversity and bioresources. proposed regulatory authority would be able to take care The country needs continuous and sustained funding of both human and environmental safety issues. The health support for R&D, some specified mission programmes, care system, agri-biotech, environmental and ecological especially to combat the problems of humankind such as security and all aspects which will benefit with appropriate control and prevention of dreadful diseases, malnutrition, biotechnological interventions. For this the already low productivity, and natural disasters. Once the mandate established institutions must be nurtured, supported and is clear, biotechnology can be an area of greatest human utilised with the optimum capacity and capability. World enterprise and a powerful tool towards socio-economic over, the scenario for biological research is changing, but progress of the country, the region and the world.

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Three decades of biotech solutions

M K Bhan1

The Department of Biotechnology (DBT) has completed 30 glorious years of its existence. Through these years, the DBT’s impact on translational science has been outstanding, whether in agriculture, vaccines, diagnostics, biological drugs, devices or in generating knowledge that enables product innovation or solution design. Having a department like DBT was critical for India because biotechnology is the source of solutions for creating new crop varieties, for designing vaccines, drugs, diagnostic devices and environmental technologies. Within the field of biotechnology there is immense potential to serve human beings, animals and our environment. I would say biotechnology is going to be a great source of solutions for the many challenges that our planet would encounter in the next couple of centuries. DBT would play a tremendous role in providing solutions to India’s problems and in nurturing the full potential of biotechnology for our country’s development. I congratulate the entire team in DBT for its magnificent efforts, the past leaders who all were outstanding and the officers of DBT and institutions who have supported its cause. Congratulations to DBT for completing 30 years, it has been a great journey contributing to strengthen the biology in India. It has been catalytic in promoting innovation, discovery and entrepreneurship, in empowering people, supporting public- private partnership, supporting creativity both in academy and industry, and being adaptive to learning all through this journey.

1Former secretary, Department of Biotechnology, New Delhi, India.

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Basic biotech research in the health sector in India: What has academia done?

G. Padmanaban1

There is always a debate as to Weapons of mass protection what basic bioscience research In today’s context, India is a global leader in vaccines, in academic laboratories supplying cheap and affordable vaccines to 150 countries. has contributed to biotech Most of these represent conventional vaccines, but products in India. The various interestingly many groups in the country have laid the schemes under BIRAC foundation for innovation in this field. The efforts are no namely, BIG, SBIRI, BIPP and less laudable than sending a satellite up in the sky, but, CRS have supported primary perhaps, are not glamorous enough to catch attention. The R&D in the biotech industry, fact of the matter is that these efforts would save millions and the number of projects of life. and industries supported would soon reach 400 and 300, respectively. Close to two The credit should go to G P Talwar as the father of modern dozen products have already become realities, mostly in vaccine research in the country. He is a pioneer who the biogeneric and devices sectors. Most of the projects invented the first birth control vaccine in the world. The have been benefited by formal and informal collaborations female vaccine consisted of a heterospecific dimer of the with the academia, besides intense project monitoring β-subunit of human chorionic gonadotropin linked non- and mentoring by subject experts drawn from various covalently to α-subunit of ovine luteinising hormone and 2 public sector R&D institutions. Substantive basic research conjugated to tetanus and diphtheria toxin as carriers . in academic institutions has shown potential for major This vaccine never made it for a variety of sociological innovations in biotechnology. reasons. However, Talwar's immunotherapeutic leprosy vaccine has been commercialised and has shown efficacy Father of proteomics as an adjunct to chemotherapy in tuberculosis and even in G N Ramachandran, the doyen of bioscience research some cancers. It is befitting that the vaccine candidate is in India, established the triple helical structure of named Mycobacterium pranii after Pran Talwar. collagen using electronic desk calculators at a time, when Cholera and tuberculosis vaccines computers did not exist in India. Issues that arose from this structure determination made him to look at contact One has to start with Sambhu Nath De who discovered the distances between C, N, O and H atoms in amino acids and cholera toxin in 1959 and also developed the rabbit ligated peptides. The concept of limiting distances was applied to ileal loop assay for toxin detection3. Amit Ghosh, presently polypeptide conformations, leading to the development at NICED, Kolkata, and his team developed the first of the Ramachandran map1. The - map was applied Indian-made live oral vaccine from a non-toxigenic strain to myoglobin, the first crystal structure for any protein of V.cholerae 01 El Tor. The strain is devoid of the cholera obtained at that time and has since become a routine tool toxin, and the gene for the ‘B’ subunit of cholera toxin was for anyone studying protein conformation. One wonders engineered into the cryptic haemolysis locus. The resulting how studies on crystal structures of proteins and functional non-reactogenic VA 1.4 vaccine was found to elicit almost properties based on conformation would have ever evolved 66% seroconversion in a single oral dose4. This is superior without this basic understanding of Ramachandran angles. to the 53% seroconversion seen after two doses with the It is a pity that GNR someone who laid the foundation for available killed vaccines. Unfortunately, after years of modern day proteomics, was not awarded the Nobel Prize. effort, the path for commercialising this 100% made-in-

1Department of , Indian Institute of Science, Bangalore, India.

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India vaccine is not clear. Anil Tyagi and his group at human rotavirus strain with a single bovine VP4 gene the Delhi University South campus expressed several M. segment. This new genotype G9P10, referred to as 116E tuberculosis antigens in BCG and a detailed evaluation strain, turned out to be a naturally attenuated candidate of the candidate vaccines against aerosol infection of M. rotavirus vaccine. Durga Rao and his associates at IISc, tuberculosis in guinea pigs using heterologous prime- Bangalore, identified another rotaviral strain, I-321 boost approach (BCG over-expressing 85C followed by with a completely different set of human and bovine BCG overexpressing α-crystalline followed by boosting gene segments. This also protected newborns against with crystalline-DNA vaccine) has given a successful reinfection. In a large scale trial with infants, 116E was candidate vaccine. Adjunct therapy can drastically reduce found to be well tolerated giving 53.6% efficacy8,9. It duration of chemotherapy5. How to take it forward? is possible that a vaccine combination with 116E and 1-321 strains could give even higher levels of protection. Malaria vaccine Sudanshu Vrati and his colleagues at THSTI, New Delhi Chetan Chitnis at ICGEB has taken up the onerous developed a Vero cell-derived JE vaccine, inactivated at challenge of developing a vaccine against Plasmodium 22 °C with formaldehyde using an Indian strain, which is vivax based on the interaction of the Duffy-binding projected for scale up under GMP conditions10. protein with its receptor, enabling invasion into the The challenge to control dengue infection is to develop human erythrocytes. The receptor-binding domain maps a vaccine that would neutralise all the four known to conserved cysteine-rich region, referred to as PvRII. A serotypes. Navin Khanna and his colleagues at ICGEB, vaccine against P vivax malaria is being developed based New Delhi, have developed a novel tetravalent dengue on PVRII and is being taken through various steps of vaccine by fusing the receptor-binding domain III clinical trial6. of the four dengue virus serotypes (DEN-1, DEN- Viral vaccines 2, DEN-3 and DEN-4). The protein expressed in P. Pastoris elicited antibodies in mice and neutralised the Shantha Biotechnics (now a Sanofi company) put infectivity of all the four serotypes, providing the basis India on the global biotech map in 1997 with the first for a safe, efficacious and inexpensive tetravalent dengue recombinant hepatitis B vaccine using a commercial vaccine11. expression system in Pichia pastoris. This offered a challenge to the imported vaccine selling at Rs 475 a Development of influenza vaccine poses a similar dose. Eventually, UNICEF wanted to buy the vaccine challenge. and his associates from India for Rs. 20 a dose for global distribution. Less at IISc, Bangalore have developed a thermotolerant, advertised, is the same vaccine made by Rangarajan at disulphide-free, and trimeric hemagglutinin stem- the Indian Institute of Science (IISc), Bangalore, using fragment immunogen, eliciting broadly neutralising the expression system indigenously developed in a antibodies against highly divergent group 1 (H1 and H5 local strain of Pichia pastoris. This was transferred to subtypes) and 2 (H3 subtype). A similar immunogen from one company in 1998 and two others in 2014. A DNA the unmatched, highly drifted influenza strains offered vaccine comprising of a mammalian expression plasmid protection against a lethal heterologous virus challenge in in E. coli, encoding rabies surface glycoprotein as a dog vivo12. A similar challenge is in the generation of broadly rabies vaccine was also developed by Rangarajan7 with neutralising antibodies seen in HIV infected patients all safety data and regulatory approvals. This could with the envelope protein as the immunogen, retaining have paved the way for the same vaccine to be used in the native trimeric structure13. Bimal Chakraborti and his humans. But it did not make it, since a cheaper vaccine, colleagues at THSTI, New Delhi have been working with perhaps, does not make commercial sense. Bhan and the efficiently cleaved Env expressed on the cell surface his associates at the All India Institute of Medical as a genetic vaccine to elicit potent, broadly neutralising Sciences, New Delhi, identified a novel reassortant of a antibodies and to assess clade specificity as well.

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Molecular diagnostics curcumin as an adjunct drug in malaria, the study has laid the foundation to use curcumin as an adjunct drug in many There are many examples where recombinant antigens infectious diseases more as an immunomodulator than as and MABs have been developed in academic laboratories a direct killing agent, with potential to have long-term and transferred to industry for making diagnostic kits. protection capability, acting as a vaccine substitute16,17. A few examples are those for malaria, HIV and hepatitis We can be proud that curcumin from turmeric, used in B. An innovative example is the development of designer ancient Indian medicine, has found validation using proteins to make a highly sensitive diagnostic kit to detect modern scientific principles. HCV, HIV, dengue virus along with hepatitis B by Navin Khanna and his associates at ICGEB. In collaboration Conclusions with the University of Turku, Finland, novel reporter By any yardstick, the examples quoted would stand out in assays based on Terbium-labelled nanoparticles have terms of innovation with a potential as significant inputs been developed. Dual assays and 3-in-1 assays to detect to produce original biotech products in the health sector, HIV, HBV, HCV and a similar 3-in-1 dengue test have all beyond biogenerics. This belies the impression that basic been developed. Some of the products are available in the research in India is not connected to applications. Each market. discovery has a story to tell regarding the stumbling Drug development blocks that need to be tackled to translate outstanding research into a product. Will the BIRAC route provide Although close to 20 biogeneric molecules have been a new opportunity for translating innovative science? developed in the industry, some strikingly novel While, India needs to have many more such examples the molecules and approaches have been developed by the quality of science behind the examples quoted in terms of academic community. A good example is the progressive innovation, novelty, patents and publications definitely improvement in the production of thrombolytics, meets high global standards. DBT supported most of starting from native streptokinase, recombinant SK and these projects and deserves encomiums for the sustained then on to the third generation clot buster (CSSK) by support. But, at this stage a strategy is needed to make Girish Sahni and his colleagues at IMTECH, Chandigarh. these innovative leads into products. The non-specific plasminogen-activation of SK was countered by fusing its core elements with fibrin-binding References domains 4 and 5 of human fibronectin14. CSSK remains 1. Ramachandran, G. N. et al. Stereochemistry of polypeptide chain configurations. J. Mol. Biol. 7, 95–99 (1963) inactive in circulation but gets activated by plasmin in 2. Talwar, G. P. et al. A vaccine that prevents pregnancy in women. Proc. the clot. The earlier products have been a commercial Natl. Acad. Sci. 91, 8532–8536 (1994) success and the clot buster, when fully validated can be 3. De, S. N. & Chatterjee, D. N. An experimental study of the mechanism a block buster. Kanury Rao and his associates at ICGEB of action of Vibrio cholera on the intestinal mucous membrane. J. have taken up a novel approach to target host factors to Pathol. Bacteriol. 66, 559–562 (1953) develop molecules against tuberculosis. Based on SiRNA 4. Kanungo, S. et al. Safety and immunogenicity of a live oral recombinant screens of kinases and phosphatases in infected murine cholera vaccine VA 1.4: A randomized, placebo controlled trial in healthy adults in a cholera endemic area in Kolkata, India. PLoS ONE macrophages, they identified host molecules essential for 9: e99381 (2014) pathogen survival15. This has led to the development of 5. Chauhan, P et al. Adjunctive immunotherapy with L- crystalline inhibitors with potential to become drugs against TB and based DNA vaccination reduces tuberculosis chemotherapy period in transferred to industry. chronically infected mice. Sci. Rep. 3, 1821(2013) Some exciting results have been obtained in my laboratory 6. Chitnis, C & Sharma, A. Targeting the Plasmodium vivax Duffy- binding protein. Trends Parasitol. 24, 29–34 (2008) with arteether-curcumin combination to treat parasite 7. Biswas, S. et al. Preexposue efficacy of a novel combination DNA recrudescence and cerebral malaria in experimental and inactivated rabies virus vaccine. Hum. Gene Ther. 12, 1917–1922 animals. Apart from the exciting possibility of using (2001)

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8. Bhandari, N. et al. Efficacy of a monovalent human-bovine (116E) 13. Chakrabarti, B. K. et al. Robust neutralizing antibodies elicited by rotavirus vaccine in Indian infants: a randomized, double-blind, HIV-1 JRFL envelope glycoprotein trimers in nonhuman primates. J. placebo-controlled trial. Lancet. 383, 2136–2143 (2014) Virol. 87, 13239–13251 (2013) 9. Glass, R.I. et al. Development of candidate rotavirus vaccines derived 14. Aneja, R. et al. Identification of a new exosite involved in catalytic from neonatal strains in India. J. Infect. Dis. 192 (Suppl 1), S30–S35 turnover by the streptokinase-plasmin activator complex during (2005) human plasminogen activation. J. Biol. Chem. 284, 32642–32650 10. Appaiaghari, M. B. & Vrati, S. Immunogenicity and protective efficacy (2009) in mice of a formaldehyde-inactivated Indian strain of Japanese 15. Jayaswal, S.et al. Identification of host-dependent survival factors for encephalitis virus grown in Vero cells. Vaccine. 22, 3669–3675 (2004) intracellular Mycobacterium tuberculosis through a siRNA screen. 11. Etemad, B. et al. An envelope Domain III-based chimeric antigen PLoS Pathog. 6: e 1000839 (2010) produced in Pichia pastoris elicits neutralizing antibodies against all four dengue virus serotypes. Am. J. Trop. Med. Hyg. 79, 3353–3363 16. Dende, C. et al. Simultaneously targeting inflammatory response (2008) and parasite sequestration in brain to treat Experimental Cerebral Malaria. Sci. Rep. 5: 12671 (2015) 12. Mallajosyula, V. V. et al. Influenza hemagglutinin stem-fragment elicits broadly neutralizing antibodies and confers heterologous 17. Padmanaban, G. & Rangarajan, P. N. Forum: Curcumin as an adjunct protection. Proc. Natl. Acad. Sci. USA 111, E2514–2523 (2014) drug for infectious diseases. Trends Pharmacol. Sci. 1282 (2015)

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The birth of DBT

Inder Verma1

In late 1983, I was visited by provided to an individual laboratory. We also encouraged a group of individuals from the DBT to initiate peer reviewed funding opportunities to the National Biotechnology all scientists with independent positions. Many members of Board (NBB) of India, led by the SAC-O were encouraged to visit individual institutions Dr. S. Ramachandran, whose and, if possible, spend some time with them. previous experience was in Though the budget of the DBT was relatively modest antibiotics and vaccines. compared to more established government departments They wanted to know how like CSIR and DST, its activities gave a big boost to India could become a player basic biological sciences. Following the appointment in the nascent biotechnology of Dr. Manju Sharma as the Secretary of the DBT in the industry. After many 1990’s, the DBT budget increased substantially, and many meetings and consultations, it was decided in 1986 by the activities were initiated. Several autonomous institutions government of India, that NBB should be converted into were established by the DBT, which included the National an independent agency: the Department of Biotechnology Institute of Immunology (NII), the National Center for (DBT), with Dr. Ramachandran as its first Secretary. Cell Sciences (NCCS), the Center for DNA Fingerprinting A unique feature of the DBT was the establishment of a and Diagnostics (CDFD), the National Brain Research scientific advisory committee overseas (SAC-O), which Center (NBRC), and the National Center for Plant I have coordinated for the past 30 years. Since its very Genome Research (NCPGR) to name a few, to carry out inception, the mandate of the DBT was very broad, and support a broad spectrum of science. ranging from aquaculture to agriculture, bioinformatics to All these new endeavors required trained manpower. biofuels, genes to the brain, and many areas in between. Consequently, the DBT also had to create special This breadth required that the SAC-O represented a fellowships to entice trained scientists of Indian origin very wide area of expertise. My strength was molecular abroad to return home. Additionally, the DBT created biology and gene manipulation; and right from the start I special courses in biotechnology to train personnel to encouraged expanding and equipping laboratories working work in diverse fields of biological sciences. A lot of in basic science. The main complaint of scientists was the effort and funding from the DBT in the 1990s went unavailability of basic reagents, like restriction enzymes, into infrastructure, buildings, and other organisational DNA polymerase and ligases, radioactive materials, and aspects. One of my own areas of scientific interest was the difficulty in releasing many of these reagents from genetic diseases and gene therapy, and while visiting a customs offices. prominent hospital in Chandigarh, I was struck by the Many well-recognised institutions had no facilities for number of children with thalassemia (a blood disease). I tissue culture, and to top it all off there was no steady source was told that this area of Punjab had a very high number of of funding. Government grants went to institutions, which children born with this disease. Knowing how effectively then trickled down to individual investigators depending the disease has been combatted in other parts of the on the whims of the administrators or departmental chairs. world, especially in the eastern Mediterranean, I felt that Continuity of funding was uncertain even in productive we needed to give the parents the opportunity of a genetic laboratories. With strong support from the SAC-O, the diagnosis and counselling. Consequently, over a dozen DBT started to fund individuals directly, and initiated clinics have been established for providing molecular the practice of block grants to a group of scientists with diagnosis and counselling for common genetic disorders shared scientific programmes. This type of cooperation like hemoglobinopathies, hemophilia and muscular created the opportunity to buy collectively an expensive dystrophy. In the post-genomic era, these genetic testing piece of equipment, not usually possible with the resources centers have now proliferated in the entire nation and

1American Cancer Society Professor of Molecular Biology, Laboratory of Genetics, Salk Institute for Biological Studies & the University of California, San Diego, California, USA.

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are taking advantage of new automated technologies important influence of the DBT has been its ability to combined with bioinformatics approaches. be a one-stop nodal agency dealing with most aspects of Following Dr. Sharma’s retirement, the position of Secretary biotechnology endeavors in the country. of the DBT was assumed by Dr. M.K. Bhan, a clinician Skeptics — and there are many — will say that after three with a passion for basic science and a deep commitment decades, the DBT has little of substance to show. Has India to translational research. He also helped in building produced high-quality scientific research that is competitive and strengthening ongoing international partnerships at an international level? Has India produced any new drugs in the areas of vaccines, diagnostics, cancer and other on par with the major pharmaceutical industries of the communicable diseases. He spotted talent and supported world? Has the DBT’s effort to build manpower succeeded, it, but realised the limitations imposed by government and is it wise to spend limited resources in so many policies, and was the chief architect of establishing the initiatives? And finally my favorite: the “deletion test”. If the DBT-Wellcome Trust India Alliance, which supports the DBT did not exist, would Indian biological sciences have funding of new investigators as well as talented established flourished to the extent that we see today? The answer to all scientists in India. It also offers the opportunity to bring these questions is decidedly mixed, but the foundation of established investigators to India from abroad. These are building a biotechnology industry on the pedestal of basic handsome grants awarded after rigorous review by an science promoted by the DBT is the right approach. international panel and one of the best gifts given to the Indian biological sciences. India still needs a large cadre of True, biological sciences in India are still not competitive talent to build a viable biotech industry. by international standards, as judged by publications in prestigious journals. Nor have we made substantial On its 30th anniversary, it is appropriate to ask what the advances in biotechnology products. I believe that the DBT has achieved, where it has fallen short, and what DBT needs to focus more on where they can make an are its plans going forward. From my vantage point, the impact, instead of becoming the central place to go to for DBT has been extremely successful in promoting and any issues or problems related to plant, aquatic, animal or supporting research activities in basic biological sciences. human health. It has too much on its plate, much of which Nearly all active scientists in the country would admit has often not been brought to fruition. Its goals need to that their scientific efforts have been boosted by the become more streamlined and more crisply defined, with DBT, either by direct or indirect support by providing a strategic plan and vision for the next decade. infrastructure and/or large equipment grants. The DBT has been helpful in fostering relationships with international I have had the privilege to be present at the birth of the DBT, institutions, philanthropic foundations and organisations. and to be part of its 30-year history. Along the way, I also It has provided resources for autonomous institutes, and forged close relationships with many scientists in India, has been a primary agency in putting emphasis on the and also scientists of Indian origin who never flinched neurosciences by helping to build the brain center, and in their willingness to participate and support science creating infrastructure for bioinformatics. in India. Over 40 scientists in many different areas have The DBT has helped write many regulatory guidelines served on the SAC-O giving their best advice, time and for the proper conduct of science and clinical activities. talent. Not one scientist of Indian origin ever refused the It has promoted relationships between academia and request to participate in any DBT-related activity, ranging the burgeoning indigenous biotech industries in the from serving on the SAC-O, reviewing institutions, country. The DBT has sponsored countless national and attending strategic meetings, or reviewing grants. This is international scientific fora to disseminate information. an incredible resource, and no one is more aware of this Many states in India, encouraged by the potential of than Dr. K. VijayRaghavan, the current Secretary of the biotechnology, are establishing biotechnology parks, DBT, who has the enthusiasm, energy and vision to lead biotechnology cities and knowledge parks with the this agency to more concrete and productive endeavors in expert advice of the DBT. It boasts of transferring over the coming days. I wish him and the DBT my best wishes 40 technologies from academia to industry. The most for success in the years to come.

12 Biotechnology: An agent for sustainable socio-economic transformation

Fighting the malaria scourge

Virander S. Chauhan1

Introduction first eradication programme was conceived in mid 1950s. Consequently, malaria was successfully eliminated from Malaria has been an enemy of the western world, parts of Asia including India but not humans for thousands of years from sub-Saharan Africa, highlighting the difficulties in and remains a major public health problem in the tropical implementation of the control tools across different regions and subtropical region of the in Africa. This global malaria eradication programme was world. Description of malaria abandoned in 1969. With decreased attention during the like symptoms of periodic next 20 years, malaria reemerged in countries like India, fevers can be found in Chinese with increased vigour. It also became clear that a serious texts (2700 BC), writings from malaria control will require newer combat tools including Mesopotamia (2000 BC), better methods of diagnosis, more effective drugs for Egypt (1570 BC), Indian Vedic scriptures (600 BC) and treatment and insecticides for vector control. Eradication detailed accounts by Hippocrates (500 BC). However, the of malaria is one of the key stated targets of the United real cause of malaria was discovered by Charles Alphonse Nations Millennium Development Goals. Through Laveran in 1880 who discovered crescent shaped bodies sustained efforts and financial efforts to control malaria, (Oscillaria malariae) while examining the blood samples a steady decline in malaria deaths since 2000 has been of infected individuals. Ronald Ross in 1897 described observed. This was made possible mainly by increased the whole sexual cycle on the gut wall of mosquito (Culex use of insecticide treated bed nets and malaria treatment 1 fatigans), while working with Avian malaria parasite, by artemisinin based combination therapies (ACTs) . Plasmodium relictum followed by elucidation of the Global Malaria Action Plan announced by WHO aims at 25 complete transmission cycle of human malaria parasites, a reduction of 90% in malaria morbidity by 2030 . This P. vivax, P. malariae and P. falciparum by Italian scientists is a highly ambitious goal and many challenges remain. Bignami, Grassi and Bastienelli. It took fifty more years But, we also know a whole lot more about the biology of before the distinct liver and blood stages of the parasite the parasite; we have access to whole genome sequences life cycle were characterised. Some of the important of malaria parasites, the vector and the host26. Advances landmarks in the history of malaria are outlined in Table 1. in genomic and proteomic methods have provided deep insights into the life cycle of the parasite, hitherto unknown Policies and programmes to eradicate malaria molecular pathways, mechanisms of immunity against Fighting malaria is urgent. With all the scientific malaria, transmission dynamics and so on26. Currently advancements, malaria still infects millions. In 2015, there are quicker and more reliable ways for diagnosis of it caused 438,000 deaths and infected 214 million malaria and, as of now, affordable treatments, which makes people worldwide1. There exists an inverse relationship this the right time to bring malaria eradication agenda as a between malaria cases and society’s prosperity. Malaria is viable goal, back on the table. considered to be a disease of poverty as well as a cause of poverty2. Efforts to control and even eradicate malaria Drugs to combat malaria have always been there. In the post-World War II era, What are the key challenges in achieving the ambitious with the success of vector control by insecticide spraying, goal of malaria eradication? Many. To begin with, we and malaria treatment with drugs like Chloroquine, the desperately need new and more effective antimalarials and

1Malaria Research Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.

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Table 1: Landmarks in malaria research Year Major Discoveries References 2700-BCE Earliest records of human malaria symptoms were found in the Carter & Mendis; 20023 Chinese Literature, The Nei Ching. 2000- 600 BCE Cox et al 2002; 20104,5 References to malaria occur in Mesopotamian, Egyptian and 400 BCE 6 Hindu Vedic texts Gardiner et al; 2005 Hippocrates described the principal symptoms of malaria 1820-1850 Quinine extracted from the Cinchona bark. Use of Quinine Cox et al; 20024 became common place Cox et al; 20105

First observation of malaria parasite in the blood of infected patients 7 by Charles Alphonse Laveran Laveran C; 1881 1880 1890-1931 Differentiation of various human malaria parasite species Grassi and Felleti, 19808 P. vivax and P. malariae- Grassi and Felleti Sacharoff, 18969; P. falciparum- Sakharov and Marchiafava & Celli Marchiafava and Bignami, 189410 P. ovale- John Stephens Stephens, J. W. W.,191411 P. knowlesii- Knowles and Das Gupta Knowles, R., Das Gupta, B.M., 1932.12 1897 Sir Ronald Ross discovered that mosquitoes transmit malaria. Ross R; 198713 1934 Discovery of Chloroquine by Hans Andersag Andersag H, 194914 1939-44 Insecticidal activity of DDT discovered by Paul Hermann Muller Paul Hermann Muller; Nobel and widely used as an anti-mosquito spray Lecture, 194915 1955-57 First documented case of Chloroquine resistance reported. Payne D, 198716 DDT resistant mosquitoes detected 1972 Artemisinin isolated from Artemisia annua by a Chinese chemist, Youyou et al., 199217 Tu Youyou 1976 P. falciparum first grown in culture by Trager and Jensen, opening the Trager and Jensen, 197618 way for drug discovery and vaccine research 1995 Rapid diagnostic Tests for malaria introduced Peyron et al., 199419 1998 UN declares 2000-10 as ‘Decade to Roll Back Malaria’ Nabarro and Tayler, 199820 2002 Genome sequencing of gambiae (mosquito) and Gardner et al., 200221 (parasite) completed.

2007 Melinda Gates and Margaret Chan endorse eradication of The malERA initiative, 200722 malaria worldwide 1992-2015 Development and licensure of RTS, S/AS01, as first ever human Agnandji et al; 201123 malaria vaccine Morrison C., 201424 Nobel Prizes awarded in the field of malaria Year Name Contribution 1902 Sir Ronald Ross Elucidating the life cycle of the malaria parasite 1907 Charles Louis Alphonse Laveran Discovery of malaria parasites 1948 Paul Hermann Muller Discovery of the insecticidal activity of DTT 2015 Youyou Tu Discovery of Artemisinin based therapy against malaria

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efficacious vaccines. There is a wide spread resistance to The fact that individuals living in malaria endemic areas chloroquine, sulfadoxine, mefloquine and more recently develop immunity against malaria and that injection of even to ACTs, that have remained the mainstay of malaria irradiated sporozoites can protect humans from infection treatment27. Use of ACTs has saved millions of lives, a suggest that it may be possible to develop vaccines against fact whose recognition resulted in award of the Nobel malaria, although the exact co-relates of immunity Prize for medicine in 2015 to Chinese chemist Youyou are still not clearly understood and development of an Tu for discovery of artemisinin. Widespread resistance effective vaccine has remained a challenge. On the other to artemisinin will severely affect malaria control efforts. hand, an increasingly large number of vaccine target Although there have been serious efforts to strengthen antigens from the three different stages of its life cycle the pipeline of possible antimalarials, the situation is far have been characterised and novel experimental vaccines from satisfactory28. To meet the malaria elimination goals, are developed for clinical trials32. A liver stage vaccine new drugs will have to do better than the current standard called RTS,S developed jointly by scientists at Walter ACT-based therapies. Since supply of artemisinin and Reed Army Institute of Research (WRAIR) and Glaxo its derivatives depends entirely on extraction from a Smith Kline (GSK) over a period of 20 years has shown plant source, several attempts to produce fully synthetic partial protection in children and infants in extensive endoperoxides like artemisinin have been made. Phase III trials33. This is the first ever malaria vaccine One such successful collaboration involving several approved for licensure with the trade name Mosquirix in 24 partners from academia, Medicines for Malaria July 2015 . While only partially protective, the story of its Venture (MMV) and Ranbaxy (now Sun Pharma), development is fascinating in the context of the unfaltering an Indian pharmaceutical company, resulted in the commitment of not only the collaborating partners but development of a totally synthetic endoperoxide called also various funding and international agencies. The RBx 11160 (Arterolane)29,30. Further support from successful licensure of Mosquirix has shown the way for Government of India led to the development of Synriam other hopefully more efficacious vaccines, illustrating at (Arterolane+piperaquine), that has shown success in the same time, the constraints, efforts and collaborations treating uncomplicated P. falciparum malaria and is finally it would require. Another vaccine based on irradiated approved for human use in India and several African sporozoites called PfSPZ, has shown remarkable efficacy countries30. Central Drug Research Institute (CDRI), in human volunteers, and this vaccine is scheduled for 34 Lucknow has also developed a synthetic molecule from the further clinical trials in field situations . Indian scientists endoperoxide family that has completed Phase I clinical in many different institutions are also engaged in malaria trials and is currently being tested against drug resistant vaccine research. The malaria vaccine group at ICGEB malaria parasite strains31. The story of development has completed a Phase I clinical trial of a combination P. of Synriam illustrates a fine example how multiple falciparum blood stage vaccine based on two key antigens 35 collaborators, including governments and local companies developed entirely in India . Phase I clinical trial of a P. in the developing world, where most of the neglected vivax vaccine based on a single key blood stage antigen is 36 diseases reside, can play a crucial role in finding solutions in advanced stages of development . to diseases like malaria. A detailed account of the current Funding from Malaria Vaccine Initiative (MVI), European state of drug discovery pipeline including several new non Malaria Vaccine Initiative (EVI) and continuous support endoperoxide based drug molecules has been provided in from the Department of Biotechnology have made it a recent review28. possible to demonstrate that highly complex translational research collaborations between research institutions and The vaccine route biotech industry are indeed possible. In collaboration It is generally believed that an efficacious vaccine against with scientists at National Institute of Malaria Research malaria will be a major asset in combating the disease. (NIMR), ICGEB scientists have recognised field sites37 that

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may be suitable for end to end development of malaria artemisinin derivatives spreads fast, the situation can turn vaccine in India following all international stringent grim very soon. On the other hand, with advances in the regulatory and safety measures. understanding of malaria parasite biology, several new drug With more than three-fourth of its population exposed targets have been identified. With better and more reliable to the malaria risk, it is not surprising that about 70% of screening methods and human challenge models made all malaria cases in South East Asian countries occur in available, with multiple collaborative efforts from academia, India. Funding for malaria research and control methods industry, government and other major funding agencies has always received special attention in India, particularly there is hope that malaria deaths will reach insignificant from agencies like ICMR and DBT. This has resulted in a numbers in the near future. critical mass of scientists involved in malaria research and [Assistance from Tajali Sahar, Aakanksha Kalra, Dr K Sony some significant contributions in our basic understanding Reddy at ICGEB and Dr. Deepak Gaur at JNU in writing of parasite biology with implications in the development this article is gratefully acknowledged.] of novel therapeutics and intervention strategies. Some notable achievements include the identification of heme References 1. World Malaria Report (2015) biosynthesis in the parasite that is essential for its liver and 2. Sachs, J. & Malaney, P. The economic and social burden of malaria. 38 mosquito stages . Extensive research on the erythrocyte Nature 415, 680–685 (2002) invasion process has highlighted the significance of the 3. Carter, R. & Mendis, K. N. Evolutionary and historical aspects of the Merozoite surface proteins (MSP-1, MSP-3)39-40 and the burden of malaria. Clin. Microbiol. Rev. 15, 564–594 (2002) 41 Reticulocyte binding-like homologous (PfRH) proteins . 4. Cox, F. E. G. History of human parasitology. Clin. Microbiol. Rev. Recently, a multi-protein adhesion complex that presents 15, 595–612 (2002) the essential PfRH5 parasite ligand to its red cell receptor, 5. Cox, F. E. History of the discovery of the malaria parasites and their vectors. Parasit. Vectors 3, 5 (2010) anchored by another protein, CyRPA to the parasite surface was discovered42. Efforts have been made in 6. Gardiner, D. L. et al. Malaria in the post-genomics era: light at the end of the tunnel or just another train? Postgrad. Med. J. 81, 505–509 elucidating the signaling pathways in the parasite that (2005) are responsible for its egress from the infected red cell 7. Laveran, A. Note surun nouveau parasite trouvédans le sang and subsequent invasion into naïve red cells43. A number deplusieursmaladesatteints de fièvrepalustre.Bull. Acad. Med. 9, of secretory blood stage proteins as well as haemoglobin 1235–1236 (1880) degradation-haemozoin formation complex have been 8. Grassi & Feletti. Ueber die Parasiten der Malaria. Centralbl. f. Bakteriol. 7, 396-430 (1890) recognised44. An enzyme, enolase has been shown to be 9. Sacharoff. Ueber den Entstehungsmodus der verschiedenen also localised on the surface of the ookinete, the mosquito Varietatender Malariaparasiten. Centralbl. f. Bakteriol. 19, 268 stage of the parasite45 and is thus being considered as an (1896) attractive transmission blocking target antigen. However, 10. Marchiafava & Bignami Estivo-Autumnal Malaria. The New if the results of basic research are to be translated into Sydenham Society, London 150 (1892) the development of new drugs and vaccines, the now 11. Stephens, J. W. W. A new malaria parasite of man. Proc. Royal Soc. well-established human challenge (CHMI) model46 needs London. B. Containing Papers of a Biological Character. 87 (596), 375–377 (1914) to be set up in India. Attempts to do that have failed so 12. Knowles, R. & Das Gupta, B. M. A study of monkey-malaria and its far. Serious efforts to involve academia and industry in experimental transmission to man. Ind. Med. Gazette 67, 301–320 addressing major health problems through institutions (1932) like BIRAC need to be strengthened further along with 13. Ross, R. On some peculiar pigmented cells found in two mosquitoes active support of the regulatory authorities in India. fed on malarial blood. Ind. J. Malariol. 34, 1786–1788 (1897) 14. Dunschede, H. B. Tropenmedizinische Forschung bei Bayer Vol.II. Finally new tools to combat malaria are urgently needed The University of California. (1971) and none is more important than discovery of new drugs 15. Hermann, M. Dichlorodiphenyläthan und neuere Insektizide. Nobel to meet the eradication goals. In fact, if resistance to lecture. 122-123 (1948)

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16. Payne, D. Spread of chloroquine resistance in Plasmodium analysis of data from a phase 3 randomised controlled trial. Lancet falciparum. Parasitol. Today. 3, 241-6 (1987) Infect. Dis. 3099, 1–9 (2015) 17. You-you, T. Studies on the Constituents of Artemisia annua Part II. 34. Hoffman, S. L. et al. The march toward malaria vaccines. Am. J. Prev. Planta Med. 44, 143-145 (1982) Med. 49, S319–S333 (2015) 18. Trager, W. & Jensen, J. B. Human malaria parasites in continuous 35. Chitnis, C. E. et al. Phase I clinical trial of a recombinant blood culture. Science 193, 673–5 (1976) stage vaccine candidate for Plasmodium falciparum malaria based 19. Peyron, F. et al. Dipstick antigen-capture assay for malaria detection. on MSP1 and EBA175. PLoS One 10, 1–21 (2015) The Lancet 343, 1502-1503 (1994) 36. De Cassan, S. C. et al. Preclinical assessment of viral vectored and 20. Nabarro, D. N. Global Health: The “Roll Back Malaria” Campaign. protein vaccines targeting the duffy-binding protein region II of Science. 280, 2067–2068 (1998) Plasmodium Vivax. Front. Immunol. 6, 1–15 (2015) 21. Gardner, M. et al. Genome sequence of the human malaria parasite 37. Sharma, S. K. et al. Epidemiology of malaria transmission in forest Plasmodium falciparum. Nature 419, 498–511 (2002) and plain ecotype villages in Sundargarh District, Orissa, India. Trans. R. Soc. Trop. Med. Hyg. 100, 917-25 (2006) 22. The Malaria Eradication Research Agenda (malERA) initiative. (2007) 38. Nagaraj, V. A. et al. Malaria parasite-synthesized heme is essential 23. Agnandji, S. T. et al. A phase 3 trial of RTS,S/AS01 malaria vaccine in the mosquito and liver stages and complements host heme in the in African infants. N. Engl. J. Med. 367, 2284–95 (2012) blood stages of infection. PLoS Pathog. 9, e1003522 (2013) 24. Morrison, C. Landmark green light for Mosquirix malaria vaccine. 39. Mazumdar, S. et al. Plasmodium falciparum merozoite surface Nat. Biotechnol. 33, 1015–1016 (2015) protein1 (MSP-1)-MSP-3 chimeric protein: Immunogenicity 25. The Global Malaria Action Plan. Key Facts, Figures, and Strategies. (2008) determined with human-compatible adjuvants and induction of 26. Sherman, IW. The Elusive Malaria Vaccine: Miracle or Mirage. protective immune response. Infect. Immun. 78, 872–883 (2010) ISBN: 978-1-55581-515-8 (2009) 40. Imam, M. et al. Plasmodium falciparum merozoite surface protein 3. 27. Bosman, A. & Mendis, K. N. A major transition in malaria treatment: J. Biol. Chem. 289, 3856–3868 (2014) The adoption and deployment of artemisinin-based combination 41. Sahar, T. et al. Plasmodium falciparum reticulocyte binding-like therapies. Am. J. Trop. Med. Hyg. 77, 193–197 (2007) homologue protein 2 (PfRH2) is a key adhesive molecule involved 28. Wells, T. N. C. et al. Malaria medicines: a glass half full? Nat. Rev. in erythrocyte invasion. PLoS One 6, e17102 (2011) Drug Discov. 14, 424–442 (2015) 42. Reddy, K. S. et al. Multiprotein complex between the GPI-anchored 29. Valecha, N. et al. Arterolane maleate plus piperaquine phosphate CyRPA with PfRH5 and PfRipr is crucial for Plasmodium falciparum for treatment of uncomplicated Plasmodium falciparum malaria: A erythrocyte invasion. Proc. Natl. Acad. Sci. 112, 1179–1184 (2015) comparative, multicenter, randomized clinical trial. Clin. Infect. Dis. 43. Sharma, P. & Chitnis, C. E. Key molecular events during host cell 55, 663–671 (2012) invasion by Apicomplexan pathogens. Curr. Opin. Microbiol. 16, 30. Patil, C. et al. Fixed dose combination of arterolane and piperaquine: 432–437 (2013) a newer prospect in antimalarial therapy. Ann. Med. Health Sci. Res. 44. Chugh, M. et al. Protein complex directs hemoglobin-to-hemozoin 4, 466–71 (2014) formation in Plasmodium falciparum. Proc. Natl. Acad. Sci. 110, 31. Shafiq, N. et al. Single ascending dose safety and pharmacokinetics 5392- 5397 (2013) of CDRI-97/78: First-in-human study of a novel antimalarial drug. 45. Mukherjee, D. et al. EWGWS insert in Plasmodium falciparum Malar. Res. Treat. 372521 (2014) ookinete surface enolase is involved in binding of PWWP containing 32. Takashima, E. et al. Vaccine candidates for malaria: what’s new? peptides: Implications to mosquito midgut invasion by the parasite. Expert Rev. Vaccines, 15, 1-3 (2015) doi:10.1586/14760584.2016.1 Insect Biochem. Mol. Biol. 68, 13–22 (2015) 112744 46. Duncan, C. J. A. et al. Can growth inhibition assays (GIA) 33. White, M. T. et al. Immunogenicity of the RTS,S/AS01 malaria predict blood-stage malaria vaccine efficacy? Human Vaccines vaccine and implications for duration of vaccine efficacy: secondary Immunotherapeutics 8, 706-714 (2012)

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Stem cell research: Beyond the headlines

D. Balasubramanian1 & Alka Sharma2

together framework for regulation. DBT, in collaboration with the Indian Council of Medical Research (ICMR), has also put forward a set of national guidelines for stem cell research. As per the current guidelines: “Any stem cell use in a patient is investigational — must only be done within the purview of an approved and monitored clinical trial and not be offered as therapy.” Moreover, the government has set up a National Apex Committee for Stem Cell Research and Therapy (NACSCRT). Sharma et al. discussed in details regarding the emerging scenario and policy concerns in two of their papers1,2. In the 1980s, “New Biology” captured India in a big They also summarize the current status of stem cells way. Scientists across the country took it up with research in India, the support offered by government enthusiasm, and research groups emerged with expertise agencies such as DBT, ICMR, the Department of Science in developing applications in areas such as recombinant and Technology (DST) and the Defence Research and DNA, immunology and monoclonal antibodies, Development organisation (DRDO). In establishing infection biology and vaccines, development biology at stem cell biology and therapy as a major area of national the molecular, cellular and tissue level, bioinformatics importance, DBT was at the forefront. Thanks to their and molecular modelling and stem cell biology and its support, today, eleven centres across India are carrying potential therapeutic applications. At this crucial juncture, out research on bone marrow-derived hematopoietic stem the Department of Biotechnology (DBT) was established cells, mesenchymal and mononuclear cells. Two or three in 1985 by India's Ministry of Science and Technology. centres are working on peripheral blood-derived stem cells, over five centres on limbal stem cells from the eye, Initiation and growth of stem cell research four on the neural system, five on liver stem cells, three on From the beginning, DBT took a proactive role in pancreatic progenitor cells, five on cardiac stem cells, three promoting new biology through workshops for capacity on cancer stem cells. two centres on dental pulp stem cells, building, providing infrastructure and equipment to one on muscle stem cells and a few centres on cord blood centres, establishing electronic communication system and Wharton’s jelly. Moreover, the DBT has provided across laboratories and importantly, offering competitive clean room facilities for handling stem cells at five centres research grants just like other departments in science and and c-GMP facilities at four places. Importantly, the DBT technology, medicine and agriculture. has established a special laboratory dedicated to stem cell In order to facilitate stem cell research, the Department research, known as Institute for Stem Cell Science and set up a special Task Force on Stem Cell Research and Regenerative Medicine (inStem) in Bangalore. Regenerative Medicine in 2001. Its mandate was to Such support, largely from the government and in part formulate and implement strategy, support research and from private industries and private foundations, has led develop programmes in the area, create a platform for to over 30 centres across the country engaged in stem cell- clinical research and schemes for setting up infrastructure related activities. Figure 1 shows the spread of a significant and equipment, institutional development, and to put number of such efforts (we admit that the picture does not

1Research Director, LV Prasad Eye Institute, Hyderabad & 2Director, Scientist F, Department of Biotechnology, New Delhi, India.

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Figure 1: Stem cell research in India, 2016. capture many companies involved in stem cell banking Manipal Centre at Bangalore have generated Human and supply, and some who have applied for approval for Embryonic Stem Cells (HESCs) from discarded grade clinical trials). III blastocysts. Two of these have been deposited in the UK Stem Cell bank, off London. (It is important to note Some representative works that there are no ethical debates on the production and While most of the work so far has been carried out using use of HESCs in India, while there is an ongoing one on ‘adult stem cells’ (such as those mentioned above), three genetically modified plants). These HESCs are now being groups at the Jawaharlal Nehru Centre for Advanced used by colleagues in India and abroad for basic research Scientific Research (JNCASR) at Bangalore, National purposes. With the introduction of the production Institute for Reproductive Research at Mumbai and of induced pluripotent stem cells (iPSCs)3, several

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laboratories in India have also successfully generated Taking cue from some earlier work8,9 that bone marrow iPSCs from terminally differentiated ones (e.g. fibroblasts cells regenerate the infracted myocardium, the cardiology taken from patient’s own skin) and used them for specific group at the All India Institute of Medical Sciences, New purposes. Delhi isolated mononuclear cells from the bone marrow of 24 patients with dilated cardiomyopathy and treated Some noteworthy examples of translational research them for myocardial infarction. Analysis of the data after using stem cells have been benefiting patients. Stem cell six months revealed an overall significant improvement in biology and its applications were in the limelight in the ventricular function10. This study and some similar studies eighties, and some laboratories in India were ready to elsewhere11 led the DBT Task Force on Stem cells to initiate adopt it and work on it. Within a couple of years of the a pilot, phase I/II multi-centre clinical study on acute report on the use of bone marrow transplantation for myocardial infarction, acute ischemic stroke, myocardium thalassemia by Thomas et al.4, clinicians at the Christian generation as well as another multi-centre trial on chronic Medical College and Hospital (CMC) at Vellore had critical limb ischemia using peripheral blood stem started bone marrow transplantation in patients5, and cells and intra-arterial delivery of adult stem cells. Data the method was rapidly adapted in over a dozen clinical obtained from these trials have been evaluated by third centres across the country. Bone marrow contains party analyst groups. Many animal models have also been hematopoietic stem cells (which generate blood cells), developed for various human diseases to establish safety mesenchymal stem cells and mononuclear cells (which and efficacy of adult stem cells with support from DBT at can be differentiated to generate other types of cells, several institutions across India. such as muscle cells). A comprehensive summary of all allogeneic stem cell transplantation for thalassemia Another important breakthrough is the successful major has been provided recently by Mathews et al.6 It regeneration of the corneal outer surface in patients is also possible to use peripheral blood stem cells (rather with damaged corneas due to chemical or thermal burns. than the bone marrow) in cases where bone marrow is Since the 1970s, it has been known that the limbus (the not advisable. Peripheral blood contains hematopoietic ring surrounding the cornea and separating it from the stem cells (though smaller in number than the marrow). sclera and conjunctiva) regenerates the corneal surface. The group at CMC Vellore has also used such peripheral In addition, it can grow back once a part of it is biopsied. blood cells to treat high risk thalassemia patients7. This dual property has allowed corneal surgeons to clean the damaged corneal surface of patients, wound heal For the clinical application of stem cells to successfully using human amniotic membrane (HAM) and transplant treat patients with thalassemia and related disorders, a bit (a few clock hours) of the limbus to treat patients. CMC Vellore has been recognised by DBT as an Once scientists discovered that the limbus houses adult important centre and provided substantial funding to stem cells, a far smaller bit of the limbal tissue could be establish laboratories, clinical facilities and the c-GMP biopsied and the stem cells from it could be cultured facility. This facility is referred to as the CMC-DBT to generate the corneal epithelium (using HAM as the Centre for Stem Cell Research, a translational unit of scaffold), which could be transplanted on the patient inStem. Currently, hematopoietic stem cells research and after the pannus tissue was removed off the cornea, and treatment are carried out in over 11 centres across India, vision could be restored to some degree. Based on the and most of them are funded by DBT2. Recently, the use of first human trial in Italy by Pellegrini et al.12, researchers hematopoietic stem cells for the treatment of thalassemia at the L. V. Prasad Eye Institute (LVPEI), Hyderabad, and other related anaemic conditions has been approved started such cultivated limbal epithelial transplantation by the Government of India. (CLET) with support from DBT and succeeded. Over the Mononuclear cells obtained from the bone marrow can years, CLET has become a popular clinical trial in over be differentiated to muscle cells such as cardiomyocytes. six centres across India. A concise review of CLET — the

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procedure, the standard culture medium, the outcome 4. Thomas, E. D. et al. Marrow Transplantation for Thalassemia. The over the years and other details — has recently been Lancet. 2, 227–229 (1982) published by Ramachandran et al.13 The CLET group 5. Chandy, M. Stem Cell Transplantation in India. Bone Marrow Transplantation. 42, S81–S84 (2008) across India has now applied to the authorities to declare 6. Mathews, V. et al. Allogeneic Stem Cell Transplantation for CLET as Proven Therapy. Recognising the work by the Thalassemia Major. Hematol. Oncol. N. Am. 28, 1187–1200 (2014) LVPEI in the area of stem cells, DBT has named it as a 7. Mathews, V. et al. Improved Clinical Outcomes of High Risk DBT Centre of Excellence in Eye Biology. β Thalassemia Major Patients Undergoing a HLA Matched Related Allogeneic Stem Cell Transplant with a Treosulfan Based In an interesting simplification of CLET, Dr Sangwan Conditioning Regimen and Peripheral Blood Stem Cell Grafts. PLoS and colleagues at the LVPEI have cultured limbal tissue One 8, e61637 (2013) doi: 10.1371/journal.pone.0061637 into corneal epithelial cells not in the laboratory, but 8. Orlic, D. et al. Bone Marrow Cells Regenerate Infarcted Myocardium. directly on the patient’s eye, in situ, in vivo, after pannus Nature. 410, 701–705 (2001) removal, wound healing using HAM and sprinkling tiny 9. Strauer, B. E. et al. Repair of Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation. bits of limbal tissue over it and finally, covering it with a Circulation. 106, 1913–1918 (2002) bandage contact lens. Termed as simple limbal epithelial 10. Seth, S. et al. Percutaneous Intracoronary Cellular Cardiomyopathy for transplantation or SLET, it works similar to CLET. A two- Nonischemic Cardiomyopathy: Clinical and Histopathological Results: year follow-up on 125 eyes, treated with SLET, is currently The First- in- Man ABCD (Autologous Bone Marrow Cells in Dilated under publication14. It is claimed that any experienced Cardiomyopathy) Trial. J. Am. Coll. Cardiol. 48, 2350–2351 (2006) and qualified corneal surgeon can adopt SLET to repair 11. Cao, F. et al. Long-term Myocardial Functional Improvement after Autologous Bone marrow mononuclear Cells Transplantation in damaged ocular outer surface, without the facility of a Patients with ST-segment Elevation Myocardial Infarction: 4 Years stem cell culture laboratory! Follow-up. European Heart J. 30, 1986–1994 (2009) 12. Pellegrini, G. et al. Long-term restoration of damaged corneal References surfaces with autologous cultivated corneal epithelium. Lancet. 349, 1. Sharma, A. Stem cell research in India: Emerging scenarios and policy 990–993 (1997) concerns. Asian. Biotech. Dev. Rev. 8, 43– 53 (2006) 13. Ramachandran, C. et al. Concise Review: the Coming of Age of Stem 2. Sharma, A. Stem cell research and policy in India: Current scenario Cell treatment for Corneal Surface Damage. Stem Cells Transl Med. 3, and future perspective. J. Stem Cells. 4, 133–140 (2009) 1160–1168 (2014) 3. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells 14. Basu, S. et al. Simple Limbal Epithelial Transplantation (SLET): Long- from mouse embryonic and adult fibroblast cultures by defined term Clinical Outcomes in 125 Cases of Unilateral Chronic Ocular factors. Cell. 126, 663–676 (2006) Surface Burns. Ophthalmol. 123, (2016)

21 Biotechnology: An agent for sustainable socio-economic transformation

India cannot afford to miss the biological revolution

Krishna M. Ella1

Diseases not only affect supported by DBT through different programmes, such health but also affect a as Entrepreneurship Development, SPARSH and IGNITE, nation’s economy, trade, India is poised to accelerate the development of innovative brand value and GDP. Over new or under-used vaccines, or even build a formidable the last 30 years, life sciences innovation eco-system. and biotechnology have The journey of Indian biotech industry began way back made tremendous impact on in 1993. The baby steps were taken by Shantha Biotech improving the health of our and Bharat Biotech. They helped the development of society. However, we face the Genome Valley Cluster that boasts of over 200 challenges from diseases, such biotech enterprises in Hyderabad today. Initially, it was as Ebola, HIV and Malaria, challenging for the industry as there was very little or no which can be catastrophic if not tackled speedily. On the understanding of the business at the policy as well as the other hand, it is heart-warming to note that collaboration regulatory level. between public and private partners have become robust While startups like Shantha Biotech and Bharat Biotech over the years — acquiring the status of a of polio-free began to take shape, academic institutions struggled to nation and introduction of an India-made ‘Rotavirus’ coordinate with industry — missing opportunities to vaccine being the most recent examples. derive and share benefits with industry. Moreover, the pre- Refreshing changes in the recent years have been a stronger 1990 restrictive economic dispensation in the country was political and scientific commitment to overcome healthcare not conducive for the promotion and funding of a new burden. Introduction of inactivated poliovirus vaccine field such as biotechnology and its applications. (IPV), Rubella vaccine and Rotavirus vaccine into the The BIRAC (Biotechnology Industry Research Assistance expanded Universal Immunisation Programme (UIP) are Council) programme by DBT, a vision by the then good examples of this transformational change in India. Secretary of DBT, M. K. Bhan, came as a strong catalyst DBT has taken the lead in social innovation partnerships. to boost Research and Development of biotech products. The future is promising as we enter into a new phase of its This was further strengthened by Yogeshwar Rao, Head, growth by supporting stakeholders in the development of Technology Networking & Business Development new vaccines and other biotech products for the National Division (TNBD), Council of Scientific and Industrial Rural Health Mission and UIP. Research (CSIR). This brought about New Millennium While the biotech industry welcomes the inclusion of Indian Technology Leadership Initiative (NMITLI) that additional vaccines into UIP, we hope that the state paved way for funding research and development in the governments are encouraged in introducing non- academia as well as in industry. UIP vaccines into their immunisation programmes to The Vaccine Grand Challenge programme by DBT safeguard the public health needs of citizens. Therefore, is yet another refreshing initiative to make India a higher budget sanction covering UIP and non-UIP leading vaccine manufacturing hub. Moving forward, expenses is the need of the hour. establishment of BIRAC has become a strong catalyst for The signs look promising for the biotechnology the industry’s growth. There had to be a paradigm shift in industry. With entrepreneurship in biotechnology being the collective viewpoints of the administrators and the life

1Chairman & Managing Director, Bharat Biotech International Limited, Hyderabad, Telangana, India.

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science scientists for a mighty leap in a largely unchartered of its vaccine requirements. For scientists in developing territory of biotechnology in the country. DBT took the countries, solving today’s problem is not innovation, it is laudable decision in 1986 to act as a premier precision the ability to predict future problems and finding solutions tool for future creation of wealth and social justice for to solve an important problem, something that matters to India. Towards 2000, the biotech industry evolved with public health. strong regulatory requirements, better understanding of There is a tremendous amount of innovation likely to good manufacturing practice (GMP) and updated clinical occur in the vaccine and biosimilar industry. The sector trials approach in India. The earliest entrepreneurial will see a host of new vaccine in the public health domain success was driven by the Technology Development Board as well as to help the nation reduce its disease burden. (TDB) with initial funding for vaccine development and In the vaccine sector, the big trends to watch out for are manufacturing projects of Shantha Biotech and Bharat the ‘Make in India’ molecule thrust and the maturity of Biotech. manufacturing, clinical trials and R & D in India. Today’s neglected diseases are tomorrow’s global diseases. For this to happen, it is very important that India builds a Therefore, it is very important that the life sciences and policy to strengthen regulatory, clinical, and R&D funding biotechnology sectors vigorously focus on tackling these for industry and academia, toughen data integrity, and challenges in collaboration with the government and offer price supporting mechanism for biotech products. health agencies. India is emerging as a major hub for global clinical trials. Tackling water and mosquito borne diseases, such as We need to capitalise on this opportunity in a qualitative typhoid, hepatitis, rotavirus, Japanese encephalitis, dengue manner. Additionally, it is important to tap the growing and chikungunya has become extremely challenging for number of graduate students of biotechnology. developing nations. Malaria is another emerging public As India moves towards becoming an economic health threat. For a developing nation, like India, vaccines superpower, multiple regulations and over-regulation have become more important than ever. could slow down the growth of the Indian biotech industry. Furthermore, India needs to be vigilant and alert to These should be eased out in a consistent manner. The small scale epidemics, e.g. H1N1, causing tremendous biotech sector looks forward to a comprehensive reforms amount of pain for the people around the country. These programme including single window clearance, a national occur in any part of the country. So immediate action on policy and a biotech fund to spur growth. a war-footing should be taken to restrain their spread Harmonisation of various laws that govern the sector and and projects initiated to develop new vaccines against adherence of all intellectual property rights, along with such diseases. Vector borne infections, such as Japanese data protection, will also accelerate the life sciences and encephalitis that used to be confined to some pockets in biotech industry. the northern states and in one location in south, have We must be in the forefront of the global biological now spread across several states. It would certainly have revolution to become the world leaders in vaccine been possible to restrain the spread of this disease, had development. With strong commitment from regulatory the public sector and private sector vaccine manufacturers bodies, data integration protection, investments in R&D, been encouraged and supported at an early stage to and proper utilisation of the strong human resource manufacture and provide vaccines. talent, India can achieve the goal of ‘Make in India’. What Looking at contributions of the developing nations to the life the industry also needs to do is to focus on infectious sciences and biotech sector, not many developing countries diseases that plague emerging nations. This challenge other than India have developed and manufactured new can be exploited for patents. We must focus on biological vaccines. In fact, India has become the major contributor revolution and move away gradually from biosimilars of vaccines to the developing world, meeting two thirds as well as the generic business approach that can harm

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the industry in the future. The industry continues to dependent on several key factors. These include human grapple with some challenges. The need of the hour is to resource development, integration of biotechnology continue with public-private collaboration. The industry institutions of the DBT, the Indian Council of Medical also needs to come together to solve future public health Research and the Indian Council of Agricultural Research challenges by constantly innovating and working closely to set up an inter-ministerial department that addresses with public sector institutions rather than looking at it as collective demands for multisectoral growth in the biotech a competition. industry. Great nations solve their problems that matter, What is vital for the nation is the transformation of and India can lead the way with a mightier public- the industry landscape to a more proactive phase that is private partnership.

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Genetically engineered crops: The path ahead

Jitender Giri1 & Akhilesh Kumar Tyagi1

malnourished. These statistics are particularly worrisome. Clearly, current farm practices cannot increase yield to match the requirements. Use of genetically modified (GM) and genetically engineered (GE) crops offers a pragmatic solution to these challenges. Norman Borlaug — father of green revolution — was also of the view that GM and GE plants hold great potential to increase production under different environmental pressures1.

Challenges, action and expectation The global population is estimated to reach 9.6 billion by 2050 — a more than five-fold rise since 1900. We need to In 2013, the World Food Prize Foundation recognised increase our crop production by at least 60% to feed all the pioneering work in the area of plant biotechnology by extra mouths. GE plants could hold the key to sustained Robert Fraley, Mary-Dell Chilton and Marc Van Montagu productivity under testing conditions. Since 1996, when done in early 1980s. They established the technology for GE crops were first grown commercially, their global stable transfer of genes into plants, which led to genetically cultivation had seen an approximately 100-fold jump — engineered crops. This allowed precision, speed and making GE crops the most accepted crop technology of breaking of boundaries of sexual incompatibility in genetic today2. In the last two decades, almost 28 countries have modification. It may be noted that plant genomes have adopted GE crops. Across the globe, these crops are now undergone numerous changes over the years leading to cultivated on an area of 181.5 million hectares (mha), which progenitors of crops, further selection and domestication is more than the total arable land area of India. Presently, of a few crop plants and their subsequent breeding. These USA is the largest producer of GE crops in the world with include duplication of whole genomes, translocations, about 73.1 mha of land under cultivation. USA has already fusions and mutations leading to assembly of the present deregulated 96 petitions of various crops like corn, cotton, day trait associated genes and their alleles. Existing tomato, soybean, canola, potato and sugar beet. Among superior alleles can be combined by breeding, thus leading other North American countries, Canada is the fifth largest to improved varieties of a particular crop; however such (11.6 mha) adopter of GE crops, viz. canola, maize, soybean genes cannot be moved from one species to another and sugar beet. Brazil (42.2 mha) and Argentina (24.3 mha) sexually incompatible crop. Gene engineering technology in South America are the second and third largest GE crop offers such a possibility. growing countries in the world, respectively. Africa’s share To feed the ever increasing world population, there is is less than 1.6% of the world's total area under GE crops. greater stress on food production and protection than However, field trials of several GE crops are under way. ever. In spite of the use of superior farm practices, yield is Maize is the only GE crop grown in five European countries showing signs of stagnation in most soils across the world. (around 0.15 mha). Approvals for release of many GE crops Changing climate and diminishing natural resources are under way in many European nations. along with competition for land use are continually firing Bt cotton, the only GE crop under cultivation in India, up this trend. Already 870 million people globally do covers around 95% of the total cotton growing area. In a not have sufficient food to eat and another 2 billion are short period of 12 years, around 7.7 million farmers have

1National Institute of Plant Genome Research, Aruna Asaf Ali Road, New Delhi-110067, India.

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adopted Bt cotton in India. As a further advancement, Forests (MoEF) and referred to as Rules 1989 which a total of 1128 varieties of Bt cotton hybrids have been provided “rules for manufacture, use, import, export and allowed to be commercially released by GEAC from 2002- storage of Genetically Engineered Organisms or Cells.” 2012 for various zones of India (http://igmoris.nic.in/ Later in 1990, the Department of Biotechnology (DBT) commercial_approved.asp). Bt cotton shows resistance to developed the rDNA Guidelines (amended in 1994) Lepidopteran insect pests, which cause massive losses, as introducing measures for research and development of high as 80% of the crop to sometimes a total crop failure3. GE crops, their large-scale production, release as well as Remarkably, cultivation of Bt cotton has reduced 95% testing in soil for field scale evaluation. In 1998, DBT of the total insecticide used against these pests. Further, introduced guidelines for biotech plant research which India’s total cotton contribution has risen from 14% involve regulations for import and shipment of GE plants (2002-2003) to 25% (2014) in the world cotton market. for research purpose. The up-dated guidelines are available Similar to Bt cotton, release of Bt brinjal was proposed by on http://igmoris.nic.in/. GEAC. However, the release was blocked in 2010 due to EPA rules in India are enforced by both MoEF and DBT opposition. Bt brinjal was later adopted in Bangladesh in through various authorised bodies. IBSC (Institutional 2013 and it is currently grown in an area about 50,000 ha. Bio-safety Committee) is the first body to review agri- China grows GE crops, including cotton, papaya, poplar, biotech applications for approval. Approved GE product tomato and sweet pepper, on over 4 mha, making China applications are then considered by a Review Committee the sixth largest adopter of GE crops worldwide after US, on Genetic Manipulation (RCGM) for monitoring field 2 Brazil, Argentina, India and Canada . Among other Asian trials and recommendations to the statutory body Genetic countries, Philippines grows GE maize covering 62% of Engineering Appraisal Committee (GEAC) for approval. 2 the total maize area . In addition, the State Biotechnology Coordination At present, approximately 18 prime crops are at various Committees (SBCC) have an important role at state levels. stages of development and/or field trials in India. These include brinjal, cabbage, castor, cauliflower, chickpea, Concerns and the way forward corn, cotton, groundnut, mustard, okra, papaya, potato, Despite demonstrating potential, GE crops have faced rice, rubber, sorghum, sugarcane, tomato and watermelon opposition in many countries across the globe. They have (http://igmoris.nic.in/). These crops have been targeted been perceived by a section of society to be detrimental for improvement in different traits, which preferentially to environment, human health and socioeconomic parity. include resistance to insect pests, viral and fungal diseases, However, scientific data to support these perceived fears tolerance to pesticides, nutritional enhancement, male need to be generated. On the other hand, successful sterility and tolerance to drought/soil salinity. As many as cultivation of large number of GE crops across the world twelve public sectors institutes and universities and sixteen indicates the farmer’s acceptance. While earlier GE different private sector organisations are contributing to crops heavily relied on genes of bacterial origin, such this research in India. genes for improving agronomic traits are now rapidly being identified from plants. With improvement in Regulation of GE crops technology, GE crops are now becoming more precise Biosafety concerns about GE crops are addressed by and free from the baggage of any irrelevant DNA stringent national and international policies and dedicated insertions in the genome. In the last two decades, GE regulatory bodies for research, evaluation and safe use crops have been largely targeted for resistance against across the world. In India, multiple agencies regulate GE herbicides/pesticides or insects. Now, the time is ripe to crops. The first set of regulations related to agri-biotech shift the focus towards engineering plants for drought products was enacted under the Environment Protection tolerance, efficient nutrient use and increased crop yield. Act (EPA), 1986 by the Ministry of Environment and An appropriately streamlined regulation of GE crop

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cultivation and educating the public on GE technology should be discontinued forthwith.” More recently in 2014, should pave the way for acceptance of GE crops. However, NAAS organised a Roundtable Meeting on “GM Crops the cost of regulatory release should be within the limits for Nutritional Security” under the Chairmanship of Dr. of public sector institutions so as to have a larger impact. M.S. Swaminathan and one of its resolutions, states: “The As per one estimate, product development, biosafety present de facto moratorium on field trials of GM crops assessment, commercialisation and public acceptance should be lifted at the earliest. It is putting the clock back (after discovery research/proof-of-concept) may require in relation to progress in harnessing the benefits of GMO an investment of 80 million rupees over seven years. technology in agriculture.” Considering all such views Internationally, the cost is estimated to be about USD 75 and debates, at present, there seems to be a rethink in million over a period of 10 years4. This demands more India in relation to use of GM crop technology. The action financial assistance from government or public-private and effect of the same, however, remains to be seen in the partnership. larger context. India cultivated GM Bt cotton in 2002. In 2009, Bt Internationally also, efforts are being made by policy brinjal was found safe for environmental release by makers to address the issue of GM crops. A detailed GEAC. However, its release did not materialise due report, regarding the advanced genetic techniques for to a moratorium in 2010. A report by six top science crop improvement, its regulation, risk and precaution, academies in December 2010 provided a scientific was provided by the House of Commons Science and analysis in view of the national debate on GM crops Technology Committee in its Fifth Report of session including Bt brinjal. The report includes information on 2014–15. In general, the report highlighted a framework world food requirement, regulatory system, concerns and for transgenic research and their release based on status of GM crops and makes recommendations on the ‘product-based’ rather than ‘process-based’ assessment 7 issue. One of the recommendations states: “After taking with due consideration to risks as well as benefits . It into consideration all available evidences and opinions, says “there is a need to reframe and widen what has been the overwhelming view is that transgenic crops, along a debate about ‘GM’, in order to initiate a new, more with traditional breeding, molecular breeding and other constructive conversation about what we want from food innovative alternatives, should be used for sustainable and agriculture. Only from that can we establish what role agriculture to meet the increasing food, feed and fibre we would like advanced crop breeding approaches to play. demand of the growing population of India.”5 In another We recommend a large scale public dialogue on the future policy paper on “Biosafety Assurance for GM Food of food and farming and a shift in the Government’s own Crops in India”, the National Academy of Agricultural frames of reference regarding these technologies. We also Sciences (NAAS), New Delhi addresses biosafety issues, recommend that the Government clarify its own thinking makes recommendations and suggests action plan for about the precautionary principle, so that it can act as a the development and utilization of GM food crops6. The better guide to policy making.” Committee on Agriculture presented its report to Indian Thus, there is a clear need to communicate the potential Parliament on “Cultivation of Genetically Modified Food benefits, risks and practices of genetically engineered Crops — Prospects and Effects” in 2012 and unanimously crops to all stakeholders of society. Additionally, efforts recommended “that till all the concerns voiced in this need to be made to provide a framework to arrive at Report are fully addressed and decisive action is taken appropriate science based conclusions regarding safety by the Government with utmost promptitude, to put in of such products. Establishment of Biosafety Support place all regulatory, monitoring, oversight, surveillance Unit (BSU) project by the Department of Biotechnology, and other structures, further research and development Government of India, is a step in the right direction. on transgenics in agricultural crops should only be done Taking the proposed Biotechnology Regulatory Authority in strict containment and field trials under any garb of India (BRAI) Bill further will help adequately address

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many issues concerned with GE crops. It also remains 4. Prado, J. R. et al. Genetically engineered crops: from idea to product. to be seen if products generated by gene-editing tools Ann. Rev. Plant Biol. 65, 769–790 (2014) are exempted from regulatory processes applicable to 5. Inter-Academy Report on GM Crops (Updated), December 2010. www.insaindia.org/pdf/Updated_Inter_Academy_on_GM_Crops. 8 genetically engineered crops . pdf 6. Biosafety Assurance for GM Food Crops in India, Policy Paper 52 References (2011) National Academy of Agricultural Sciences, New Delhi. 1. Borlaug, N. E. Ending world hunger. The promise of biotechnology and the threat of antiscience zealotry. Plant Physiol. 124, 487–290 (2000) 7. Advanced Genetic Techniques for Crop Improvement: Regulation, Risk and Precaution (2015) House of Commons Science and 2. James, C. (2014). Global Status of Commercialized Biotech/GM Technology Committee, London. Crops: 2014. ISAAA Brief No. 49. ISAAA: Ithaca, NY. 8. Editorial: Crop conundrum. Nature. 528, 307–308 (2015) 3. Qaim, M. The economics of genetically modified crops. Ann. Rev. Resour. Econ. 1, 665–93 (2009)

28 Biotechnology: An agent for sustainable socio-economic transformation

Forensic science: Why India is rooting for its DNA identification Act

Jayaraman Gowrishankar1 & Madhusudan R. Nandineni1

Bangladesh. The law for enabling DNA identification has been passed by Parliaments of more than sixty nations around the world. There are two major goals commonly sought to be achieved with DNA Acts. The first is enforcement of standards for performance of DNA profiling in and reporting of data by accredited laboratories. This goal is somewhat unexceptionable and indeed required for achieving uniformity to enable the exchange of data across territorial jurisdictions so as to bring international In 2006, the authors, from the Centre for DNA criminals to justice. The second purpose of these Acts is to Fingerprinting and Diagnostics (CDFD) in Hyderabad establish a DNA Data Bank for assisting in identification were invited by the Bangladesh Government to offer of repeat and serial criminal offenders. However, in this training to their personnel in DNA profiling technologies regard, some concerns have been raised related to the for human identification and to assist in establishing possibility of invasion or breach of individual privacy the first s u c h laboratory in Dhaka. Eight years later, rights. In other words, will the likelihood of Government Bangladesh had enacted a law to enable DNA profiling becoming Big Brother increase when DNA Data Banks are applications for criminal and civil investigations. set up? India, however, is yet to have an Act of its own, though a Such concerns have been addressed and allayed on several Bill for the purpose is in the works by the Department of counts in other countries that have passed their own Biotechnology for introduction in Parliament. DNA Acts earlier. First, the DNA profiles to be stored are The value of DNA profiling for individual identification not for an entire population but for specified categories of is so well recognised by the scientific community that any individuals (representing perhaps one percent of the total) argument one makes in support of passage of the DNA — those in conflict with the law, such as convicts Bill in India will be tantamount to preaching to the and suspects of major crimes, and those likely to benefit choir1. As currently practised, the technology is not only by technology, such as relatives of missing persons (so very mature but also highly accurate, to the extent that that their DNA profiles can be compared with profiles of it is often referred to as setting the gold standard in all unidentified deceased individuals). In all cases, other of forensic science2. Since 1994, when the UK was the than convicts and suspects, DNA profiles will be obtained first to pass its law, many other nations have enacted their and stored only with written consent. own. The list includes countries such as USA, Australia, The second and important reason for this expression of Canada, France, Japan, South Korea, and Germany, with confidence against privacy concerns is that DNA markers substantial benefits accruing to all of them in terms of for human identification have been deliberately so chosen solving violent crimes. Similar laws have also been enacted as to reveal nothing about an individual’s characteristics by Algeria, Botswana, Brazil, Chile, China, Colombia, or traits3. They are, hence, also referred to as neutral Egypt, Indonesia, Iran, Libya, Malaysia, Morocco, Namibia, markers. Even as DNA profiling technologies change in Oman, Saudi Arabia, Tanzania, Thailand, Trinidad and future, this feature — that the markers for identification Tobago, Tunisia, Uruguay, Venezuela, Zimbabwe and are neutral — will remain as an inalienable one.

1Staff Scientist, Centre for DNA Fingerprinting & Diagnostics, Hyderabad-500 001, India.

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DNA profiling can be very useful for identification of victims of disasters. Photo shows one of the sites in Uttarakhand state in the Indian Himalayas ravaged by flash floods and landslides that killed thousands of people in June 2013. © Devinder Kumar, CDFD

The Acts also provide for substantial penalties, including diagnostic tests would outnumber those for DNA-based imprisonment for misuse or unauthorised use of samples identification by at least a thousand-fold. collected, or data generated or stored in connection with Historically, the first technology (from the era of 1980s DNA profiling for human identification. In this context, and 90s) to be employed in DNA profiling for individual however, it is worth noting that whereas DNA profile data identification had involved slab gel electrophoresis, are from neutral markers, the samples themselves are Southern blot hybridisation, and detection of products more prone to misuse and to identify theft (because with the use of radioactive chemicals4. Today’s technology one can, with today’s technology, determine the complete involves capillary electrophoresis, polymerase chain genome sequence of an individual from miniscule reactions and detection of products by non-radioactive biological samples). Nevertheless, samples obtained fluorophore-based approaches. For the future, additional for DNA profiling are not the only or even the major new and evolving technologies are being explored and potential culprits in this regard, since biological samples implemented that would be useful for expanded or niche collected by medical laboratories around the country for applications: these include the use of single nucleotide

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polymorphisms (which might have advantages over young man, who is believed to be the same as one who the existing technology when the biological samples to be had jumped parole nine years ago after being convicted tested are very old, degraded, or contaminated) and of and imprisoned for the rape of a foreign national, since next-generation-sequencing, especially with crime-scene no identification records of the convict are now traceable. samples to infer the phenotypic traits of an unknown The convict’s father himself, formerly a top-ranking police assailant (such as race, eye or hair colour)5,6. officer, has declined consent to provide a DNA sample to 7. In such a situation, one Of course, one would be naive to assume that the enactment establish (or exclude) paternity is left to wonder how far the country may need to travel of a DNA Bill for India will serve as a panacea for all ills to ensure that its rule of law exists, not on paper alone, for and deficiencies of its forensic investigation capabilities, uniform application. let alone of its criminal justice delivery system. Two ratios will offer a glimpse of the magnitude of our problem: the In late 2012 and 2013, Bangladesh suffered two horrendous number of cases in which DNA profiling is being currently workplace disasters (fire in a garment factory and collapse undertaken is less than two percent of that in which it is of a commercial building), in which more than 1200 needed; and the sum total of all cases subjected to DNA people died. Bodies of many victims had been charred profiling in the last 20 years is roughly 0.05 percent of that beyond recognition, and compensation claims arising in a country such as the USA (after adjusting for size of from both accidents were also predicated on furnishing of the two populations). Lack of adequate finances is a simple kinship evidence. It is likely that these tragedies provided but insufficient explanation, especially for a nation that a chance for the country’s DNA Act to be drafted and projects itself as being on the threshold of modernization, passed shortly thereafter. One does hope that India also as a ‘shining’ state. It is estimated that the annual passes its own Act soon, without need for the trigger of additional cost for implementing DNA testing for forensic similar tragic events to catalyse the process. investigations in full measure across the country is about References 900 million rupees, i.e. around 14 million US dollars. 1. Jobling MA & Gill P. Encoded evidence: DNA in forensic analysis: Nature Reviews Genetics 5, 739-751 (2004). Thus, the fact is that the Indian system for criminal forensic investigations and policing today is riddled 2. Committee on Identifying the Needs of the Forensic Sciences Community, National Research Council. Strengthening Forensic with inefficiencies, archaic rules and practices, lack of Science in the United States: A Path Forward. ISBN: 0-309-13131-6, professionalism and even integrity, and an absence of a top- http://www.nap.edu/catalog/12589.html (2009). down approach for plan formulation and implementation 3. Kayser M & de Knijff P. Improving human forensics through advances which is most necessary in the present situation. We in genetics, genomics and molecular biology. Nature Reviews Genetics 12, 179-192 (2011). hope that the Indian DNA Identification Act will provide 4. Gill P et al. Forensic application of DNA ‘fingerprints’.Nature , 318, an impetus to shaking up the system so that forensic 577-579 (1985) investigators, police personnel and officers of the judiciary 5. Kayser M. Forensic DNA Phenotyping: Predicting human appearance are all sufficiently educated and motivated to deliver as per from crime scene material for investigative purposes. Forensic Science international norms. International: Genetics 18,33-48 (2015) 6. Børsting C & Morling N. Next generation sequencing and its We cite just one example of a systemic failure here, which applications in forensic genetics. Forensic Science International: would have been farcical were it not true. Law enforcement Genetics 18,78–89 (2015). authorities have been unable to confirm the identity of a 7. https://en.wikipedia.org/wiki/Bitti_Mohanty

31 Biotechnology: An agent for sustainable socio-economic transformation

Bugs, food and intelligence quotients: The complex biology of malnutrition and its consequences

Gagandeep Kang1

Four decades ago, Indian bacteria and its interaction, significantly underestimating scientists showed that the guts the complexity of the human gut microbial ecosystem. The of ‘normal’ Indian children availability of culture-independent approaches to analyse are different from those in the structure and function of microbial communities in more developed countries, the gut is now permitting insights that were previously with the presumed nearly- inaccessible. sterile upper gastrointestinal Recent studies, combining field sample collection from tract colonised with a range healthy and malnourished children with microbiome of anaerobic and aerobic analysis and establishment of model systems, have shown bacteria1. These findings are that the microbiomes in malnourished children are more extreme in malnourished functionally less mature than that in healthy children children and adults r e p o r t e d l y resulting from high of similar age and from similar locations4. Using 16S environmental exposure to pathogens, which not only ribosomal sequencing to identify bacterial taxa in the caused overt diarrhoea but also abnormal architecture of children’s faecal samples, patterns that differed in key the villi and malabsorption of nutrients in a gut colonised taxa between malnourished and healthy children were by bacteria along its length2. High rate of malnutrition detected. Supplementary feeding of these children with was then common in India. Various feeding programmes commercially available or locally made ‘therapeutic’ had been developed and implemented with varying levels foods resulted in some weight gain but not reversal to the of success. level of healthy children or height gain5. The microbiome However, a lot has changed in four decades — the mortality immaturity in the malnourished children showed some due to diarrhoea decreases every year, in part due to better improvement during treatment but regressed within rehydration methods and better access to care. Many months when the feeding was stopped, indicating that the feeding programmes have significantly decreased acute re-programming of the microbiome maturity would not malnutrition —marasmus and kwashiorkor, the forms of be easily achieved by diet alone. severe malnutrition, once common, now rarely occur in most parts of India; but stunting, or reduced height, a The immaturity of the gut microbiome in malnourished sign of chronic malnutrition, is declining much more children may be responsible, in part, for its inability to slowly3. Although nutrition is a matter of eating food and play a role in energy harvest and nutrient assimilation and using it for growth, metabolism and repair, new tools to the consequent lack of effect on stunting. The microbial investigate human biology help in understanding possible flora functions relevant to growth include fermentation of reasons of why the ingestion of adequate energy and dietary polysaccharides, anaerobic metabolism of proteins protein does not necessarily result in an acceleration of and peptides, biosynthesis of vitamins and possibly, the linear growth in stunted children. absorption of ions and regulation of a number of host metabolic pathways. The human gut contains trillions of microbes, which provide several metabolic functions that are not encoded in Data from animal models indicate that the relationship our own genome. Before the development and application between the microbiome, the immune system and intestinal of sequence-based molecular tools for microbiome epithelial cells affects the absorptive capacity of the gut. analysis, culture-based methods were used to identify When B cells, responsible for IgA antibodies acting

1Christian Medical College, Vellore, Tamil Nadu, India.

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as defence at mucosal surfaces, are absent (as in B-cell When a child is sick, the immune system requires knockout mice), there is lower transcription of a large metabolic resources to fight the infection in addition to the number of genes involved in metabolism, especially in demands of the multiplying micro-organisms that cause fat absorption. However, if the gut lacks microbiota, the infection, furthering the nutritional deficit9. Nutrients the effect on fat absorption is lost. Normally, controlling used to fight disease are not available for brain growth and regulating the microbiota are undertaken mainly by resulting in less cognitive development. It has also been IgA but in the absence of IgA this protective response suggested that continued or repeat infections could rewire becomes the role of intestinal epithelial cells, with an metabolic pathways, leading to permanent investment of associated decrease in their metabolic and absorptive more energy in the immune system. Thus, even in the functions6. This may explain why children, who have absence of an infection, fewer nutrients are available for multiple infections or extensive intestinal exposure to brain development. Using available datasets around the microbes, have malnutrition. Thus, the development of a world, scientists have found that countries with high levels functionally mature microbiome in young children might of infectious diseases consistently have lower average require lower exposure to potential pathogens as well as IQ scores. Incredibly, this correlation is stronger than any a diet that provides nutrients for growth and repair. The other measure including education. In some settings with window of opportunity for rebalancing the gut microbiota high rates of infectious diseases, the IQ is up to 20 points is not yet known but will require interventional studies lower than in people in healthier countries. In Asia, for in order to reduce the consequences of early childhood example, Japan, South Korea, Taiwan and Singapore have malnutrition. the highest IQs. In many of these countries, changes in This necessary reduction in stunting is not only important average intelligence have been rapid, increasing by 10–15 to prevent or treat malnutrition, it also has the potential points in a single generation, with education certainly to significantly enhance future human capital. This, given contributing but leaving the possibility that decrease in accumulating evidence that stunting, particularly in the disease and improvement in nutritional status might play first two years of life when brain growth is maximal, affects a role. cognitive development and intelligence. Studies in India While cleaning up the environment, improving hygiene and elsewhere using culturally appropriate tools to assess and food and water safety and education are necessities intelligence have shown that children who are stunted for any nation striving for the health of its population have a lower intelligence quotient (IQ) than children with and economic prosperity, the ability to investigate disease normal growth7, 8. This may affect school performance and pathogenesis and its reversal through intervention in future earning capacity. humans have never been more exciting. This has long This is important not only in the context of the individual been considered challenging because access to the child and his or her family but also at the level of the gut, where infection, absorption and secretion happen, population. Although measuring cognitive development, requires invasive procedures unethical in young children particularly in children, is challenging. Many tools have without major pathology. New imaging and mass- been adapted and validated. The intelligence quotient (IQ) spectrometric techniques are permitting investigation test is used as a measure of cognitive ability. When average of intestinal function in health and disease. Stable IQs are measured for a country or geographic region, it isotope methods enable tracking water and nutrients correlates with many factors including temperature, gross from ingestion to body composition10. The complexity domestic product, secondary education and nutrition. of microbial communities and their functions are Newborns expend the majority of the metabolic output in being resolved through next generation sequencing and developing the brain. A recent hypothesis has proposed bioinformatics analyses11. Multi-modal imaging methods that the absence of infectious diseases allows healthy babies permit quantitative study of structural and functional to have more metabolic energy for cognitive development. brain development in neonates and young children.

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But why bother studying problems such as malnutrition stop eating13. Therefore, the growth of the microbiome that we can largely address without necessarily might participate in appetite regulation. Other studies understanding the biology of disease? It is clear that indicate that short-chain fatty acids produced by colonic the health problems in the future are going to be microbiota stimulate anorexigenic gut hormones and significantly related to lifestyle, particularly activity and increase leptin synthesis14. Metagenomic and biochemical diet relating to the new form of malnutrition-obesity. analyses show that the microbiome of obese individuals Our genomes have been enriched over millennia with has an increased capacity to harvest energy from the diet. alleles favouring energy conservation. Body fat, an energy- Metabolic studies have demonstrated an alteration of the dense disposable reserve, accumulates when nutrients metabolism of bile acids, branched fatty acids, choline, are in excess but its loss is defended against vigorously. vitamins (i.e. niacin), purines, and phenolic compounds Although about 25% of obesity is heritable, genome-wide associated with the obese phenotype. These associations association studies have implicated m o r e t h a n 100 demonstrate consistently that human gut microbial genes that account for a small fraction of obesity12. profiles are altered in malnutrition and metabolic disease, While some hormonal and environmental determinants with decreased diversity and functional richness associated of obesity are clear, the role of the microbiome is being with disordered intestinal function and disease (Figure studied in both animals and humans. In animals, eating 1). However, validation and the establishment of causality increases the number of gut bacteria. Some bacteria are challenging. Among approaches being considered, then produce peptide YY that stimulates the release system biology combined with new experimental of satiety hormones, thus sending a signal to the host to technologies may help to disentangle the complex

Figure 1: Alterations in the gut microbiome affect barrier, immune, permeability and absorptive functions of the intestinal tract.

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Healthy gut environment Altered gut environment

Robust regulation Lack of regulation Healthy development of microbiota Dysbiosis, immature microbiota Tolerance of commensal flora Commensal tolerance lost Barrier protection Impaired innate defences and translocation of microbes Healthy mucus layer Thinner mucus layer Permeability barrier Increased permeability Anti-microbial activity Lack of anti-microbial activity Production of vitamins and short-chain fatty acids (SCFAs) Decreased production of vitamins and SCFAs Absorption of nutrients Impaired absorption Tissue repair Tissue pathology Cell renewal Cell damage

interactions of diet, microbiota and host metabolism. As 4. Ghosh, T. S. et al. Gut microbiomes of Indian children of varying nutritional status. PLoS One. 9, e95547 (2014) in the case of stunting, there are opportunities to explore how sustainable alternations of the microbial flora can 5. Subramanian, S. et al. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature. 510, 417–421 (2014) affect nutrient assimilation or appetite regulation to 6. Shulzhenko, N. et al. Crosstalk between B lymphocytes, microbiota control obesity. and the intestinal epithelium governs immunity versus metabolism in the gut. Nat. Med. 17, 1585–1593 (2011) There is a change in the scale of the challenges in disease biology that we can begin to address using the technologies 7. Ajjampur, S. S. et al. Effect of cryptosporidial and giardial diarrhoea on social maturity, intelligence and physical growth in children in now available and in development. Well-designed studies a semi-urban slum in south India. Ann. Trop. Pediatr. 31, 205–212 that bring together complementary skills in medicine, (2011) science and analytics will generate new insights that 8. Kvestad, I. et al. Diarrhea, stimulation and growth predict neurodevelopment in young North Indian children. PLoS One. 10, offer the opportunity for a deeper understanding of the e0121743 (2015) biology of malnutrition and its consequences. These are 9. Eppig, C. et al. Parasite prevalence and the worldwide distribution of large problems that require scientists to harness curiosity cognitive ability. Proc. Biol. Sci. 277, 3801–3808 (2010) and explore the mechanisms by which a pathologic state is 10. Borgonha, S. et al. Total body water measurements by deuterium created and can be corrected. The consequences of success dilution in adult Indian males and females. Indian J. Physiol. for science, medicine and society will be tremendous. Pharmacol. 41, 47–51 (1997) 11. Gupta, S. S. et al. Metagenome of the gut of a malnourished child. Gut References Pathog. 3, 7 (2011) 1. Albert, M. J. et al. Jejunal microbial flora of southern Indian infants in 12. Apalasamy, Y. D. et al. Obesity and genomics: role of technology in health and with acute gastroenteritis. J. Med. Microbiol. 11, 433–440 unravelling the complex genetic architecture of obesity. Hum. Genet. (1978) 134, 361–374 (2015) 2. Baker, S. J. Subclinical intestinal malabsorption in developing 13. Breton, J. et al. Gut commensal E. coli proteins activate host satiety countries. Bull World Health Organ. 54, 485–494 (1976) pathways following nutrient-induced bacterial growth. Cell Metab. pii: S1550–4131(15), 00566–5 (2015) 3. Rehman, A. M. et al. Chronic growth faltering amongst a birth cohort of Indian children begins prior to weaning and is highly prevalent at 14. Chakraborti, C. K. et al. New-found link between microbiota and three years of age. Nutr. J. 8, 44 (2009) obesity. World J. Gastrointest. Pathophysiol. 6, 110–119 (2015)

35 Biotechnology: An agent for sustainable socio-economic transformation

Green medicine: The next big thing?

Ram Vishwakarma1

Modern medicine stands out heart disease, cancer, diabetes, Alzheimer’s and other as one of the most remarkable diseases — without a clear causal mechanism remains far human achievements of from satisfactory. Therefore, sustainability and limits of the last 100 years — a the current model are now being questioned, and a space result of synergy between for integration of concepts/drugs and practices of age-old multidisciplinary sciences1, alternative traditional systems (e.g. TCM and Ayurveda) where diverse disciplines has been created. Interestingly, these arguments are of chemical, biological and being encouraged by new scientific discoveries in clinical sciences enabled network pharmacology of natural products2 and the role discovery of life-saving of food constituents in health homeostasis and disease drugs (small molecules and progression3. This new paradigm of medicine is referred to biologicals), vaccines, diagnostics and surgical procedures. as “Green Medicine”, where ideas from advances in disease This silent revolution has brought a dramatic increase in life biology, network pharmacology and wisdom or concepts expectancy and quality of life, which in turn enables rapid of indigenous medicine are harnessed for next- generation economic development and prosperity across the globe. medication and practices. This focuses more on stimulating The current drug discovery model has been remarkably the body’s own resources and extraordinary ability to successful in harnessing the new knowledge of disease repair and rebuild tissues and organs to prevent or reverse biology in identifying/validating new targets amenable illnesses, rather than a single-gene/single-protein/single- to intervention by small organic molecules or protein inhibitor approach. These new ideas aimed at chronic and therapeutics. In addition, this reductionist approach lifestyle related diseases are emerging at an opportune (high affinity targeting of enzymes and receptors), time when the biotechnology revolution (genomics and coupled with the newly acquired chemical ability to systems biology) is maturing to set the stage for this 3rd control the drug-like properties (solubility, membrane revolution in medicine4. permeability, pharmacokinetics and oral-bioavailability) Historically, modern medicine has drawn heavily from led to the discovery of second-generation “best-in-class” indigenous systems of medicine practiced worldwide. therapeutics based on the original pharmacophores. From a quick overview of the history of modern medicine Later, advances in biotechnology (molecular cell biology (USFDA Orange Book), it becomes obvious that most and immunology) provided newer insights in disease of the “first-in-class” drugs and pharmacophores biology, which in turn gave birth to the second revolution in (antibiotics, anticancer, anti-diabetic, CNS, blood- medicine (monoclonal antibodies and growth hormones). pressure and cholesterol lowering, immunosuppressant Much of the credit for these discoveries must go to a and antimalarial) were discovered through exploration sustainable collaborative model, which evolved between of biodiversity (medicinal plants and microorganisms) leading universities, medical hospitals and pharmaceutical — many of them with recorded use of hundreds of years companies in the Western countries, suitably enabled in traditional medicine. If one follows the scientific by regulatory and market mechanisms. This so-called threads of the discovery of most of the “magic bullets” we “reductionist discovery paradigm” has achieved great take for granted (such as aspirin, ephedrine, morphine, success in fighting infectious diseases(parasitic, bacterial quinine, vincristine, reserpine, camptothecin, colchicine, and viral). Yet managing chronic, complex diseases — taxol, brevetoxin, cyclosporine, FK-506, rapamycin,

1CSIR — Indian Institute of Integrative Medicine, Jammu 180001, India.

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podophyllotoxin, artemisinin, ivermectin and many microbial and marine biodiversity for finding solutions to more), the root of discovery invariably leads to a traditional chronic diseases afflicting India and the rest of humanity. system of medicine (Indian, Chinese, African or South However, this will require continued and even greater American) or longstanding empirical observations by funding support, integration with global discovery system, tribal populations. During the development process, the a roadmap and strategy for critical resources and expertise initial natural leads were invariably modified by medicinal and enabling regulatory pathway for preclinical and chemistry to achieve desired PK profile, safety and efficacy. clinical development of new discoveries of NCEs as well Perhaps, one of best example of this lineage of modern as botanical/herbal drugs. As the new advances in biology, medicine with biodiversity is the natural product lovastatin pharmacology and chemistry are ushering in a new era of from a fungus in Japan as potent HMG-CoA reductase medicine, there are few specific areas which are opening up inhibitor, followed by the development of the blockbuster entirely new opportunities for next-generation medicines. cholesterol-lowering statin drug Atorvastatin (Lipitor). Some of these new areas deserve special attention by DBT The journeys of the natural products used in various in coming years. traditional systems of medicine have been remarkable, enriching chemistry and interfacing biology (nucleic Small molecule natural products in acids, proteins, carbohydrates, lipids, vitamins, hormones regenerative medicine and neurotransmitters). Therefore, it is no surprise that Treatment of chronic diseases (cardiovascular, over 50% of USFDA approved small molecule drugs are neurodegenerative, musculoskeletal, diabetes and cancer) directly derived or inspired by natural pharmacophores. depends on our ability to control cell fate, allogenic Case studies of some of the recently approved drugs, e.g. rejection and access to selectively differentiated stem cells. fingolimod, eribulin and yondelis, are indicative of this Cell-based phenotypic and pathway specific screening of trajectory. With such a remarkable track record, that too natural products and their synthetic analogues provide with rudimentary tools and limited understanding of a great new opportunity to selectively control stem cell disease biology, it can be safely predicted that plant and proliferation, differentiation and de-differentiation. microbial biodiversity, coupled with their recorded use in Recent results5 show great promise in discovering effective the indigenous medicine, will remain a treasure trove for medicines for tissue repair and regeneration. A recent green medicine. example6 — where the key transcription factors could As we celebrate the 30 years of the Department of be replaced with small organic molecules (including Biotechnology — which has so assiduously and generously Indian natural product Forskolin) for reprogramming of nurtured the diverse areas of disease biology, plant pluripotent stem cells from somatic cells — indicates the and microbial biotechnology — the opportunities for future for regenerative medicine. If the natural resources addressing more challenging issues of chronic diseases are are coupled with stem cell biology, very exciting science at hand in India. On hindsight, it looks pretty remarkable and new therapeutics will emerge. that DBT actually rescued the area of “medicinal plants Protein structure similarity clustering and fold- and natural products chemistry” in late the 1980s — ironically, when other primary sources of PI-driven based identification of bioactive scaffolds funding were turning hostile to this sub-field in which Bioactive secondary metabolites from plants and microbes India once had global leadership position. The DBT recognise three sets of proteins: the first comprises the task-forces for medicinal plants and plant biotechnology enzymes involved in their biosynthesis, the second involved played an important role in sustaining research in this in their transport (e.g. ABC transporters and PGPs) and area, which is now turning out to be a game changer for the third being the target protein(s) they activate/inhibit. next generation medicines. Today, India is in a strong Evidence reveals that these metabolites exhibit individual position to harmonise modern medicine with age-old preference for binding proteins of same fold, irrespective indigenous systems of medicine and harness rich plant, of sequence or function7. Examples of proteins of different

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sequence and function sharing the fold similarity and consequences for the questions such as: How do natural being inhibited by the same metabolite are emerging; this products (mostly chiral) arise in evolution and adapt to presents an opportunity for classifying proteins on the diverse functions? How they are synthesised and how basis of fold similarity and look for (in silico) small natural the rate and timing of their production is controlled? molecules interacting with them, providing rational basis Eventually, some of these discoveries will be translated for new drug discovery and design. to new medicines.

Inhibition of therapeutically important Novel probes and reagents to decipher protein- protein interactions membrane and cell biology Most of the events in cell biology and immunology are The reversible modulation of the processes, such as driven by protein-protein interactions that are specific plasma membrane organisation of signalling platforms, and tightly regulated. The small molecule natural products GPI mediated anchoring of surface proteins, endocytosis, have evolved in biological systems precisely for regulating trafficking and translocation of nuclear receptors, is the these so-called “non-druggable” events. Finding natural best done through chemical biology approaches. Since inhibitors of such therapeutically important protein- living systems are highly dynamic and synchronised, protein interactions (e.g. IL1-IL1R, TNF trimerisation, there is need of small molecule probes for real time nuclear-receptor association and translocation) is quantification of enzyme activities and receptor turnover. considered to be the “holy grail” of drug discovery. Efforts Since many natural products are transported through through natural products chemistry could be rewarding active mechanisms specific to individual pathways, there for the identification of hot-spots of interaction and are great opportunities in this area of cell biology, which designing oral therapies. Since natural products are will be starting points for systems biology modulation and designed to interact with proteins, there is an opportunity drug discovery. for discovery of inhibitors of therapeutically important protein-protein interactions8. Network pharmacology: less for more In a new approach to target complex multi-factor diseases, Chemical ecology: new ideas for green such as diabetes and age-related neurodegenerative medicine disorders, it is possible2 to engage a number of protein Chemical ecology is a new discipline driven by the targets involved in one major pathway (e.g. PI3K/AKT/ recognition that organisms (plants, microbes, insects mTOR axis) through a number of low affinity ligands or mammals) invariably use small-molecules to and derive overall aggregate high affinity (nanomolar) communicate with each other in diverse ways (smell, response enough to impact on disease progression. This taste, vision, mating, symbiosis, deterrence, pathology polypharmacology approach appears to be a way forward and pharmacology)9. Since the vocabulary of living for complex diseases of multiple aetiologies. Many of the things is overwhelmingly chemical, it is believed that natural product constituents of food products need to be the understanding of the information content of the looked at from this perspective to tailor person specific mediating molecules is going to radically change the diets and medications3. A recent example10 of linking gut way we look at mechanism of biological communication microbiome, food ingredients and glycaemic control in and species survival. Despite ideal biodiversity and diabetes patients is hinting towards a new direction to ecosystems, surprisingly no efforts have been made in manage chronic diseases. India in this area. First welcome step towards this new frontier is a major programme launched by DBT in 2015 Allosteric vs. competitive inhibitors (through the efforts of late KS Krishnan), networking The current model for drug design has so far had overt many investigators from the North East region and emphasis on high affinity competitive inhibitors that Bangalore Biocluster. These studies may have far reaching target either the active catalytic site of an enzyme or ligand

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binding site of a receptor, leading to off-target liabilities. National repository of natural products However, natural products are designed by evolution For the success of almost all the areas mentioned above, to interact more often with the allosteric sites of protein there is an urgent need to establish a national repository of targets (e.g. rapamycin targeting mTOR), and this specific natural products, which will have pure natural products, feature has not been leveraged in targeting “un-druggable” purified fractions with biomarkers and standardised proteins. Other than the natural products from terrestrial extracts as per pharmacopeia guidelines. Such a resource plants and microbes, marine biodiversity offers huge is absolutely essential for translational efforts. untapped potential for discovering allosteric modulator of protein targets and assemblies11. Isoform selectivity holds In conclusion, it is worth mentioning that there is now far the key to understand redundancy in biological system greater appreciation worldwide of the potential of “green and most isoform selective inhibitors are invariable of medicine,” where nature is looked at the ultimate source natural origin. for inspiration and solution to the problems of health and disease, with integration of indigenous systems with Diversity oriented synthesis around approved modern medicine. In this regard, the decisions by US- drug-like scaffolds FDA and recently by Indian DCGI to create a regulatory approval pathway for botanical and phytopharmaceutical Since natural products occupy biologically relevant drugs are important milestones12. chemical space, they are endowed with the ability to bind to their biosynthetic enzymes as well as to their target References macromolecules. Natural products are the libraries of pre- 1. Goodman & Gilman’s Pharmacological Basis of Therapeutics, 12th Ed, validated, functionally diverse structures, where a single Bruton, L. L., Chabner, B. A. & Knollmann, B. C., Eds. McGraw-Hill (2011) substance selectively modulates a number of unrelated 2. Kibble, M. el al. Network pharmacology applications to map the unexplored target space and therapeutic potential of natural macromolecular and cellular targets. Hence, diversity- products. Nat. Prod. Rep. 32, 1249-1266 (2015) oriented synthesis offers great opportunities for discovery 3. Special issue Food and Biology. Cell. 161, 1–175 (2015) of new pharmacological activities starting from a common 4. Harvey, A. L. et al. Nature Rev. Drug Discov. 14, 111–129 (2015) scaffold. DOS libraries are to be screened against new and 5. Zhu, S. et al. Chemical strategies for stem cell biology and clinically validated drug targets such as the RTKs, GPCRs regenerative medicine. Ann. Rev. Biomed. Engg. 13, 73–90 (2011) and phenotypic end-points 6. Hou, P. et al. Pluripotent stem cells induced from mouse somatic cells by small molecule compounds. Science. 341, 651–654 (2013) Biocatalysis for green medicine 7. Van Hatten, H. & Waldmann, H. Biology oriented synthesis: Harnessing the power of evolution. J. Am. Chem. Soc. 126, 11853– 11859 (2014) Since more than 80% of globally produced organic 8. Milroy, L-G. et al. Modulators of protein-protein interactions. molecules are made using catalytic processes, the Chem. Rev. 114, 4695–4748 (2014) importance of efficient biological catalysis is continuously 9. Special issue Chemical Ecology. Nat. Prod. Rep. 32, 886–1379 (2015) increasing. Extremophiles (bacteria and fungi) provide 10. Zeevi, D. et al. Personalized nutrition by prediction of glycemic an ideal setting for discovery of such robust biocatalysts, responses. Cell. 163, 1079–1094 (2015) which can further be improved through directed evolution 11. Bharate, S. B. et al. Kinase inhibitors of marine origin. Chem. Rev. 113, 6761–6815 (2013) and structural biology approaches. This approach may also 12. Botanical Drug Development, Guidance for Industry, US-FDA and enable incorporation of caged amino-acids and co-factors the new “Phytopharmaceutical drugs” guidelines notified by DCGI through synthetic and genetic methods. (Govt. of India) (2015)

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Frugal medical innovations: Vision 1010 for maladies of India

Prashant Jha1 & Balram Bhargava2

We will not make any fuss • BioScoop: Contactless, self-sealing biopsy of solid about accepting India’s organs weakness upfront. Yes, • Sohum: A handheld neonatal auditory screening our healthcare is afflicted device by almost every malady. Health indices of India are An interesting pattern begins to emerge when you look at the receiving end of every at these medical devices. Healthcare challenges that are analysis1. Just when we have unmet because of prohibitive costs of technologies can managed to declare a win be solved within constraints of money, time, skills and against polio, we seem to be materials. When solutions come that way, they lead to losing the battle against every game-changing innovations. While the general perception imaginable disease — tuberculosis, diarrhoea, diabetes, is that cheaper is poorer, when a product is engineered to obesity and hypertension. meet the constraints of cost, skill and time, it is not only cheap, but also better. A testimony to this is the USFDA Is there any hope? Yes, absolutely. This belief sprouts from clearance to Consure4. our success in running the Biodesign programme at the All India Institute of Medical Sciences (AIIMS) — modelled We read several reports comparing the spending on on the Stanford’s Biodesign programme that professes healthcare as a percentage of GDP; we often hear that need-driven innovations, aptly captured by Edison’s India’s spending statistics stack poorly against the Wests statement: “Anything that won’t sell, I don’t want to in general and the United States in particular. The invent.”2 In the last eight years of running this programme immediate questions that come to mind is whether higher in partnership with Stanford, we have added a value- spending in healthcare has led to a healthier population focus to the programme centred around the Gandhian in those countries. Has it led to higher satisfaction philosophy of “The world has enough for everyone’s need towards healthcare services in the US? While one would but not for everyone’s greed.” In a classic case of east-to- extrapolate the higher spending to better outcomes, the west diffusion, the Stanford Biodesign programme has ground reality is just the opposite. In fact, ‘ObamaCare’ or now shifted its focus on bringing down healthcare costs3. affordable healthcare is the buzzword among the decision Some of the key innovations (www.sibiodesign.net/ makers in America. While there is no denying the fact that product) from the School of International Biodesign India must increase spending on healthcare, we must not symbolise a frugal take on key healthcare challenges: take the same direction that the Western world took a few decades ago — that more is better. • Consure: A faecal catheter that reduces cost of managing faecal incontinence Instead, we must learn from the mistakes they made and define our own paradigm — more for less for more. If we • Windmill: Single-operator foetal resuscitator were to leapfrog this and create our own paradigms of • ReliGO: Cardboard splint for stabilisation of lower healthcare spending, we could emerge as a global Guru limb fractures in rational spending in healthcare and invention driven • BRUN: Labour monitoring tools for everyone — by need, not greed. The hopes we are trying to project every bed is an ICU are based on some incredible success that India has

1Fellowship Director & 2Professor of Cardiology and Executive Director, School of International Biodesign at All India Institute of Medical Sciences, New Delhi, India.

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achieved in last two decades. As a nation, we leapfrogged high. Not only have they charted new paths, they have the pandemic of over-priced medicines by shrugging also created jobs for fellow countrymen. away the western-way of monopolies and evergreening • Share knowledge: While technical know-how must of pharmaceutical intellectual property. We have found be protected to reward the innovator, there should our own solution — ‘generics’. It was the Indian industry be a trustworthy system that encourages people embracing generics that served the entire developing to share knowledge and gives credit to deserving 5 world . India is now the ‘Pharmacy of the World’. We candidates. Intellectual conservatism of wisdom must dream for a future, where we would be the world leader be discouraged. Sharing wisdom — of success and in generic medical devices. failure alike — breeds an ecosystem. Here we share three formulae from our playbook for Vision 1010: If we were to create ten devices that impact achieving this goal: ten million patients in the next ten years, we would have • Break silos: Deeply ingrained in our education system to set the frugal medical device ecosystem in India in is the creation of silos. An engineering institution is perpetual motion. a university in its own and so is a medical college. DBT has been very instrumental in bringing IIT References 1. http://mospi.nic.in/Mospi_New/upload/Manual-Health- Delhi and AIIMS together, and the results speak for Statistics_5june15.pdf (Accessed: Dec 31, 2015) themselves. 2. www.thomasedison.org/index.php/education/edison-quotes/ • Kindle the entrepreneurial appetite in youth: Our (Accessed on Dec 30, 2015) experiences have taught us that whenever we have 3. http://news.stanford.edu/features/2015/biodesign/ (Accessed on Dec 31, 2015) brought young physicians, engineers, designers and 4. http://www.accessdata.fda.gov/cdrh_docs/pdf13/k133465.pdf researchers together, it has worked like magic in (Accessed on Dec 31, 2015) creating novel solutions. Whenever we have given 5. http://www.assocham.org/newsdetail.php?id=5196 (Accessed on Dec them the wings of entrepreneurship, they have soared 31, 2015)

41 Biotechnology: An agent for sustainable socio-economic transformation

The TB battle: How well are we fighting the bug?

Jaya Sivaswami Tyagi1

Figure 1

The year 2015 is a milestone year in the worldwide war against TB — it is the last year of the Stop TB Strategy before adoption of the 20- year End TB Strategy, whose goal is to end the global TB epidemic by the year 20351. In the Indian context, this is certainly a daunting task, considering that India figures

in WHO’s three new High Burden Country Lists for TB, Figure 1: Global projections of TB incidence – 2015 to 2035. TB/HIV and MDR-TB. The adoption of existing and new tools is crucial to achieving an accelerated rate of decline in incidence to end the TB epidemic. India’s fight against TB control was initiated in 1906 with (Source: WHO End TB Strategy, 2014). the establishment of the Mary Wilson TB sanatorium in Tilaunia, Rajasthan. Treatment modalities changed with the advent of chemotherapy and evolved over clos e to Koch’s discovery of the TB bug in 1882. It became evident 90 years into the present day DOTS treatment strategy that a cocktail of eminently suitable for rapid spread that is incorporated into the Revised National TB Control of the bug. Subsequent to acquiring an infection, two Programme (RNTCP)2. The RNTCP covered the entire alternative outcomes are possible, namely frank disease country by 2006. Yet, India has the world’s largest number or latent infection, reflecting the remarkable plasticity of of TB cases at 23% of the global total. Although lakhs of interaction between human host and TB pathogen. A lives are saved, both the annual mortality (due to TB) robust immunity is associated with bacterial adaptation and incidence rate remain very high at over 200,000 and to a dormant quiescent state, often leading to a lifelong 167 cases per 100,000 population, respectively3. It is now latent infection. However, when a lowering of immunity evident more than ever before that the battle against TB occurs, reactivation of the disease takes place. According is to be fought on several fronts and extends beyond to WHO estimates, one-third of the world’s population and implementation of biomedical strategies. A multipronged 40% of India’s population play host to the TB bacillus as and accelerated approach with enhanced resources is a latent TB infection, highlighting the magnitude of the necessary to meet the targets of the End TB Strategy, problem in high burden countries. Thus, it stands to namely to reduce TB deaths by 95% and bring down reason that eradication of latent infection holds the key to new cases by 90% till 2035 (Figure 1). TB elimination. Also, despite the availability of anti-TB drugs, the long duration of treatment is often associated Knowing the enemy: the TB conundrum with poor compliance resulting in incomplete cures and the Our current appreciation of the complex challenges development and spread of drug resistance. This emphases in TB control stems from a rich legacy of public health the need to shorten treatment duration. Moreover, experiences and research that commenced with Robert persistent organisms are poorly cleared by standard therapy,

1Department of Biotechnology, All India Institute of Medical Sciences, New Delhi-110029, India.

42 Biotechnology: An agent for sustainable socio-economic transformation

Figure 2

2 Biomedical tools, interventions and strategies 13 Integrated, Bold for TB control patient‐ policies and Intensified centered supportive research TB care systems and Pillar 3 of the WHO End TB Strategy recognises the need and innovation prevention for intensified research to achieve the goal of ending the global TB epidemic. Priority R&D areas include understanding pathogenesis and immunity, developing PoC diagnostic tests including triage test and one for latent TB, vaccines that protect people of all ages against TB, new therapeutics and novel regimens to combat the challenges of drug resistance, to shorten treatment and to cure LTBI, and importantly, implementing research to facilitate the adoption of new tools by the control programmes. Figure 2: The 3 Pillars and 4 Principles of WHO End TB Strategy. Significant progress has been made, and several useful A multi-pronged approach requires to be adopted for ending the tools are in the pipeline and in various stages of testing5. global TB epidemic by 2035. A boost in research funds by closing funding gaps and clear pathways for translation are immediate needs for underscoring the requirement for new drugs that target development and rapid uptake of new tools. persistent/dormant bacteria. Other factors also fuel the Early contributions to TB control from India TB epidemic and lead to the progression of a latent TB infection to active disease. These include malnutrition, Landmark studies from India have made lasting lowered immunity (e.g. as in HIV infection, ageing, contributions to the development of TB control strategies diabetes, smoking and silicosis), environmental factors worldwide. Indian studies demonstrated for the first time the efficacy of chemotherapy in a domiciliary (e.g. indoor air pollution, inadequate ventilation), and setting in lieu of sanatoria-based treatment. This finding socio-economic conditions like poverty, urbanisation revolutionised the outlook towards TB treatment and and overcrowding. Thus, while diagnosis and treatment enabled the formulation of the DOTS programme used are undoubtedly the cornerstones of TB control by the worldwide. The utility of microscopy for case finding and medical approach, social, sanitation and public health the efficacy of Short Course Chemotherapy, with drugs interventions, along with improved standards of diet and administered on an intermittent basis were also first living can contribute significantly to the decline of TB, as demonstrated in India. Another notable contribution was documented in records from the pre-chemotherapy era4. in the area of vaccine efficacy analysis. The efficacy of the In recognition of the enormous scale and complexity of this mass BCG campaign started from 1951 was questioned public health problem and towards ending the global TB when the results of a meticulously designed BCG vaccine epidemic by 2035 (less than 10 cases per 100,000 persons clinical trial in Chingleput district, Tamil Nadu were per year), the End TB Strategy of WHO proposes a three- decoded in 1980, revealing that the vaccine did not offer pillared integrated approach. It includes providing patient- protection against pulmonary TB. Following extensive centred care and prevention, combining universal health review, the mass BCG campaign was dropped but coverage policy and social protection, and intensified continued in children to afford protection against serious research for discovery of new tools, interventions and childhood forms of TB. The three national TB institutes strategies and their rapid implementation (Figure 2). In play a pivotal role in various aspects of TB control such as this context, it is heartening that many leads generated by programme development, training and capacity building, TB researchers in India have the potential to be translated developing laboratory tools, providing quality assurance, into useful tools towards fulfilling the mandate of the End assessing disease burden, monitoring of the programme TB Strategy. and influencing TB control policies2, 6.

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Research in the post-genomic era been generated in laboratories through funding support of various agencies. Many of these have the potential for Research contributions from a large number of Indian progressing to novel tools for TB control. Sustained effort groups over recent years, particularly since the TB genome on the part of researchers, combined with the assured was decoded, have greatly enhanced our understanding commitment of funding agencies including biosafety of biochemical, physiological and metabolic processes laboratory support, will be needed to fulfil the target. In in the tubercle bacillus. Noteworthy contributions have addition, a clear pathway is needed to guide tool-specific been made in many areas including DNA replication, translation of laboratory findings, including interactions transcription, translation and recombination processes with the RNTCP and national TB laboratories. Several and mechanisms, deciphering of gene regulatory, redox Indian institutions and Industries are actively engaged in and metabolic control strategies, lipid and polyphosphate developing these tools. More efforts are required to make metabolism, bacterial adaptation to stresses and an impact. And it is urgent because the development signalling mechanisms, molecular basis of host-pathogen and adoption of new tools and interventions constitute interactions and the strategies used by both to subvert each an essential pillar of the End TB Strategy, without which other, dormancy and biofilm models to study bacterial the goal of ending the TB epidemic is likely to remain a adaptation, immune signalling mechanisms, systems mission impossible. biology and molecular genetic approaches to identify novel drug targets and mechanisms of drug resistance, and also References identification of host factors as novel intervention targets 1. World Health Organization. The End TB Strategy. Global strategy and targets for tuberculosis prevention care and control after against TB. Structures have been elucidated for a large 2015. (Available from: http://www.who.int/tb/post2015_TBstrategy. number of TB proteins. These span almost all the pathway pdf ?ua=12014) categories and offer ample opportunities for rational drug 2. Agarwal, S. P. et al. The history of tuberculosis control in India: design to fight the TB bug. These efforts are summarised in Glimpses through decades. Tuberculosis Control in India. 15-22 (2005) comprehensive publications7, 8, 9. 3. WHO Global Tuberculosis Report, 2015 (Available from http://www. who.int/tb/publications/global_report/en/) Concluding remarks 4. Ortblad, K. F. et al. Stopping tuberculosis: a biosocial model for sustainable development. Lancet. 15, 00324–4 (2015) Lasting contributions made by Indian biomedical scientists 5. WHO, The global plan to stop TB 2011-2015: Transforming the fight in formulating control strategies in previous years were towards elimination of tuberculosis. WHO Stop TB Partnership (2010) possible due to concerted efforts by all stakeholders in http://apps.who.int/iris/ handle/10665/44437#sthash.FcRQMu0W. dpuf an environment of commitment and urgency to mitigate 6. Agarwal, S. P. et al. The role of the national institutes in tuberculosis the TB public health problem. Several decades later and Control. Tuberculosis Control in India. 78-94 (2005) despite programmatic efforts, TB remains a public health 7. Tyagi, A. K. & Dhar, N. Recent advances in tuberculosis research in challenge, and not surprisingly, the End TB Strategy calls India. Adv. in Biochem. Engg. Biotechnol. 84, 211–273 (2003) for an integrated approach that encompasses biomedical, 8. Special section: TB in India. Tuberculosis. 91, 343–496 (2011) public health and social measures. Original leads have 9. Special section on Tuberculosis. Current Science. 105, 594–675 (2013)

44 Biotechnology: An agent for sustainable socio-economic transformation

Big data for a big country: Mind the gap

Binay Panda1, 2

The advent of high-throughput (GTEx) and future large population-wide programmes, technology for nucleic acids, will touch hundreds of petabytes by 2025. Dealing with proteins and metabolite this unprecedented scale and pace (velocity) of data profiling has revolutionised production will require precise and accurate solutions for life science research. In the data storage, analysis, sharing and security. Additionally, last five years, experiments the heterogeneous nature, multi-dimensionality and on individual exomes, the complexity of biological data will require deep genomes, transcriptomes, understanding of multiple quantitative domains like epigenomes, proteomes and mathematics, computer science, physics, statistics and metabolomes have produced information technology, outside of biology, medicine and data in the scale of petabytes. agriculture. The unprecedented scale at which data is being generated What can India learn from the past efforts elsewhere and in genome science requires large compute power to store how can scientists and institutions in India prepare to and analyse such data. For example, it is estimated that deal with large amounts of data? We will need to build 21 10 supercomputers are required to store the total amount infrastructure at multiple levels, both local and in cloud 1 of information encoded in DNA of the biosphere . (Figure 1), to deal with data at this massive scale. Firstly, Furthermore, some anticipate that the computing we need to put processes to check sample quality at the resources needed to handle genome data will exceed that source (hospitals, research universities and institutions). of the social networking site Twitter and the popular Once the genome centres get good quality samples they 2 video sharing website YouTube .While providing answers need to produce high quality sequence data, which to to many of the puzzling and unanswered questions in a large extent is resolved by the instrumentations and biology is now possible using the high-throughput tools biological assays available from commercial vendors. and the data that they generate, dealing effectively with the Second, there would be need to build hardware and cloud data deluge and making biological meaning out of it will computing infrastructure for effectively storing, securely require eclectic solutions. For the first time in biology, the sharing and transferring information from the genome cost of data storage and computing is set to overcome the centres to a centrally managed server. Third, we need cost of data production. to design user-friendly and intuitive software, allowing It is important to understand the scale and volume of researchers to perform smart analysis, visualisation and the data before we discuss solutions. For example, the interpretation of data. Fourth, we need to build robust Pan-Cancer Analysis of Whole Genomes (PCAWG) databases towards collaboration, data sharing securely project of the International Cancer Genome Consortium for a wider dissemination. Last, and equally important, (ICGC) and The Cancer Genome Atlas (TCGA) project will be to create policies and ethical guidelines for data are coordinating analysis of more than 2,800 cancer whole sharing, protection standards with proper encryption genomes to make the data available over cloud. Genome and authentication safeguards and ownership. In this along with other high-throughput data and associated context, we can learn and follow policies and guidelines metadata from this effort alone will run into several put together by consortia like the Global Alliance for petabytes. Data from cancer consortia along with data Genomics and Health (https://genomicsandhealth.org). from other large consortia, like the Exome Aggregation What is the status of India's infrastructure and how do we Consortium (ExAC), the Genotype-Tissue Expression plan to deal with the challenges? Whether one supports

1Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, & 2Strand Life Sciences, Bangalore, India ([email protected]).

45 Biotechnology: An agent for sustainable socio-economic transformation

Figure 1: Infrastructure requirement for big data in life sciences research

India’s involvement in large sequencing projects or vendors who are helping manage a large amount of data3, not, we need to be ready to utilise the data coming out easier download and analysis. India’s strengths in fields from genome centres. In case of India-centric diseases like, frameworks and models, data-and metadata mining and population-specific genetic variations, we need to and management, design and integration of platforms, generate our own data. The price for generating genome- parallel and distributed systems and database design and scale sequencing information has come down drastically implementation will come handy in optimising low-cost (below 1 lakh rupees in reagent cost for sequencing a design, infrastructure and protocols for data storage and single human genome at 30X coverage). India needs to sharing. By leveraging the best practices in information focus on developing inexpensive hardware and assays technology, India can thus create an infrastructure but for sequencing smaller genomes and/or a small number can also be a global leader in inexpensive design of this of genes in human genome for clinical applications. India infrastructure (both at local level and in cloud) for data 21 also needs to focus on building databases. We need to analysis, sharing and security at Zettabyte (10 bytes) or 24 build India-centric diseases and mirror genomic data even Yottabyte (10 bytes) scale. present in large databases outside of India, for example None of these is possible without high-bandwidth the national centre for biological information (NCBI) in connectivity and proper policy framework. The USA the European Bioinformatics Institute (EBI) and Government’s initiatives on digital India (DI), Internet DNA Data Bank of Japan (DDBJ) for faster download of things (IoT) and infrastructure initiatives like national of sequence information. The databases need to link the knowledge network (NKN) to connect the educational vast amount of data currently stored outside government- and research institutions and universities, will help in supported centres like NCBI, primarily with commercial realising the dream of accessing big data anywhere and

46 Biotechnology: An agent for sustainable socio-economic transformation

everywhere. However, solving big data problem to enhance spur innovation. Government needs to engage with the innovation in biotechnology is not attainable without industry in order for the fruits of big data in biology to a proper big data policy from the Government and an reach the citizens through products and services. In order institution that can store, archive and hold all the research for this to happen, the industry needs to see a financial data. Setting up a nodal institution under the Department incentive. While engaging positively and encouraging of Biotechnology to administer, store, archive and make entrepreneurship through various schemes in the areas of big data in biotechnology widely available/accessible big data in medicine and agriculture, Government must should be a priority. Such an institution should follow a make sure that the information for a common Indian is hub and spoke model. Institutions around the country, utilised ethically and within a proper legal, cultural and the data generating ones (the spokes) will generate and financial framework. In molecular medicine, for example, transfer data to this central institution, which will then be the three important stakeholders, government, industry 4 responsible for quality control of the data, building proper and academia, have to work together and in synergy . and long-term infrastructure for data archiving, building In an interconnected world knowledge is no longer the databases, making data sharing protocols on the cloud monopoly of a selected few. You don't have to attend the and data availability across the country. Additionally, best universities to learn from the best professors; nor the government needs to come up with white papers access the best libraries to get access to journal articles; or and policy documents in the area of information access. buy expensive hardware to analyse large datasets. All of the An “Open National Science Information Access Policy” above can be achieved Online. Therefore, access through document should detail who owns one’s genome data universal connectivity has become more important than and set guidelines for data distribution and sharing. physical possession. This requires providing 350 million The first step in making this a reality is to mandate free young Indians below the age of 25 years with free, open and immediate availability of all scientific information, and uninterrupted access to all scientific information. including all raw data, scripts and codes, while maintaining However, the access to data and information must be confidentiality. In this direction, the Open Access policy followed through with advice from domain experts as data from the Department of Science and Technology (DST) do not necessarily translate into solution and more data and Department of Biotechnology (DBT), Government of do not lead to understanding causation of many unsolved India on research manuscripts is praiseworthy. However, it problems in biology. If done rightly, big data could vitalise needs to go further and mandate making raw data, scripts, innovation and employment in India for the next few and codes openly and immediately available. Finally, in decades. addition to scientists, the Government needs to engage References a wider layer of experts, sociologists, lawyers, jurists, 1. Landenmark, H. K. et al. An estimate of the total DNA in the genetic counsellors, anthropologists and parliamentarians biosphere. PLoS Biol. 13, e1002168 (2015) in formulating the policies and help the parliament make 2. Stephens, Z. D. et al. Big Data: Astronomical or genomical? PLoS Biol. appropriate law in the area of human data sharing and data 13, e1002195 (2015) distribution. 3. Schatz, M. C. Biological data sciences in genome research. Genome Res. 25, 1417–1422 (2015) Once the infrastructure, institutions and the policies are 4. Panda, B. Whither genomic diagnostics tests in India? Indian J. Med. in place, we need to put the best practices into action to Pediatr Oncol. 33, 250–252 (2012)

47 Biotechnology: An agent for sustainable socio-economic transformation

Biosafe laboratories: A luxury in resource-constrained regions

Dhinakar Raj Gopal1, Aravindh Babu R. Parthiban1 & Mohanasubramanian Bhaskaran1

Biosafety is defined as the Advanced Technology (BRAAT) laboratory to Lawrence containment principles, Livermore National Laboratory put a number of research technologies and practices workers at risk. Similarly the 2007 outbreak of foot-and- that are implemented to mouth disease in the United Kingdom due to a leak of prevent unintentional the virus from a site jointly operated by The Pirbright exposure to pathogens and Institute and Merial resulted in huge economic loss and toxins due to their accidental a temporary embargo in animal trade with the European release. Biosecurity is the Union. In order to handle such diverse levels of threats, protection of pathogens from posed by various types of organisms, different biosafety misuse, theft or intentional containment levels are used. release by means of proper Figure 1 illustrates a basic model floor plan of a biosafety institutional and personal security measures and laboratory level III. In addition, experiments using the procedures. Bioterrorism involves the intentional release above organisms on laboratory animals must be carried or dissemination of biological agents such as bacteria, viruses, or toxins in a naturally occurring or a human- out in Animal Biosafety Level (ABSL) facilities, where modified form.Biocontainment is the containment of strict containment levels (ABSL I – IV) are followed extremely pathogenic organisms usually by isolation similar to the above; while experiments involving large or in secure facilities to prevent their accidental release, loose housed animals with designated high risk pathogens especially during research. are handled in BSL-III Agriculture (BSL-III-Ag). While GMP/GLP clean rooms operate under positive pressure Why do we need biosafety? to exclude contaminants from entering the area, biosafe The essence of biosafety is protecting the individual laboratories work under negative pressure to prevent (research worker), environment and organism (research escape of pathogens from inside to the environment. material). Past experiences of biosafety failures in many Is biosafety much ado about nothing? western countries have often resulted in big disasters and huge economic losses. For example, in 2006, the The primary argument posed to the proponents of incident involving the accidental transfer of live anthrax biosafety is ‘how was biological research undertaken in from the CDC’s Bioterrorism Rapid Response and earlier times?’ To add substance to this claim, many of

Biosafety level - I Suitable for work involving well characterised agents, which are not known to cause disease in immune competent adult humans and present minimal potential hazard to laboratory personnel and the environment, e.g. Lactobacillus sp Biosafety level – II Suitable for work involving agents that pose moderate hazards to personnel and the environment, e.g. Peste des petits ruminants virus Biosafety level - III Suitable for work with indigenous or exotic agents that may cause serious or potentially lethal disease through inhalation (aerosols), e.g. foot-and-mouth disease virus Biosafety level - IV Suitable for work with dangerous and exotic agents the pose a high individual risk of aerosol transmitted laboratory infections and life threatening disease that is frequently fatal and for which there are no vaccines or treatments, e. g. H5N1 influenza, Ebola viruses

1Translational Research Platform for Veterinary Biologicals, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India.

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Figure 1: A model floor plan of a Biosafety level-III laboratory.

the vaccines that are currently in use, were developed Institute was established away from populous regions and tested prior to the biosafety era. For example, Louis at 7500 feet above sea level in the Kumaon hills. All the Pasteur’s rabies vaccine was passaged in monkeys and difficulties in the transportation of people and equipment rabbits a number of times, an experiment which was not to this isolated area were endured for the requirement of performed as per today’s biosafety standards. However, biosafety, at least to the extent of avoiding unintentional this virus is still in use as a vaccine. The other argument release or spread of organisms even if not in the context is that very few laboratory accidents involving pathogenic of protection of the research worker. The present biosafety organisms have been documented even in the recent times. concepts not only protect against the spread but also Although these arguments sound agreeable to some, personnel and environment, which is highly justified. during this era of technology and development they may Resource constraints not hold ground to a technically qualified person. Even during earlier times, natural biosafety measures were The resources required for any biosafety laboratory considered while identifying a site for a laboratory facility. would involve establishment, validation and continuous For example, during 1893, the Indian Veterinary Research maintenance. All these processes are cyclical and never

49 Biotechnology: An agent for sustainable socio-economic transformation

ending. However, it is not only the infrastructure or the funded as a part of a proposed research grant. However, equipment that will facilitate biosafety; rather more at present no such mechanism exists in our country. important is the attitude of the working personnel, who Any institution running a BSL/ABSL laboratory is strictly and scrupulously follow the laid-down procedures. denied funding, for maintenance of the facility, when it If a three-minute shower is prescribed, the workers must approaches a research-funding agency. These laboratories strictly adhere to it. If they compromise this procedure are often suggested to generate their own revenue for this for frivolous reasons, such as lack of hot water, not only purpose, which is unrealistic. do they put themselves at risk but also their co-workers Alternative approaches to biosafety requirement and the environment. Therefore, along with infrastructure a substantial amount of resource is required for training Alternative approaches to assays requiring high and awareness campaigns, especially in countries like biosafety containments are recently gaining momentum. India. In addition to the above resource requirements, Development of assays that can be performed at low BSL two important constraints are felt at the ground level, viz. for the detection of high-risk pathogens can be helpful, uninterrupted power supply and optimal and continuous especially in resource constrained regions like India. One usage of the facility. Any biosafety laboratory must run 24 such approach is the use of pseudotypes for performing x 7, and any break-down results in breach of biosafety and quantitative and qualitative serology of infectious diseases requires revalidation of the entire facility. This puts great such as rabies and influenza. In this approach, the rabies/ pressure on the research institutions in India, which do influenza viral envelope is engineered on a retroviral core not have direct control over the electricity supply and have containing a reporter gene (Mather et al., 2013; Figure 2). to rely on the state governments for this. Also, such power These surrogate viruses can be used in place of the actual usage comes at a huge cost. In addition, most universities rabies/influenza viruses in a serum neutralisation assay, institutions engaged in biological research cannot afford thereby negating the need for biosafety containment. The to recruit full-fledged support engineers with expertise in Translational Research Platform for Veterinary Biologicals running and maintaining such laboratories. (TRPVB) has already initiated research into this approach with the support of Viral Pseudotype Unit, University of Although many institutions are able to succeed in Kent and University of Westminster. obtaining grants for the initial establishment of biosafe laboratories by convincing the authorities of its needs, Regulatory guidelines for biosafety laboratories they fail to factor in the operational requirement for the Biotechnology research is regulated through institutional subsequent years in terms of annual maintenance and biosafety committees, review committee on genetic validation. This has resulted in a situation where a number manipulation and genetic engineering advisory of biosafety laboratories have been established but are not committee. However, no such agency is available to fully operational. approve and validate biosafety laboratories in India, The concept of establishment of several ABSL facilities unlike that of GMP/GLP facilities, which are regulated and the likelihood of their continuous usage are largely by Drug Controller General of India. The Department of unrealistic as animal experiments on target species are Biotechnology has initiated some effort in this direction carried out only on potential promising lead molecules, to develop mechanisms for validation and certification of after results of extensive research in laboratories and biosafe laboratories. laboratory animals. In this context, it is felt that a few ABSL laboratories across the country may be established Biosafety in the context of emergency but their operation should be on a revenue-earning model. preparedness Additional factors, such as the purchase and transport of India needs to work on diseases that do not normally occur animals, feed, veterinary care, necropsy and disposal can in the country but are considered a potential threat. Such be provided at a nominal cost, which in turn should be research cannot be carried out at this moment extensively,

50 Biotechnology: An agent for sustainable socio-economic transformation

Figure 2: Strategy of a lentiviral pseudotype based serum neutralisation assay for the detection and quantification of antibodies against Rabies/ Influenza viruses. Image courtesy: Jennifer Evans and Ashley Banyard, Animal and Plant Health Agency, United Kingdom. due to the lack of BSL facilities. In turn, the emergency when trade occurs between such countries by unreported preparedness of the country is largely hampered. However, but prevalent diseases. Under these circumstances, if such facilities exist throughout the developed nations. For nation-specific highly biosafe labs are available to handle example, the United Kingdom has established a state of and test for such pathogens, trade can occur between these the art laboratory for research on exotic diseases with fool countries without the fear of incursions of unreported proof biosafety procedures and containment at a cost of diseases. There also exists a dichotomy between scientific 1450 crore rupees (http://www.pirbright.ac.uk). India publications from a country and diseases reported, which should not be left behind in infrastructure generation and lowers the credibility of the diseases reported from a capacity building in the area of emergency preparedness. country. Furthermore, Indian biological research fraternity requires such facilities for their research to be globally accepted. Biosafety and veterinary research: The path ahead More than 70% of animal diseases are zoonotic. It is, Trade related biosafety therefore, essential that laboratory based research does Although OIE monitors disease occurrence globally, not add to already existing genetic diversity of potentially some countries do not report assiduously to such world dangerous organisms existing and circulating. Therefore, agencies. Hence, there is a likelihood of disease incursions, it is important that laboratory based research is performed

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strictly adhering to biosafety practices and regulations. • Uninterrupted power supply to these laboratories In this connection the following challenges need to be To sum up, the answer to the question raised in the title is addressed: an emphatic 'NO'. However, consideration should be given • Creating wide spread awareness on biosafety during establishment of such facilities for their operational requirements and utilisation needs.

• Establishing and enforcing regulations on biological References research 1. Laboratory biosafety manual, World Health Organisation, 3rd Edition available at http://www.who.int/csr/resources/publications/biosafety/ • Establishing all inclusive biosafety experimentation WHO_CDS_CSR_LYO_2004_11/en/ units 2. Biosafety in Microbiological and Biomedical Laboratories (BMBL) • Funding support to biosafety laboratories for annual 5th Edition, Centres for Disease Control and Prevention, National Institutes of Health, available at http://www.cdc.gov/biosafety/ maintenance publications/bmbl5/bmbl.pdf • Establishing licensing, validation and technical audit 3. Current progress with serological assays for exotic emerging/re- modalities for BSLs emerging viruses. Future Virol. 8, 745–755 (2013)

52 Biotechnology: An agent for sustainable socio-economic transformation

The biodiversity-biotechnology nexus: Where do we stand?

Uma Ramakrishnan1

Stop what you are doing and sustainable sources of water is to increase forest cover and look outside your window! decrease biodiversity loss. While we link human health I hope you can see plants and wellbeing to medical interventions, lasting solutions and insects, and you may also may be technologically simpler. Social justice requires hear or see some birds. There that resources be shared equitably. Many of the world are certainly lots of microbes poorest people are critically dependent on biodiversity out there that one cannot see, or food. which nonetheless play an Let us think about medical interventions in the context important role in our lives! of human health. How does one find medications We are lucky to share the that cure diseases? Human societies have been using earth with so many other natural ‘drugs’ for a very long time, and biodiversity organisms — a whole host of species of animals, plants and has always been a sustainable source of traditional microbes — the elements of biodiversity. This biodiversity medicine. Modern biotechnological tools provide us the is not distributed equally around the globe. For example, abilities to scientifically analyse active compounds in plant tropical regions have more diversity than other regions. extracts and to test their efficacy. We have just begun We live in the tropics; India with around 2% of global to unveil the vast treasures of medicinal plants in two land cover houses approximately 10% of all species in the Indian biodiversity hotspots – the Himalayas and the world! In fact, four of 34 biodiversity hotspots in the world Western Ghats. It is worth mentioning that Tu Youyou, fall within India’s boundaries. one of the winners of the 2015 Nobel in physiology and The spectrum of life-forms in our country is truly medicine, has been conferred with the most prestigious fascinating, but why might the Department of award for her research on the antimalarial properties of Biotechnology (DBT) be interested? Here are two artemisinin (also known as qinghaosu), a product from fundamental reasons. The DBT is concerned with the Artemesia plant — which has been used in traditional fostering human welfare through integrating biology and Chinese medicine for the last 2,000 years! The DBT has technology. Human welfare is very strongly linked to taken several efforts to investigate the distributions of biodiversity: the air we breathe, the water we drink, and medicinal plants and assess their active compounds. the food we eat comes to us as a service from biodiversity. While some diseases can be cured by medication, others are Nature provides us these (free) services, and without progressive. Often, scientists use laboratory-based animal them we cannot survive. The nexus between human models to study the cause and progression of a disease. wellbeing and biodiversity is vital, and the strongest However, we do not have that many models to choose evidence for this comes from the detrimental effects of from. It turns out that here too, biodiversity could provide the loss of biodiversity on human health. For example, us with deep insights. Consider the curious case of the intact functioning of ecosystems provides clean water spiny African mouse Acomys. Researchers have recently that safeguards human health. Eutrophication of lakes and discovered that this species has a remarkable ability to other natural water bodies will impact human health and heal wounds very fast, without scarring. This species wellbeing, and unclean water (e.g. poor sanitation) may now provides us with a unique model for studying skin lead to high disease burden. The best way to ensure safe, regeneration — why such regeneration is not so common

1National Centre for Biological Sciences, TIFR, Bangalore, India.

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in mammals. Many such instances exist: the naked mole rat health. India is poised to be a region where emergence that lives an incredibly long life, and elephants that don’t will be common: high human population density, high seem to get cancer despite being huge! Exploration and biodiversity and high conversion, and loss of biodiverse careful observations of Indian biodiversity will definitely spaces. Another important reason for us to study and lead us to interesting organisms and life strategies, which better understand better biodiverse natural spaces is to may hold key answers to human health and well-being. gain information on handling disease outbreaks effectively. Such insights that could lead to mechanistic molecular What causes disease emergence? Can it be predicted investigations of biological phenomena would never have beforehand? Are there ecological correlates of disease been realised without field-based or natural history-based emergence? While the emergence of pathogens correlates observations. Sadly, so far, Indian biodiversity scientists with regions of high biodiversity, the final verdict on this have not often worked with developmental biologists, cell is not yet out. Tracing host-switching events (from wildlife biologists and geneticists. Much remains to be done in this to humans) and how infections spread, will require large- field including exploring marine biodiversity, chemical scale study of the nature-people interface in the context signalling and mechanisms of communication in nature. of infectious disease. This might be a very interesting Hopefully, DBT will initiate work in this direction in the application of biotechnological tools in infectious disease future, because such endeavours will allow us to synthesise research. our knowledge in the context of the wide array of diversity Apart from quantifying biodiversity, using it for model- in nature. system based research and studying it in the context of Today, studies on biodiversity mainly use molecular diseases would be interesting. In addition, it is fascinating biology tools as standard methods. One of the main roles to try and understand how various species present in an of biotechnology in the study of biodiversity begins with ecosystem interact with each other. We are now relatively its role in describing biodiversity. How do we actually well versed with the language of evolutionary change: know how much biodiversity is out there? Such research genes are made up of DNA, and changes in DNA sequence has been dominated by natural history and taxonomy for result in phenotypic change and in evolution. However, we a long time — where scientists collected, described and are less well-versed with language(s) by which organisms classified organisms, and organised them into bins called communicate. How might one individual communicate species. Today, researchers use tools like phylogenetics. with another in the same species? How do plants interact Sequencing DNA from several different species allows us to with insects in nature? Many such interactions are quantify which organisms belong to the same group versus mediated by chemicals, and chemical ecology provides different ones. Such approaches of assessing diversity have detail description of such communication. For example, been called DNA barcoding, and the DBT has funded how do plants attract some insects and repel others? How several DNA barcoding initiatives on butterflies, frogs and do insects know which plant is the right one for them other taxa. New and exciting opportunities in biodiversity to lay eggs on? How do plants and insects communicate research using cutting-edge tools, like Next Generation with each other? These questions constitute the field of Sequencing (NGS) and genomics, are sure to yield chemical ecology. Understanding such communication is fascinating insights into how Indian biodiversity has been fascinating and useful, because it may help us learn how accumulated, and why certain places have more diversity to repel insects or control behaviour of certain animals. than others. The prospects of understanding biological interactions The loss of biodiversity may have detrimental impacts. in nature through chemical ecology are tremendous. Recent studies suggest that human induced factors, like Given the potential applications of such discoveries, these biodiversity loss and climate change, are responsible for explorations provide an exciting interface between a the increased emergence of infectious diseases. Infectious deeper understanding of basic science using technological diseases that spill over from wildlife to humans are called approaches and innovations and applications, making it zoonoses, and these are tremendous burden to human an area of tremendous interest for the DBT.

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Although the DBT has played a very important role this process. The prospects for chemical ecology research in providing social equality in India, the fact remains in biodiverse regions like the north-east are tremendous perhaps understated and underappreciated. How can and it may lead to some interesting innovations in the near social equity be achieved in a country as diverse as India, future. and in particular, what role may biotechnology play in In summary, the diversity in life forms on our planet is such a process? The DBT has taken this responsibility very fascinating. Understanding this diversity requires cutting seriously through its grants in the north-eastern region. edge technology, making it a prerogative for the DBT to aid In the northeast, very high biodiversity areas are thrown scientists in this endeavour. Deconstructing biodiversity together with ethnically and culturally diverse people with will require new research directions like chemical ecology. relatively low economic opportunity. Could biodiversity Biotechnological approaches to biodiversity research and its provision of bio-resources provide a means to allow us to unravel scientific principles right here, in our economic opportunity (and social justice) in the north- backyard. Such scientific enterprise is fascinating and also east? A DBT Institute in Imphal seeks to attempt this. A helps us connect better with our immediate surroundings new multi-institutional programme with researchers from and our country. This would certainly inspire the younger the north-east and other parts of India will attempt to generation, feeding their curiosity and building a scientific glean understanding from nature that could be of use to temperament, both critical for a better future. So let us humans, and build scientific capacity in this region through embark on this journey to learn more about India.

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India holds the key for solutions in global health

Trevor Mundel1

In 2011, shortly after joining cure TB in under two months; a vaccine that can protect the Bill and Melinda Gates both children and adults; diagnostic tests that don’t rely Foundation (BMGF), I was on sputum samples; better monitoring tools to document invited to attend the first adherence for drugs that require prolonged treatment; Grand Challenges meeting and innovative financing mechanisms to help scale up in Delhi, co-hosted by BMGF programs that work. Efforts in India to pilot many of and India’s Department these innovations are showing promise and are being of Biotechnology (DBT). supported by the government. However, the nature of The meeting brought the problem is serious enough that constant focus and researchers, government new partnerships are needed to reach the required level officials, industry experts of impact. and policy people together and was an ideal venue to Growth-stunting is another major problem in India. The help get me up to speed on many issues in the global health arena as well as exciting developments in India. prevalence of stunting in children under five years of age 2 It turned out to be a rich learning experience with a is close to 50% in certain areas . The factors contributing talented and committed group of partners who possess to stunting and potentially to impaired cognitive both real scientific depth and passion for solving development are complex and not fully understood. A problems within India and globally. range of causes including nutritional deficiencies, open defecation, and exposure to mycotoxins have been I heard repeatedly from experts across the board the implicated yet we don’t really understand their relative need to customize solutions for local context instead importance. There is great interest in understanding of simply borrowing existing solutions from the west, a the factors involved so that targeted and effective philosophy that DBT has embraced in much of its work. interventions can be developed that are appropriate for For example, we jointly launched with DBT a “Grand the local context. Challenge” to identify Indian innovations to “Reinventing to Toilet” that are uniquely suited to the India context. At the Gates Foundation, we recently launched a program As part of that meeting, the Gates Foundation and called Healthy Birth, Growth and Development to gain a DBT signed a Memorandum of Understanding (MoU) comprehensive understanding of stunting. DBT played to capture our mutual interests in pursuing innovative a lead role along with WHO in helping to bring Indian approaches to developing new preventive and investigators together to discuss potential solutions therapeutic interventions to solve health, food and and pool data from multiple studies to gain deeper nutritional inequities. understanding of this issue from the Indian context. As India has a high burden of diseases that affect the part of this effort, the Biotechnology Industry Research poor and is a hotbed of innovation aimed at finding Assistance Council (BIRAC) launched a Grand Challenge solutions for these problems; the growing tuberculosis in 2015 focused on innovations to ensure all children (TB) epidemic serves as a good example. TB prevalence thrive with funding from DBT and the Gates Foundation. is reaching alarming levels for both drug resistant and I hope to see great strides in our understanding of this sensitive forms1 and innovation is needed across the issue and implementation of solutions for this hidden yet value chain: new drugs, and a universal regimen that can major problem.

1President, Global Health Division, Bill and Melinda Gates Foundation.

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The accomplishment of polio eradication in India in As I look at the next 5-10 years, I see huge potential in 2014 provided a huge boost in confidence to the global India for the next generation of low cost vaccines, new community that major efforts at disease elimination can drug formulations and advances in biologics. To realise be successful in India. Many diseases that affect the poor this, it is critically important that regulatory process such as lymphatic filariasis (elephantiasis), kala-azar and reforms keep pace with technological changes and the malaria have effective, low cost treatments available today. strong culture of innovation in India. By building upon the successful experience with polio, Moving new discoveries through development and India is in a unique position to lead the way towards the ultimately delivering them to people in need is a challenge elimination and eventual eradication of these diseases too. all countries face. From my first meeting with them in India is the most important supplier of affordable vaccines 2011, I have come to highly value the contribution of DBT and therapeutics to developing markets, especially for in this arena. I commend them for pioneering new models global institutions such as GAVI and the Global Fund3. to address these issues through approaches that help DBT’s partnership with the National Institutes of Health connect innovators with ideas to funders, experienced (USA), Program for Appropriate Technology in Health developers and others with crucial skillsets. (PATH), and with local vaccine manufacturers has had a catalytic role in the development of an indigenous, References 1. Dheda, K. et al. Tuberculosis. Lancet (2015) doi: 10.1016/S0140- low-cost and effective rotavirus vaccine in India, soon 6736(15)00151-8 to be introduced in the Indian Universal Immunization 2. Stop Stunting. 2015 Progress Report, Unicef South Asia. http://www. Program. Introduction of this vaccine in India will save unicef.org/rosa/2-PR-stopstunting.pdf thousands of lives lost every year due to dehydrating 3. Rezaie, R. et al. Innovative drugs and vaccines in China, India and rotavirus diarrhoea. Brazil. Nat. Biotechnol. 30, 923-926 (2012)

57 DBT Institutions • Autonomous Institutions • Public Sector Undertaking (PSUs) Biotechnology: An agent for sustainable socio-economic transformation

National Institute of Immunology, New Delhi

The National Institute of Immunology (NII) is committed epigenetic influences on development and function of to advanced research with a view to understand body’s the body and its defence mechanisms. defence mechanisms for developing modalities of immune • Translational research in the area of vaccines and system manipulation that can intervene with disease drug development. The research is focused on processes. The institute’s research thrust areas under designing novel immunogens, anticancer agents and immunology and related disciplines cluster in four main therapeutic inhibitors against pathogens of public themes, namely 1) Infection and Immunity 2) Molecular health significance. Design 3) Gene Regulation and 4) Reproduction and Development, where cutting edge research in modern • Integrated research in human disease biology, where biology is being carried out employing multiple complex questions of susceptibility to and spread overlapping disciplines of biochemistry, molecular of diseases in field conditions are intended to be biology, cell biology and structural biology. addressed using systems approaches.

The research areas of interest are: NII has developed collaborative programmes with both National and International Universities and Scientific • Basic biology of T and B lymphocytes. Institutions to synergise research activities. NII also • Elucidation of mechanisms used by the immune cooperates with the biotech industry on a broad interface system in response to infectious pathogens and ranging from technology transfer to joint R&D programmes characterization of the strategies used by a variety of and policy development initiatives. NII is a founder partner pathogens to establish infection and disease. in the development of a coordinated thrust in this direction • Analysis of the processes that control reproduction through a supra-institutional Biotech Science Cluster and development to understand genetic as well as coming up in the National Capital Region.

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The Institute also has provisions for state-of-the-art have enormous impact in developing strategies for teaching and training facilities in advanced biological intervention with diseases. sciences using an interdisciplinary approach so as to inculcate the highest level of aptitude and ability in the Ongoing activities and programmes: country’s skilled manpower pool. • R&D to investigate the mechanisms used by the immune system in responding to infectious pathogens Major achievements (in last 5 years): and molecular characterization of the strategies used • Development of an efficient method for making by a variety of pathogens to create infection. transgenic animals, an indispensable tool in modern • Research has been further extended on dissection biology research. of the fundamental rules of molecular design and • The institute has made a major leap in terms recognition, by cutting-edge research in the post- of obtaining patents for various methodologies genomic field of proteomics. developed. A total of 28 patents were filed nationally • Questions on control of reproduction and and internationally, of which 15 patents have been development and understanding genetic as well as granted while the others are being evaluated. environmental defects, especially involving studies • Three technologies have been transferred to the with the human immune system, are being addressed. industry, namely formulation of long-acting insulin, • Teaching and training in advanced biological sciences production of recombinant human and buffalo to inculcate the highest level of aptitude and ability growth hormone and a vaccine for controlling fertility in the country’s skilled manpower pool through in female dogs. seminars and workshops. • Published significant number of research papers For further details please visit NII website: (319) in high quality journals that will eventually http://www1.nii.res.in

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National Centre for Cell Science, Pune

The National Centre for Cell Science (NCCS) established human cells/cell cultures, cell lines of both existing with mandate of basic research, teaching & training and (typed) and newly developed hybrid cells, including as a national repository for cell lines/hybridomas etc. The hybridomas and serve as National Reference Centre centre is located in the midst of academically enriched for tissue culture, tissue banking, cell products, data environment of University of Pune campus, Pune. During bank etc. its transformative years, the centre has undergone several • To establish and conduct postgraduate courses, changes to facilitate achievement of its goals. workshops, seminars, symposia and training The centre has expanded its scientific charter to strengthen programmes in the area of mammalian tissue culture basic research in the areas of cancer biology, cell biology, and transgenic animals etc. immunology, genomics and proteomics. • As a bridge between science and industry to provide and promote effective linkages on a continuous basis The areas of interest of the centre are: between various scientific and research agencies/ • Basic research in the areas of Cell Biology, Cancer laboratories and other organizations including Biology, Infectious diseases, Immunology, Molecular industries working in the country. Biology, Proteomics, Genomics, Diabetes and • Enter into inter-institutional collaboration with Tissue Engineering that leads to enhancement in national and international organizations in goal- understanding the events at molecular level. oriented research programmes as required in the • As a National Repository, centre receives, identifies, country for the betterment of society and advancement maintains, stores, grows and supplies animal and of Science and Technology.

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Major achievements (in last 5 years): know-how has been transferred to Indus Biotech Pvt. Ltd, Pune. • The repository has procured more than 2000 cell lines. Currently, the depository possess 1, 50,000 accessions, • Technology commercialised which are highest in the world. ■■ Cryopreservation of Hematopoietic Stem Cells • Experimental Animal Facility (EAF) supplies (AFMC, Pune) standardized laboratory animals such as rabbits, ■■ Use of phosphono-derivatives of selected aliphatic inbred mice and rats of high quality. acids for anti-malarial activity and use of selected • Published 295 scientific publications in total during amino acid-zinc complexes as anti-malarials 11th plan and many of them published in high impact (Shreya Life Sciences, Mumbai) factor peer reviewed journals. ■■ Protocol for preparation of aqueous extract of • Many lead compounds have been identified and Fenugreek seeds, which possesses hypoglycaemic some of the notable compounds are: activities comparable to that of Insulin and protocol ■■ Anti-malarial (Zinc-di-L-prolinate from muscle for thermostable extract preparation from a Protein hydrolysates) Rich Fraction of Fenugreek Seeds (TEFS), which has a potential application in the management of ■■ Anti-HIV activity (anti-HIV-1 molecule active dyslipidemia and obesity (Indus Biotech Pvt. Ltd., against HIV and other viral strains) Pune) ■■ Hypoglycemic activity (Extract of Fenugreek seeds; Technology is transferred to Indus Biotech Pvt. Ltd, Ongoing activities and programmes: Pune) • R&D in areas in cell biology, signal transduction, ■■ Hypolipidemic activity (heat stable preparation cancer biology, diabetes, biodiversity, infection from Fenugreek seeds extract; Technology is and immunity, chromatin architecture and gene transferred to Indus Biotech Pvt. Ltd, Pune) regulation, stem cells, proteomics, bioinformatics and • Technologies developed/transferred with proof of regenerative biology. concept: • Translational research programmes in tuberculosis, ■■ Creation of artificial bone-marrow-like systems biology and HIV/AIDS. environments to modulate stem cell fate in- vitro. • Program on HIV, cell & tissue engineering and ■■ Protocol for preparing aqueous extract of immuno-therapeutics for translational research. Fenugreek seeds possesses hypoglycemic activities, • Diabetes and development of microbicides. comparable to Insulin at cellular and molecular • Cell signalling and differentiation processes of cell level. and their application. ■■ Protocol for thermostable extract preparation • Mass education programmes for awareness in science from a protein rich fraction of Fenugreek and technology and enhancement of teaching and Seeds (TEFS) decreases accumulation of fat in training programme. adipocytes and upregulates LDL receptor in liver. The potential applications are in the management For further details please visit NCCS website: of dyslipidemia and obesity. The laboratory scale http://www.nccs.res.in

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Centre for DNA Fingerprinting and Diagnostics, Hyderabad

Centre for DNA Fingerprinting and Diagnostics (CDFD), Escherichia coli with the aid of genetic and molecular Hyderabad, provides services in DNA fingerprinting approaches. and related analysis and facilities to crime investigation • Cell cycle regulation. agencies, and undertake research and training activities in • Molecular pathways controlling cell survival and cell death. DNA fingerprinting and its applications. • Computational analyses of biological data sets CDFD has emerged as an Institute of National and available on the public domain as well as those International repute that provides DNA-based services generated by collaborating groups. for human DNA profiling to law enforcement agencies & other authorities of the nation, diagnosis & counselling • Understand the development and patterning of of genetic disorders in children and families, certification central nervous system (CNS) using model organism of purity of basmati rice for export; and also undertakes Drosophila melanogaster. basic, applied and R&D work related to the services above • Molecular events of inflammatory diseases and and in other frontier areas of life sciences. CDFD uniquely possible therapeutic approaches. combines the service and research components of its • Molecular genetics to study different aspects of mandate in such a way that each of the activities supports genetic processes. and enriches the other. • Understand the biology of various forms of cancers The areas of interest are: that are either common in the Indian population or • Bacterial Genetics towards understanding different are distinctly different from their western counterpart. physiological processes in the model bacterium • Plant microbe interactions.

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Major achievements (in last 5 years): 17 patents have been obtained, and 5 new patent applications were filed. • Centre has been successfully involved both in providing services, based on modern high-technology Ongoing activities and programmes: DNA-based methods, of direct benefit to the public, • Services and service-related research and training as well as in performing fundamental research of activities in DNA fingerprinting, and diagnostics for international standards in frontier areas of biological genetic disorders. science. • Genetics and Genomics of Silkmoths. • 458 cases of DNA profiling were handled. 7479 • Cell signalling in human health and disease, with the cases of DNA diagnostics were undertaken. Medical objective to uncover novel signalling mechanisms. Genetics Unit has been established with NIMS, Hyderabad where 955 patients were examined. 855 • Understanding the mechanism of transcription termination and anti-termination in prokaryotes. basmati rice samples were analysed for purity under APEDA-CDFD Centre. • Studies on mammalian genetics. • Centres of Excellence namely in Genetics and • Computational and functional genomics. Genomics of Silkmoths, Microbial Biology and For further details please visit CDFD website: Mycobacterium tuberculosis, were established. http://www.cdfd.org.in • 193 papers were published in international journals.

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National Brain Research Centre, Manesar, Haryana

National Brain Research Centre (NBRC) is the only • Investigating learning, memory and human neuronal institute in India dedicated to neuroscience research and disorders using Drosophila as a model system. education. Scientists and students of NBRC come from • Neuronal development and regeneration using diverse academic backgrounds, including biological, Caenorhabditis elegans. computational, mathematical, physical, engineering and • Viral and inflammatory triggers of neurodegenerative medical sciences and use multidisciplinary approaches to diseases. understand the brain. The vision of NBRC is to grow into a world-class institute for brain research and create a vibrant, • Theoretical neuroscience and functional brain active neuroscience community by catalysing the overall imaging. growth of this discipline in the country. The expected • Signal transduction and gene regulation in Glioma. benefit from this initiative would be the generation of • Neurological disorders involving protein misfolding. skilled manpower in this important area of research who would help in this frontier area of science. The knowledge • CNS stem cells as models of Alzheimer’s and Prion base generated from research in this centre would help Diseases. in the development of diagnostic tools and therapeutic • Understanding the molecular details of non-coding strategies for treatment of brain-related disorders. RNAs mediated cellular reprogramming.

The areas of interest are: Major achievements (in last 5 years): • Molecular interactions in gliomagenesis; hypoxic • Significant research leads have been obtained in the environment and cell signalling, Genetics of dyslexia. Research and Development activities on:

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■■ Development of rationale therapies for Ongoing activities and programmes: neurodegenerative and infectious diseases of • Molecular and cellular basis of NeuroAIDS; the nervous system through understanding of Human neural stem cell as models for studying pathogenic mechanisms. neurodegeneration. ■■ Development of cognitive retraining modules for • Understanding the structural and functional basis improving brain function in head injury patients. of brain using neuroimaging modalities (MRI/DTI/ ■■ Development of computational tools for speech fMRI/MRS/EEG) in neurodegenerative and neuro- analysis. oncological disorders; Computational modelling of ■■ Cognitive science. neurocognitive processes. ■■ Stochastic activation for MR imaging - enhancement • Medical image/signal processing, Alzheimer disease, and identification. Parkinson Disease, Brain stress quantification, Biomarkers using multi-model imaging (MRI/fMRI/ ■■ Systems neurobiology/neuroscience. MRS) Technology. ■■ Stem cell research. • Adult neurogenesis, Development of Auditory ■■ Development of the brain-machine interface. system in humans. Song control system in zebra • Thirty-three research papers have been published in finches. the journals having impact factor 5 and above. • Multi-institutional programme on molecular genetics • Eight patent applications have been filed. and pathogenesis of complex neuro developmental • Technology has been developed for use of minocycline disorders. in JE. • Development for a community programme with • Facilities have been established for Neuroimaging, capability of cohort studies. Translational Neuroscience, Electromyography & For further details please visit NBRC website: Neurometry and for Clinical Psychometry. http://www.nbrc.ac.in

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National Institute of Plant Genome Research, New Delhi

National Institute of Plant Genome Research (NIPGR), • Plant Development and Architecture New Delhi is carrying out research on functional, • Plant Immunity structural, evolutionary and applied genomics of plants. • Root Biology and Nutrition The Institute has mandate to undertake, promote and co- ordinate research, develop human resource and to serve • Seed BiologyEpigenomics and Molecular Breeding as information resource in identified aspects of plant genome. NIPGR is poised to contribute towards frontier Major achievements (in last 5 years): areas of Plant Biology such as, Computational Biology, • Research leads have been obtained in genetic Genome Analysis and Molecular Mapping, Molecular engineering of potato, rice, sweet potato expressing Mechanism of Abiotic Stress Responses, Nutritional AmA1 gene with improved nutritional quality. Genomics, Plant Development and Architecture, Plant • Suppression of N-glycan processing enzymes in Immunity, Molecular Breeding, Transgenics for crop tomato by RNA interference for enhancement of fruit improvement and other emerging areas based on plant shelf life. genomics. The research programme aims to contribute • Sequencing of about two million bases from tomato to the understanding of the structure, expression and chromosome 5 as part of the Indian Initiative on function of genes along with arrangement of genes on Tomato Genome Sequencing. plant genomes and manipulation of plant genes/genomes to breed improved varieties of food and industrial crops • Next Generation Sequencing Challenge Programme for high yields and of better quality products. undertake for sequencing the whole genome of chickpea. The areas of interest are: • 160 research publications in high-impact journals of • Genome Analysis and Molecular Mapping international repute. • Molecular Mechanism of abiotic stress response • Selected technology know-how transferred to • Nutritional Genomics industry.

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• Establishment of a National Plant Gene Repository. proteins involved in light controlled plant growth and development. Ongoing activities and programmes: • Utilize molecular biology approaches along with • Research and development in frontier areas of Plant tissue culture and genetic engineering technology Biology such as Computational Biology, Genome to identify important genes and manipulate Analysis and Molecular Mapping, Molecular these for generating transgenic plants with Mechanism of Abiotic Stress Responses, Nutritional improved agronomic characters and pathogen/stress Genomics, Plant Development and Architecture, resistance. Plant Immunity. • Basic research on gene regulation and mapping that • Molecular cloning, characterization of genes and their would aid in achieving mandate of NIPGR. uses in increased shelf-life of fruits and vegetables. For further details please visit NIPGR website: • Genetic and molecular investigations of regulatory http://www.nipgr.res.in

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Institute of Bioresources and Sustainable Development, Imphal, Manipur

The Institute of Bioresources and Sustainable • Characterized few novel fibrinolytic enzymes in Development (IBSD) Imphal, Manipur started in 2003 traditional fermented foods associated with bacteria; with the mandate of bioresources development and their Characterized microbial community in soibum and sustainable use through biotechnological interventions Ngari developed; Functional starter culture for soibum for the socio-economic growth of the North Eastern production. region of the country. Overall aim of the institute is to • Thirty-two isolates of rhizobacteria of mandarin set up a state-of-the-art biotechnology research facility orange rhizosphere identified by 16s RNA gene in Imphal, which is at the centre of the Indo-Burmese sequence analysis; Enterobacter ashuriae RCEZ biodiversity hotspot for sustainable development of Accession 673774 and Enterobacter sp. RCE5 Acc. No. bioresources by using tools of modern biology, study and JN673777 developed as biofertilizer. document the unique biodiversity and bioresources of • Multi-locational field experiments of efficient biogeographic junction of Indian and oriental landmasses, biocontrol agents Trichoderma and Pseudomonas undertake biotechnological interventions for sustainable fluorescens against soft rot of ginger rhizome showed development and utilization of bioresources, generate promising results. technological packages for employment generation and • Completed documentation of knowledge on herbal economic progress of the region and undertake capacity medicine of 30 traditional practitioners (5990 years) building (human resource development) in bioresources in nine districts of Manipur. conservation & utilization. • Domestication and seed production technology of The areas of interest are: two indigenous ornamental fishes. • Medicinal Plant/Horticultural • Low-cost fish feed formulation (Rice bran: Mustard • Animal Bioresources cake: silk worm pupae waste=8:3:1) is found to show promising results in feeding experiment. • Microbial Bioresources • Computational tools such as SSRepeater, REcutter • Bioresources Database & Bioinformatics and GLogo developed at Bioinformatics Unit. Major achievements (in last 5 years): • Technologies developed: • A Fresh Water Cyanobacterial and Microalgal ■■ Production technology for fermented soybean using Repository created. activated starter culture Bacillus subtilis MTCC 5480.

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■■ Formulation technology and enhancement of • Virus indexing and genetic fidelity testing of micro protein content in fresh water Spirulina platensis. propagated plants. ■■ Production technique of micro rhizome and mini • Food safety evaluation of traditional fermented foods rhizome for disease-free planting material of elite through microbiological and toxicological analyses ginger variety. and development of diagnostic kit. ■■ Production, extraction and purification process • Holistic approach on exploration, characterization and for novel fibrinolytic enzyme fromBacillus subtilis domestication of wild silk moth for socioeconomic MTCC 5481. perspective and eco-conservation. ■■ A low-cost technique for conversion of floating • Development of in-situ model for predicting crop aquatic biomass of Loktak Lake. response to bio-inputs application in soil of varying Ongoing activities and programmes: physico-chemical and biological properties. • Mapping and Quantitative assessment of potential • Bio-prospecting of endophytic microbial diversity wild plant resources for food and nutritional security of medicinal plants for isolating novel potential based on traditional knowledge of ethnic groups. therapeutic agents. • A flagship programme on traditional fermented food For further details please visit IBSD website: of NE India. http://ibsd.gov.in

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Institute of Life Sciences, Bhubaneswar

The Institute of Life Sciences (ILS), an autonomous institute ■■ Molecular biology of abiotic stress has been brought under the fold of the Department of ■■ Microbial Genomics and Bio-prospecting of Biotechnology, Government of India in 2002. The mandate Extremophiles of ILS is to undertake basic and translational research in ■■ Molecular and biological characterization of frontier areas of life sciences. Major research areas of the oncogenes involved in leukaemia and solid tumours institute are Infectious Disease Biology, Gene Function and Regulation and Translation Research and Technology • Translational Research Development. • Proteomics and molecular biology of abiotic stress response and tolerance The areas of interest are: • Macromolecular Crystallography, Biochemistry and • Infectious Disease Biology Biophysics ■■ Immunobiology of metazoan parasites • Human/Medical Genetics ■■ Antibiotic Resistance, Boifilm and Bacterial Pathogenesis Major achievements (in last 5 years): ■■ T cells and the immune response • Development and characterization of monoclonal antibody against non-structural protein-2 of ■■ Genome instability and DNA polymerases Chikungunya virus has been done. ■■ Immuno-Genomics and Systems Biology • Structure-functional prediction and analysis of cancer • Gene Function and Regulation mutations in protein kinases has been carried out. It

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has implications for targeting genomic variants with • Studies on trans-lesion DNA synthesis (TLS) in Yeast personalized drugs. and Humans. • Development and evaluation of hexaplex PCR for rapid • Involvement of Y-family Pols during replication and detection of methicillin, cadmium/zinc and antiseptic- maintenance of eukaryotic telomeres. resistant Staphylococci, with simultaneous identification • Metagenomics and functional genomics of of PVL-positive and PVL-negative Staphylococcus microorganisms for gene prospecting. aureus and coagulase-negative Staphylococci. • Cancer Nanotechnology: Nanotechnology-based drug • Comparative genome sequence analysis of Sulfolobus delivery for cancer. Rapamycin loaded nanoparticles acidocaldarius and 9 other isolates of its genus for for cancer therapy. factors influencing codon and amino acid usage. • Macromolecular conjugation for improving • Anoxybacillus suryakundensis sp. nov, a moderately therapeutic index of anti-cancer drugs. thermophilic, alkalitolerant bacterium isolated from • Use of Magnetic nanoparticles for drug delivery, in hot spring. vivo imaging and as diagnostic agents. • A method for preparing a water dispersible magnetic • Development of plant derived mammalian immune nanoparticle formulation has been developed. responsive defensin proteins/peptide and its • ILS has published nearly 140 scientific publications in implication in translational research. International Journals out of which 19 research papers • Pathogenesis of Vibrio cholerae. have been published in journals with impact factor 5 or above. 10 patent applications have been filed. • Elucidating the cellular and molecular mechanism of development of severe P falciparum malaria in Ongoing activities and programmes: humans. • Gamma herpes virus and interactions with host For further details please visit ILS website: factors. https://www.ils.res.in

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Translational Health Science & Technology Institute, Faridabad

The Translational Health Science and Technology Institute and diseases. The generated knowledge may be (THSTI) is designed to be a dynamic and interactive incorporated in THSTI institutional networks organization with a mission to conduct innovative developing diagnostic and therapeutic modalities. translational research and develop research collaborations • Centre for Bio-design (CBD) is planned to promote across disciplines and professions to accelerate the strategic basic research and an effective translational development of concepts into tangible products to route of science into development of novel technology improve human health. Translating knowledge for platforms, implants, devices, diagnostics and imaging. It health care is the main aim of THSTI. This Institute will support a multidisciplinary approach of combining integrates multidisciplinary scientific teams from the novel technological concepts and clinical expertise. fields of medicine, science and technology for harnessing • The Policy Centre for Biomedical Research translational knowledge. The process is directed towards (PCBR) will provide support in domains of Vaccine, the production of biomedical innovations for use in Diagnostics, Medical Devices and Drugs for various phases of health care. Concerted effort is focused translation to humans and translation to practice on developing health technologies to benefit the most by analysing policy gaps and innovating ideas for disadvantaged people. technology diffusion and demand creation. The areas of interest are: • Drug Discovery Research Centre (DDRC) will THSTI has set up Centres of Research in a number of combine multiple disciplines in order to generate interface areas relevant to translational research namely, a robust and versatile pipeline for drug discovery Vaccine and Infectious Disease Research Centre (VIDRC), research. This includes capabilities for analysing large- Paediatric Biology Centre (PBC) and Centre for Bio- scale data in order to identify the most promising design (CBD) with distinct mandates: targets for further drug development applying • Vaccine and Infectious Disease Research Centre systems-level approaches. (VIDRC) has a mission to study infectious disease • Centre for Human Microbial Ecology (CHME) and pathogens and understand host-pathogen will determine and identify structure and dynamics interactions at the molecular and cellular level with of microbial communities in healthy and various an aim to generate translational knowledge for disease conditions in humans and the contribution of developing prophylactic and therapeutic measures alterations in the microbiome composition to human against diseases prevalent in India. health and disease. • Pediatric Biology Centre (PBC) is conducting • These efforts are augmented by two of THSTI’s research on biological basis of childhood health extramural centres, the Clinical Development

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Services Agency (CDSA) and the National Biodesign Ongoing activities and programmes: Alliance (NBA). • Comprehensive research program on pathogens, Major achievements: vaccines and other therapeutics (spanning basic through translational research). • A method and device for detection of anti- transglutaminase antibodies. • Population-based studies on infectious diseases. • Technology of recombinant human tissue • Product and process development including vaccine transglutaminase for development of tests for celiac formulations and analytic research in partnership disease has been transferred industry. with industry. • THSTI has become a member of INDO-U.S. Vaccine • Clinical development of vaccine and therapeutics Action Program (VAP) on tuberculosis research. The through phase I – III. program aims to establish Cohort Research Units • Serves as a centre of excellence for training future (CRUs) involving clinical sites, and TB research researchers in the fields of science and technology laboratories to address fundamental research using relevant to the vaccine and infectious disease research. clinical samples. • Biology of vaccine immunogenicity. • Many bilateral/multilateral agreements have been • Characterization of the immune system in neonates signed for research, innovation, higher education, and infants. training and capacity building for R&D related to human health. • Synthetic and medicinal chemistry for drug discovery. • THSTI & IAVI partnered together to establish a • Pharmacology and analytical biochemistry for drug laboratory in India to conduct a joint research program. discovery and development. • More than 50 research papers have been published in For further details please visit THSTI website: the reputed scientific journals. http://www.thsti.res.in

74 Biotechnology: An agent for sustainable socio-economic transformation

Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram

Rajiv Gandhi Centre for Biotechnology (RGCB) has the • Developing and retaining a sustainable pipeline mandate of carrying Out Research and Development of biotechnology professionals across a range of on Fundamental Research, Technology Development, related disciplines including fundamental science, Translational Science and Training & Education in the technology development, translation, policy and area of biotechnology. RGCB mainly focuses on research outreach through efforts in education, training and and early translation of research leads in human, animal career development. and plant diseases viz., cancer research, chemical biology, • Advancing translation and dissemination of human molecular genetics, molecular reproduction, scientific knowledge on the role of disease and mycobacterium research, cardiovascular disease biology, human health; pursuing appropriate and effective molecular neurobiology, cholera and environmental means of engagement of the broad range of institute biology, viral disease biology & plant disease biology; and stakeholders and the public in-health research and fostering & promoting collaboration and joint ventures public health promotion. between academia, industry and government. Major achievements (in last 5 years): The main areas of interest are: • Devised a new scheme for classifying cancer-related • Understanding the biology that defines basic microRNAs into three categories: “causal”, “non- mechanisms involved in the disease process and its causal” and “not enough information” reflecting their implications for human health. potential roles in cancer progression. This scheme, • Turning research into technology innovation and on beta-tested on oral cancer-related microRNAs, can to business. be applied to prioritize the list of microRNAs to be • Trans-disciplinary health science to inform individual, expression profiled in any given cancer type. clinical and public health decision making to improve • The comprehensive miRNA target prediction server is health. available at www.tarmir.rgcb.res.in.

75 Biotechnology: An agent for sustainable socio-economic transformation

• Developed a cell-based assay for identifying Ongoing activities and programmes: compounds that can target tumor stem cell population. • Chronic disease biology of cardiovascular diseases • Confirmed the “ancestral” phenotype of M. (CVD), cancer, chronic obstructive pulmonary tuberculosis from South India and the presence of disease and type 2 diabetes. novel insertion regions. • Tropical disease biology. • Isolated and identified an antimycobacterial molecule • Design and synthesis of a biodegradable polymer of (Ethyl p-methoxycinnamate) from Kaempferia galanga, nano size as drug delivery system and developing new an Ayurvedic medicinal plant and it inhibited multidrug strategy for the chemical synthesis of mini-proteins. resistant (MDR) clinical isolates of M. tuberculosis. • Nanoparticle-based controlled drug delivery. • A novel simple end-point assay for Ca2+-channels invented. • Degradable polymer scaffolds for cell differentiation. • Identified differentially displayed genes in testis in • Solid phase peptide synthesis. relation to human male factor infertility, and their • Cancer genomics, cardiovascular genomics. functional role is being addressed. • Genomics and proteomics. • More than 100 research papers have been published • Plant disease biology. in the reputed scientific journals. Some patent applications have been filed for the technologies For further details please visit RGCB website: developed by the institute. http://rgcb.res.in

76 Biotechnology: An agent for sustainable socio-economic transformation

National Institute of Biomedical Genomics, Kalyani, West Bengal

The National Institute of Biomedical Genomics (NIBMG) cause of oral cancer. These results have been published is the first institution in India explicitly devoted to research, in Nature Communication. training, translation & service and capacity-building in • Funding for eight research projects have been biomedical genomics. The overall aim of NIBMG is to obtained from extra-mural sources, including one provide basic research evidence using biomedical genomic from the U.S. National Institutes of Health. approaches for betterment of public health programmes • Collaborations with over twenty institutions, and services, establish state-of-the-art infrastructure for including several in the north-eastern Indian region genomic and proteomic analyses, promotion of better and one in the U.S.A. have been established. public health through the establishment of genomics infrastructure in hospitals and medical colleges, anchor • Establishment of a Biomedical Genomics Centre in young talent on the national soil and build capacity in the S.S.K.M. Hospital & Medical College, Kolkata. This Biomedical Genomics through organizing specialized Centre will empower clinicians to conduct research in courses in Medical Biotechnology, and to enable better disease-genomics and will also foster collaborations understanding of new medical to permit between basic scientists of NIBMG and clinicians. faster but more discriminating uptake by health care • More than 60 research papers have been published in providers. reputed scientific journals.

The main areas of interest are: Ongoing programmes and initiatives: • Cancer genomics • Genomics of host-susceptibility to infectious disease • Research on complex traits and diseases • Gene-expression profiling in health and disease • Maternal and infant sciences • Metagenomics in relation to immunity and growth • Genomics and epigenomics of chronic diseases • Creation of more Biomedical Genomics Centres in hospitals/medical colleges • Genomics and proteomics of infectious diseases • Creation of a Centre of Statistical & Computational • Statistical and computational genomics Genomics, within NIBMG • Major Achievements (in last 5 years): • Development of statistical methods to enhance the power • NIBMG is involved in oral cancer project as a part of discovering associations from genome-wide data of the International Cancer Genome Consortium. • Biology of stem-like cancer cells from human oral This Indian project has already made a global mark tumours by (a) discovering five new genes that are recurrently altered in oral cancer, (b) identifying that inactivating • PG and Doctoral programmes on Biomedical Genomics DNA alterations in tumour-suppressor genes and not For further details please visit NIBMG website: activating alterations in oncogenes, is the primary http://www.nibmg.ac.in

77 Biotechnology: An agent for sustainable socio-economic transformation

Regional Centre for Biotechnology, Faridabad

Regional Centre for Biotechnology (RCB) is an academic for biotechnology education, training and research (and institution established by the Department of Biotechnology, shall, in due course, be constituted as an autonomous Govt. of India with regional and global partnerships body under an Act of the Parliament). It is a “Category II synergizing with the programmes of UNESCO as a Centre” in terms of “the principles and guidelines for the Category II Centre. The primary focus of RCB is to establishment and functioning of UNESCO Institutes and provide world-class education, training and conduct Centres”. innovative research at the interface of multiple disciplines to create high-quality human resource in disciplinary The main areas of interest are: and interdisciplinary areas of biotechnology in a globally • Interdisciplinary education and training in competitive research milieu. The programmes of the biotechnology. Centre are designed to create opportunities for students • Carry out and promote multi-disciplinary innovative to engage in multi-disciplinary research where they learn research in biotech sciences. Contemporary research biotech science while integrating engineering, medicine at the interface of disciplines with integration of and science, to provide solutions for human and animal science, engineering and medicine and emphasis health, agriculture and environmental technologies. The on the relevance to the regional societies is being vision is to produce human resource tailored to drive undertaken. Broad range of areas synergizing with innovation in biotechnology, particularly in areas of new opportunities and also to fill talent gap in deficient areas. biotech science being pursued are: The Centre is an institution of international importance ■■ Biomedical science

78 Biotechnology: An agent for sustainable socio-economic transformation

■■ Bioengineering & devices • Molecular biology of thrombosis, coagulation, ■■ Biochemical and biophysical sciences inflammation, strokes, infractions and ischemia in disease conditions ■■ Climate science, agriculture and environment • Molecular determinants of genomic integrity and plasticity ■■ Biotechnology regulatory affairs, IPR and policy • Cell division, intercellular communication and Major achievements: cellular dynamics • Since its formal beginnings in 2010, RCB has • Unlocking the chemistry of cancer and nanomedicine grown from strength to strength by adjusting to • Structural biology of host-microbe interactions in changing times and setting the highest standards. health and disease, bacterial pili and biofilm RCB has accelerated efforts in multidisciplinary • Ubiquitin-mediated signalling in cellular processes facets of biotechnology while initiating new research • Molecular biology of infectious and idiopathic programmes as well as myriad educational and inflammation training activities. • Genetics of vertebrate skeletal muscle development, • Training activities are continuing in terms of differentiation, stem cell-mediated regeneration and laboratory-based workshops, visiting students on disease study tours from within and outside India and working • Signalling pathways in effector triggered immunity of of project trainees as part of the under-graduate and plant post-graduate curricula. • Complement regulatory proteins in autoimmunity • More than 50 research publications have been made • Transcription regulation: structure and mechanism in reputed scientific journals. • Functional genomics and molecular genetics of the Ongoing programmes and initiatives: legume-powdery mildew interaction • Structural biology of immune recognition, molecular For further details please visit RCB website: mimicry and allergy http://www.rcb.res.in

79 Biotechnology: An agent for sustainable socio-economic transformation

National Agri-Food Biotechnology Institute and Bio-Processing Unit, Mohali, Punjab

National Agri-Food Biotechnology Institute (NABI) institute and small & medium industries. The unit will and Bio-Processing Unit (BPU) are autonomous support, strengthen and promote innovation through institutions that began to function as a member institutes several initiatives. It will support R&D research resource of the Mohali Biotechnology Cluster at Knowledge City, units in the State and region. Mohali (Punjab). These two institutions are the nodal organization for knowledge generation and translational The main areas of interest are: science leading to value-added products based on • Agri-Biotechnology: Comparative genomics for gene innovations in agri-food biotechnology. NABl, BPU discovery and function, molecular breeding, genetic and an Agri-Food Biotech Park (ABP) being set up under resource prospecting, value added designer crops, public-private partnership are co-located. The NABI, BPU transgenic crops, association genetics etc. and ABP would therefore comprise an agri-food biotech • Food Science & Technology: Food processing cluster that would act as a “biotechnology hub” in the & technology, bioprocess engineering & energy region. The agri-food cluster has been developed to link optimisation, post-harvest food stability, biochemistry three essential related biotechnologies of crops, food and & metabolic profiling, flavours & dyes, food safety nutrition and carry out bench to market activity through etc. its state and regional resource networks. It is also planned to set up a translation unit in NABI to establish linkages • Nutrition Science & Technology: Novel foods, in the region among relevant R&D units, management nutrition for wellness, nutraceuticals, nutrigenomics

80 Biotechnology: An agent for sustainable socio-economic transformation

and nutritional biology, foods and nutrients for • More than thirty research papers have been published public health including: biofortification, biosynthesis and some patent applications have been filed. Training and molecular breeding, public health nutrition has also been imparted to undergraduate and post technologies, bioactives of nutritional value from graduate students. plants & microbes. Ongoing programmes and initiatives: Major achievements: • Functional Genomics for Nutritional and Processing • R & D carried out for improving cereals for nutrition Quality in Food Grains. and processing quality includes functional genomics • Accelerated Breeding For Processing Quality in for enhancing mineral nutrition and processing Wheat. quality in wheat. • Genetic Transformation of Banana for Quality • Accelerated breeding for quality improvement aimed Improvement. at marker discovery and development of puroindoline gene database of Indian cultivars. • Quality & Post-harvest Stability of Farm Produce. • The programme on improving fruits for post-harvest • Developmental Biology for Crop Improvement. quality and nutrition carried out with the aim of • Development of Genomic Resources for Grain quality enhancement and post-harvest stability of Crops. tropical fruits, genetic transformation of banana for • Development of Genomic Resources for Horticulture quality improvement, biology of seed development in Crops. custard apple and litchi, development of approaches for modulation of trait through rootstock signalling For further details please visit NABI website: and RNA-guided genome editing using CRISPR-Cas http://www.nabi.res.in; and sytem for crop improvement. BPU website: http://www.bpu.res.in

81 Biotechnology: An agent for sustainable socio-economic transformation

Institute for Stem Cell Biology and Regenerative Medicine, Bangalore

The Institute for Stem Cell Biology and Regenerative • Chemical Biology and Therapeutics Medicine (inStem) emphasizes collaborative research in • Inflammation and Tissue Homeostasis stem cell biology. inStem’s mandate to allow this cross- disciplinary, multi-pronged approach to research, straddles • Regulation of Cell Fate the divide between clinical and laboratory research in • Technologies for the Advancement of Science stem cell biology. Research at inStem, encompasses a wide range of topics in stem cell biology: from questions about Major achievements: the fundamental mechanisms that control differentiation • Research Groups have focused on development and renewal, to clinical studies on the impact of stem of purpose-built technologies e.g. new sensors for cells on recovery from stroke/injury. The institute is also detecting sub-cellular events; new materials for home to the Wadhwani Centre, a generous philanthropic drug delivery and new approaches in genome-wide donation dedicated to the study of stem cell biology of interrogation of stem cell properties. The team is the nervous system as well as cardiomyopathies. inStem’s called Technologies for the Advancement of Science. fast-growing, young and enthusiastic atmosphere ensures • A humanized mouse model with human beta-myosin that its work is at the very forefront of science. Research at has been developed for use in further studies. inStem is well-supported, with access to facilities at both NCBS and Centre for Cellular and Molecular Platforms • inStem centre for inflammation and tissue (C-CAMP). Together these three institutions serve as part homeostatis is working on caspase-8. It is known that of the Bangalore Biocluster. inStem is also the umbrella caspase-8 may act as a sensor to monitor epidermal organization for three initiatives: inStem itself, the Centre integrity. The group is investigating the mechanism by for Stem Cell Research (CSCR) located at CMC Vellore which caspase-8 gene expression is normally reduced and an Extramural Program in Stem Cell Research in epidermal cells at the wound site. Preliminary (EPiSTEM), a funding initiative for support of stem cell evidence suggests that the downregulation of this research nationwide. gene is partly due to methylation of caspase-8 locus, a similar phenomenon which has been documented in The main areas of interest are: various cancers. • Brain Development and Repair • A collaborative effort on determining the • Cardiovascular Biology and Disease entire glycome of hydra, a model system has

82 Biotechnology: An agent for sustainable socio-economic transformation

been accomplished and its role in regeneration • Collaborative programme on basic and translational demonstrated. investigations related to stem cell and regenerative • More than 100 research papers have been published medicines. in reputed high impact scientific journals. About 20 • The scientific program on basic biology, model patent applications have been filed. Human resource systems, cardiac hypertrophy & iPS, epithelial biology have been developed through PhD, MD and other & molecular oncology, neuronal stem cell. educational & training and exchange programs. • Research programmes on molecular medicine. Ongoing programmes and initiatives: For further details please visit inStem website: • Collaborative programme for discovery and analysis http://instem.res.in of drug targets in the stem cell/oncology.

83 Biotechnology: An agent for sustainable socio-economic transformation

National Institute of Animal Biotechnology, Hyderabad

National Institute of Animal Biotechnology (NIAB) is Major achievements: aimed to harness novel and emerging biotechnologies and • The main campus of NIAB is being developed in about take up research in the cutting edge areas for improving 100 acres of land within the campus of University of animal health and productivity. The Institute’s focus of Hyderabad; in the interim facility, NIAB has initiated research will be on Animal Genetics and Genomics, research programs on infectious diseases such as mastitis, Transgenic Technology, Reproductive Biotechnology, leptospirosis, brucellosis, FMD, PPRV and NDV. Infectious Diseases, Bioinformatics and Nutrition Enrichment. The Institute aims at translational research • Two multidrug resistant strains of Staphylococcus leading to the development of novel vaccines, diagnostics aureus were isolated from mastitis animals and and improved therapeutic molecules for farm animals. The detailed studies taken up to develop mechanism to overcome multi-drug resistance. Institute also promotes bio entrepreneurship by providing support environment for commercial tenants involved in • An immunoassay for screening of leptospirosis was the development of farm animal based products. developed by employing a Heme-binding protein A (HbpA) from leptospira and the same is being The main areas of interest are: validated on samples from infected and uninfected • Inflammation Biology humans and cattle. • Animal Genetics and Genomics • The program on brucellosis was directed towards understanding the essential mechanisms of increased • Infectious Disease pathogenicity and identifies the virulence factors ■■ Bacterial Disease enabling Brucella spp. to survive and replicate in the host. ■■ Viral Disease • More than 75 research papers have been published in ■■ Protozoan Disease reputed scientific journals.

• Reproductive Biotechnology Ongoing programmes and initiatives: • Genetic Engineering • Research on systematic studies on Infectious • Bioinformatics diseases, Animal Genetics and Genomics, Transgenic

84 Biotechnology: An agent for sustainable socio-economic transformation

Technology, Reproductive Biotechnology, Bio- • NIAB aims to start the following programmes: informatics and Nutrition Enrichment. Efforts are on ■■ M.Sc. in Quantitative Genetics and Genomics in to understand host-pathogen interactions involved collaboration with University of Hyderabad and in bacterial (brucellosis, mastitis), viral (NDV, FMD, Roslin Institute, University of Edinburgh, UK. PPRV) and protozoan (Babesiosis, Theleriosis and ■■ Ph.D. in Animal Science in collaboration with Toxoplasma gondii) infections for the development of University of Hyderabad. diagnostics, vaccines and therapeutic molecules. ■■ Ph.D. in Veterinary Sciences in collaboration with • Problems associated with animal reproduction i.e. geno- Indian Veterinary Research Institute Summer mics-based approaches to identify fertility associated Training programmes on Animal Biotechnology. markers in bull calves, stem cell biology for multiplication of elite livestock, identification of biomarkers for early detection of pregnancy and development of strip-based For further details please visit NIAB website: kit for heat detection in buffaloes. http://www.niab.org.in

85 Biotechnology: An agent for sustainable socio-economic transformation

Biotech Science Clusters

DBT, as a part of its biotech strategy, proposed creation of multi-institutional regional clusters at Faridabad, Bangalore and Mohali to ensure synergistic connectivity between partner institutions and with other stakeholders; build and maintain common infrastructural resources for research, translation and validation; enable the creation of cluster-wide resources, including human capacity, physical and technological infrastructure, translational platform, entrepreneurial and community connectivity and global engagement. There are three clusters: NCR Biotech Science Cluster, Faridabad; Bangalore Biotech Science Cluster and Mohali Biotech Science Cluster. III (BSL-Facility); Inter-Institutional Centres for Cross These clusters have proposed establishment of Advanced Disciplinary Research; Programme Management Unit Technology Platform Centre (Phase-I); Experimental for Population-Based Research/Hospital-Based Research Animal Facilities; Office of Connectivity & Governance & Technology Innovation; Phenomics Platform Centre; Structure; Policy Centre; Translational & Technology Bioengineering for Regenerative Medicine Facility; Bio Validation Centre; Data Centre; Mechanical Workshop for Innovation Accelerator Facility and India Bioscience Biodesign and Nanoengineering; Biobank and Repositories; Research Networking Program. Short-Term Educational & Training Facilities; Common Infrastructural Facilities; Bioincubator; Research For further details please visit DBT website: Hospital Partnership Programme; Bio-Safety Level- http://dbtindia.gov.in

86 Biotechnology: An agent for sustainable socio-economic transformation

Public Sector Undertakings

Biotechnology Industry Research Assistance Council, New Delhi

Biotechnology Industry Research Assistance Council not only on the funding support, but also on making (BIRAC), was set up by the Department of Biotechnology available the right infrastructure, mentoring and other for promoting and mentoring innovation research for networks for technology transfer and licensing, IP and affordable product development. With the approval of business mentoring including regulatory guidance. Lastly the cabinet, BIRAC was set up as a public sector, ‘not-for- BIRAC’s Strategic Partnership group works closely with profit’ Section 25 (now Section 8) company and registered all partners – national and international which includes under the Companies Act, 1956 (1 of 1956) on 20th Government departments and Ministries both Central March, 2012. BIRAC is providing enabling support and and State, industry organizations, international bilateral empowering the entire innovation ecosystem and more agencies, philanthropic organizations and corporate than 200 companies – large, small and medium start- sector, to leverage the strength and expertise and mobilize ups and entrepreneurs are a part of BIRAC’s Innovators resources and extend the outreach of its activities for network. BIRAC has its registered office in New Delhi. affordable product development. The mission of BIRAC is to facilitate overall growth of BIRAC has worked on the critical components of the biotech sector by mentoring and supporting generation ecosystem to give shape and implement its mandate and and translation of innovative ideas, products and processes more importantly show tangible outcomes that reflect the into viable bio-enterprises, enabling creation of biotech positive results catalysed by BIRAC. products and services and encouraging entrepreneurship. • BIRAC’s Impact The vision of BIRAC is to stimulate, foster, and enhance ■■ Funding support ~INR 1450 Cr the strategic research and innovation capabilities of the ■■ Support to 300 companies Indian biotech industry, particularly SME’s, to make India globally competitive in biotech innovation and ■■ Mentoring to 509 Projects and 150 Individuals/ entrepreneurship to create affordable products and Entrepreneurs provide services for addressing the problems of the larger section of society. To serve various dimensions of its mandate, BIRAC operates mainly in 3 verticals. Investment schemes provide funding support to entrepreneurs, start-ups, SMEs and Biotech Companies for all stages of the product development value chain from discovery to proof of concept to early and late stage development to validation and scale up, right upto pre-commercialization. There are also special product development missions. The second vertical is Entrepreneurship Development which focuses

87 Biotechnology: An agent for sustainable socio-economic transformation

■■ 23 Products/Affordable Technologies developed, 19 Early Stage Technologies developed and 45 IP created

BIRAC Support at various stages of Product Development • Fostering Innovation and Reducing ‘Innovation Risks’- Promoting Entrepreneurship ■■ Biotechnology Ignition Grant ■■ Bio-incubators • Empowering, Enabling & Driving the Indian Biotech Innovation Ecosystem for Affordable Product Development ■■ Small Business Innovation Research Initiative (SBIRI) ■■ Biotechnology Industry Partnership Programme (BIPP) ■■ Contract Research Scheme (CRS) • Social Innovation BIRAC launched – Sparsh – Social Innovation Programme for Product Affordable & Relevant to Societal Health, with the objective to promote biotechnology products and solutions for maternal and child health. The programme ■■ Indo French Centre for the Promotion of Advanced has another component – SIIP (Social Innovation Research, BPI France, and French Embassy in India Immersion Programme), a fellowship scheme intending to ■■ Partnership with Department of Electronics create a pool of social innovators who can identify the gaps and Information Technology, GoI, for Industry in healthcare needs of various communities and help in innovation programme on Medical Electronics bridging them through innovative product development. ■■ SRISTI, IIM Ahmedabad for promoting grass root • Building Strategic Alliances level innovations ■■ DBT-BIRAC-GATES Foundation ■■ Wadhwani Initiative for Sustainable Health (WISH) ■■ BIRAC–DBT–WHO–PATH Multi-Stakeholder for scale up of the innovations supported by BIRAC Consortium on Affordable Technologies for • Future Outlook: BIRAC is planning to launch the Women & Child following intiatives : ■■ Partnership with CDSA for Management of BIRAC ■■ Creating Translational Facilities to move research Supported Clinical Trials leads forward ■■ Wellcome Trust, UK ■■ Launching BIRAC Industry Sponsored Research (BISR) ■■ UK Trade and Investment (UKTI) for promoting ■■ Initiating “National Mission on Biologicals” Indian innovations in the EU ecosystem ■■ Launching RAPID especially in Wheat & HPV vaccine ■■ USAID and IKP Knowledge Park for a joint funding ■■ Launching an institutionalized Mentorship programme for TB Diagnostics Programme for Start-ups & SMEs ■■ Centre for Entrepreneurial Learning, University of For further details please visit BIRAC website: Cambridge, UK www.birac.nic.in

88 Biotechnology: An agent for sustainable socio-economic transformation

Bharat Immunologicals and Biologicals Corporation Limited (BIBCOL)

Bharat Immunologicals and Biologicals Corporation achieved a turnover of Rs 173.88. crore and Rs 208.76 Limited (BIBCOL) is a Central Public Sector Unit (PSU), in the year 2012-13 and 2013-14 and profit after tax of under the administrative control of the Department of Rs. 501.54 and Rs 640.65 respectively. Company has Biotechnology (DBT), Ministry of Science & Technology, ambitious plan for diversification into other vaccines Government of India. BIBCOL is a leading biotechnology and biologicals in the years to come. company based in Uttar Pradesh India. The company has its OPV plant in state of Uttar Pradesh. India. BIBCOL was established in 1989 with the novel theme to achieve the country as polio free nation. BIBCOL’s principal mission is to save the lives of millions of children from avoidable disability, through polio vaccination. Since its inception, it has contributed significantly to the eradication of Poliomyelitis in the country through the National Immunization Program. BIBCOL is continuingly growing and secured its position among the top 20 Biotech companies in India, as revealed by recent market surveys only due to its cGMP certified infrastructure, highly skilled manpower and constant support from DBT, Government of India. BIBCOL has started its journey with single product (tOPV) but gradually added more products and now produces Diarrhoea Management Kit, Oral Polio Vaccine (mOPV, bOPV and tOPV), and Zinc Dispersible Tablet. BIB Zinc dispersible Tablets. For last three years BIBCOL has been performing exceptionally well and from a sick company, the company has become profit making company, and

tOPV Vials with dropper Combo kits (Zic tab + ORS)

89 National Biotechnology Development Strategy 2015-2020

Promoting bioscience research, education and entrepreneurship

Department of Biotechnology Ministry of Science & Technology Government of India National Biotechnology Biotechnology: An agent for sustainable socio-economic transformation Development Strategy 2015-2020

The Way Forward

IIn the last three decades, the efforts by the Department of Biotechnology, provided the impetus for and helped in building indigenous capabilities in health, food and environment. It also laid the foundation for offering research support to biotech industries through launching of major PPP programs and spearheaded new frontiers of biotech research by drafting guidelines for transgenic plants, recombinant vaccines and drugs and stem cell therapy. It unfolded enormous opportunities and challenges which have resulted in building a strong foundation and base for India to grow as a major bioeconomy in the years to come. There is now a paradigm shift in the relationship between government, academia, industry and civil society. This is critical for the new era of science-driven, society relevant innovation and entrepreneurship. DBT is committed to building newer instruments for connectivity. To accelerate the pace of growth of biotechnology sector at par with global requirements the DBT announced the National Biotechnology development Strategy 2015-20. The National Biotechnology Development Strategy-2015-2020 is the direct result of formal and informal consultations over the past two years with over 300 stakeholders including scientists, educators, policy makers, leaders of industry and civil society, voluntary and non-government organizations, regulators and international experts. The consultations offered an opportunity to discuss and evaluate technological, societal and policy aspirations, critical success factors as well as barriers that will impede growth and put them in newer and broader perspective and action plan. The strategy seeks to address a number of identified challenges in terms of tailor-made human capital for scientific research and entrepreneurship; research priorities, resources, and core facilities; creation of investment capital; intellectual property regime; technology transfer, Promoting bioscience research, education absorption, diffusion and commercialization; regulation standards and accreditation; biotechnology partnerships between public and private sectors both nationally and globally and public understanding of biotechnology. The key elements detailed and entrepreneurship out in the sectoral priorities are: 1. Building a Skilled Workforce and Leadership 2. Revitalizing the knowledge environment at par with the growing bioeconomy 3. Enhance Research opportunities in basic, disciplinary and inter-disciplinary sciences 4. Encourage use-inspired discovery research 5. Focus on biotechnology tools for inclusive development 6. Commercialization of technology - nurturing innovation, translational capacity and entrepreneurship 7. Biotechnology and Society – Ensuring a transparent, efficient and globally best regulatory system and communication strategy 8. Biotechnology cooperation- Fostering global and national alliances Department of Biotechnology 9. Strengthen Institutional Capacity with redesigned governance models Ministry of Science & Technology

Government of India 91 Biotechnology: An agent for sustainable socio-economic transformation

10. Create a matrix of measurement of processes as well as outcome The envisaged mission is to: Provide impetus to utilising the knowledge and tools to the advantage of Humanity, Launch a major well directed mission backed with significant investment for generation of new Biotech Products, Empower scientifically and technologically India’s incomparable Human Resource, Create a strong Infrastructure for R&D and Commercialisation and Establish India as a world class Biomanufacturing Hub. The key elements would be implemented in collaboration and partnership with other Ministries, Departments, State Governments and international agencies towards achieving: • Making India ready to meet the challenge of achieving US$100bn by 2025 • Launching Four Major Missions – Healthcare, Food and Nutrition, Clean Energy and Education • Creating a Technology Development and Translation network across the country with global partnership-5 new clusters, 40 Biotech incubators, 150 TTOs, 20 Bioconnect centres • Strategic and focussed investment in building the Human Capital by creating a Life Sciences and Biotechnology Education Council

92 Ministry of Science & Technology Government of India

Global Biotechnology Summit Celebrating Biotechnology: Destination India 5th - 6th Feb, 2016 at Vigyan Bhawan, New Delhi www.dbtindia.gov.in Special Volume on Special Volume Government of India of Government Biotechnology Ministry of Science & Technology, Ministry Science & Technology, of An agent for sustainable sustainable for agent An 30 Years of Department of Biotechnology, of Department of 30 Years socio-economic transformation transformation socio-economic

Biotechnology An agent for sustainable socio-economic transformation Supported by Media Partner Partner Media Special Volume on Special Volume Government of India of Government Biotechnology An agent for sustainable sustainable for agent An Ministry of Science & Technology, Ministry Science & Technology, of socio-economic transformation transformation socio-economic 30 Years of Department of Biotechnology, of Department of 30 Years