In-Depth – Page 7 – The KGP Chronicle

Crafted from paper

Cell culture is integral to biological research. It provides a model to study the standard physiology and biochemistry of cells, the effect of drugs on cells, how cells behave under different culture environments. But the growing of cells on flat plastic surfaces does not accurately model their state inside the body. Hence scientists are increasingly using various three-dimensional (3D) cell culture strategies that allow cells to grow or interact with their surroundings in a way they actually do inside the body.

The prevalent 3D culture systems are mainly scaffolds, hydrogels and 3D printed models. Producing them is time consuming and requires a lot of technical skills. Often there are batch to batch variations. The base materials are also expensive. So, the development of cheap, portable and experimentally flexible 3D models has become necessary. A team of researchers at IIT Kharagpur has provided the answer by utilizing commercially filter paper for mammalian cell culture, which has been rarely reported.

Filter paper has often been used in making point-of-care devices (such as paper fluidics), but so far they have not been used this way. Composed of randomly arranged cellulose fibres, filter paper lacks cell adhesion motifs, making it amenable to being used as a paper substrate. However, for making it a suitable substrate, modification techniques had to be implemented. The main breakthrough achieved by this group is the use of a technique that makes it possible to fabricate cheap and affordable paper substrate for 3D mammalian cell culture.

The research group led by Prof. Tapas Kumar Maiti of the Department of Biotechnology, IIT Kharagpur has developed paper-based devices using LaserJet methodology (to defines cell culturable area) followed by (3-Aminopropyl)triethoxysilane (APTES) or glutaraldehyde/PAMAM treatment of the devices. This increases the interaction of the cell or other biological macromolecules (such as proteins/DNA) with the paper matrix. In order to further provide essential biochemical cues required to maintain physiological behavior of cells, they coated the amino-functionalized paper with natural extracellular matrix proteins.

Their results showed that the developed paper devices favoured the adhesion, proliferation, and 3D growth of multiple cell types including normal, transformed, cancerous, and stem cells as compared to the pristine paper matrix. These established 3D cultures on the paper matrixes (“in vitro paper-based tissue models”) could be extended for in vitro applications such as on-paper coculture models, on-paper gene expression analysis (immunocytochemistry/in-cell ELISA), drug screening and cell invasion assays. Further, such 3D culture could also be used to address relevant biological questions pertaining to cell-matrix interaction, cell-cell interaction, matrix confinement effects and so on.

It would be interesting to note that the cost incurred for procuring a conventional plate for coculture and transwell migration studies is Rs 7,000. The paper devices fabricated by the team of researchers at IIT Kharagpur cost Rs 100-200. Low media requirement and multiplexibility of the developed paper devices further cuts down the overall cost of biological assays.

The researchers also evaluated the systemic toxicity and antigenic response of the paper matrixes and found that the treated paper substrates significantly reduced the immunogenic response in the host, along with enhanced cellular infiltration and cell spreading of the infiltrated cells in the mouse model as compared to pristine paper substrates. This could provide the opportunity to use paper as a cheap and affordable substrate for the development of humanized animal models.

Prof. Maiti said, “Considering the simplicity, cost-effectiveness, and multiplexibility of the paper-based liver models, it is deemed to be ideal for developing cell-based bioassays especially in the resource-limited settings. Moreover, such technological advancement in the field of paper-based cell culture could open up new vistas in the field of biotechnology and engineering and could be used to disseminate the cell culture-related knowledge at the school/college levels.”

The team, consisting of Prof. Suman Chakraborty of the Department of Mechanical Engineering, Prof. Sudip Kumar Ghosh of the Department of Biotechnology and researchers Mr. Tarun Agarwal, Mr. Pratik Biswas, and Ms Aruja Rustagi from the Department of Biotechnology have applied for patent of their technology. The paper, ‘Biofunctionalized cellulose paper matrix for cell delivery applications’, was published in the International Journal of Biological Macromolecules ( Download paper https://www.sciencedirect.com/science/article/pii/S0141813019309109 and https://www.sciencedirect.com/science/article/pii/S0927776518305940)

Paper chase

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Like many other sectors, Artificial Intelligence is all set to impact jurisprudence. In countries such as USA, Britain, Japan, Singapore and Australia, it is already changing the way lawyers do business. AI is being used to perform legal research, review documents during litigation and conduct due diligence, analyse contracts to determine whether they meet pre-determined criteria and to even predict outcomes. AI is yet to sufficiently penetrate the legal field in India though. But that may soon change.

At IIT Kharagpur, the Department of Computer Science and Engineering is conducting a slew of research work on the application of AI in the legal field. A recently released paper by the research group on the ‘Identification of Rhetorical Roles of Sentences in Indian Legal Documents’ won the prestigious ‘Best Paper Award’ at JURIX 2019, the International Conference on Legal Knowledge and Information Systems, held in Madrid during December 11-13, 2019. For more than 30 years, the annual JURIX conference has provided an international forum for research on the intersection of Law, Artificial Intelligence and Information Systems.

The research team at the CSE Department has used a novel method to automate the reading of a legal document by using a more evolved Machine Learning technique. Instead of the usual ‘Conditional Random Fields’ that use handcrafted features to train the machine, they have used two deep neural models to understand the rhetorical roles of sentences in a legal case judgment.

Automatically understanding the role of sentences in a legal case judgment is important as it can help in several downstream tasks such as summarization of legal judgments, legal search, case law analysis and other functions necessary for legal research. For a country like India, which uses a common law system that prioritizes the doctrine of legal precedent over statutory law, and where legal documents are often written in an unstructured way, the difference AI can bring is phenomenal, says Prof. Saptarshi Ghosh of the Department of Computer Science and Engineering, who is leading the team.

Taking judgments from the Supreme Court of India, the team has segmented the 50 documents by labeling sentences using multiple human annotators (three senior law students from IIT Kharagpur’s Rajiv Gandhi School of Intellectual Property Law), performing extensive analysis of the human-assigned labels and then developing a high quality gold standard corpus to train the machine to carry out the task. “We use this annotated dataset in our experiments to automate the task of assigning semantic roles to sentences,” says the paper.

As mentioned before, prior attempts to automate identification of rhetorical roles of sentences in legal documents have depended on handcrafted features such as linguistic cue phrases indicative of a particular rhetorical role. These features depend on legal expert knowledge which is expensive to obtain. Besides, these features are often developed keeping in mind one specific domain. The neural methods used by Prof. Ghosh’s team automatically learn the features given sufficient amount of data and can be used across domains.

The two models used are – Hierarchical BiLSTM model and Hierarchical BiLSTM-CRF model. The models, which undertake a seven-class labeling, are seen to perform better in the task of classification than baseline ML methods that use handcrafted features. The performance of the models is compared based on the 50 manually annotated documents by using standard metrics of evaluation for the performance of the algorithms. The results show that the “latent features learnt by the neural models are better than the hand-crafted features used in prior works,” says Prof. Ghosh. Not only that, the comparison between the automated and human-generated labellings show that the former reflect the same confusion around labels in which there is confusion among the human annotators. In other words, using the neural models, the machine correctly identifies the subjective rhetorical roles of sentences.

Prof. Ghosh’s team consists of his students, Paheli Bhattacharya and Shounak Pal, as well as researchers from the Tata Research Development and Design Centre, Pune, and Swansea University, United Kingdom. Automating the identification of rhetorical roles of sentences in legal judgments, which will go a long way to aid legal research, is only one facet of the team’s efforts to enhance the application of AI in the legal field. Prof. Ghosh’s team, particularly Paheli, is using network and text analysis to understand if two legal documents are similar – which will further enhance the automation of legal research.

“We are trying to build an AI system which can give guidance to the common man about which laws are being violated in a given situation, or if there is merit in taking a particular situation to court, so that legal costs can be minimized. Together with experts at RGSOIPL, we will also try to use AI to investigate pendency in Indian courts and its solution,” says Prof. Ghosh, who says that given that IIT Kharagpur has its own law school, it is uniquely suited to carry out research along these lines.

The project is being supported by the Science & Engineering Research Board (SERB) of the Department of Science and Technology, Government of India, under the project, ‘NYAYA: A Legal Assistance System for Legal Experts and the Common Man in India’. The project, which started in June 2019 and will continue till 2022, is being conducted jointly by IIT Kanpur and IIT Kharagpur.

Building Knowledge Portal of India

For most people outside the country, India is a land of antiquity, of ancient wisdom and knowledge. The preservation of said antiquity and the wealth of cultural heritage, however, has proved to be a challenge in our country. Locating the original material is itself a task but by no means the largest hurdle. Worn, yellow and tattered pages need careful supervision and expert handling of the material. Apart from the expertise required in traditional preservation of antique documents, the digital age calls for the preserved material to not just be digitized, but also be accessible to users of all ages, at all places and at all times. In the West, institutions like the British Library and the US Library of Congress have been digitally preserving cultural artifacts for a while now.

Closer home, National Digital Library of India (NDLI) – an MHRD initiative executed by IIT Kharagpur – is set to deliver 21^st Century solutions to age-old problems of preservation of cultural artifacts for posterity. Proud hosts to original digital copies of Kheror Khata – Satyajit Ray’s handwritten screenplay manuscripts, NDLI has carefully archived a series of cultural wealth that narrates the nation’s story of being and becoming. Digital copies of Jugantar and Amrita Bazar Patrika newspapers are available in NDLI, which have fascinating recordings of India’s history during and post Independence.

However, that is just the tip of the iceberg. India’s wealth of knowledge heritage is as diverse as the inter-web is vast.

Presidency University Kolkata is a 203 years old heritage institution that started its journey in 1817 as Hindoo College. In the year 1855, Hindoo College was transformed to Presidency College by the then British Government. The alumni and teachers of this great institution have helped shape the nation in the fields of economics, science, arts and every nuance in between. Some priceless and antique publications like the Presidency Register of 1934 comprising historical reports, data and a list of students since 1817 of Hindoo-Presidency are the prized possession of the Presidency Alumni Association with no other copy available. These records, data, reports, and articles have been digitized and hosted by an alliance of the Presidency Alumni Association and the National Digital Library of India. In a symbolic coming together of a National knowledge platform with a heritage Institution to pave the way for India’s knowledge heritage, these documents, reports, articles are now available at zero-cost on National Digital Library of India site: https://www.ndl.gov.in/ for anyone, anywhere to access freely to learn, share and grow.

Registration to NDLI is free.

The platform is also available as an android as well as an iOS app.

All in days’ work

Two back-to-back workshops organized by the Bioprocess & Bioproduct Development Laboratory (PI: Prof. Ramkrishna Sen) of the Department of Biotechnology, IIT Kharagpur along with the collaborators from USA and Australia from January 2-5, 2020 under the Government of India’s Scheme for Promotion of Academic and Research Collaboration (SPARC) brought to students latest news on how the scientific community the world over is bracing up for a future that will see biofuels replace petroleum and green technologies being employed in a world that is seeing the steady depletion of natural resources. The bottom-line of both the workshops were the pursuit of new technologies for a sustainable future.

Prof. Seider, Prof. Tewari (Director, IITKGP), and Dr. Venkata Mohan (extreme right)

“We are presently living in a linear economy, where we ‘take, make and throw’. But this is a cradle-to-grave attitude. We have to move towards a circular economy, where producing energy from biogenic waste will play a significant role,” said the S. S. Bhatnagar awardee, Dr. S. Venkata Mohan from the CSIR-Indian Institute of Chemical Technology, Hyderabad.

In the first workshop on ‘Sustainable biorefinery for Waste Valorization, organized by Prof. Sen’s group in IIT Kharagpur jointly with the University of Pennsylvania, USA from January 2-3, 2020, the Indian and US researchers and experts discussed the challenges and breakthrough technologies that inform the search for future renewable energy sources.

Professor Warren D. Seider from the University of Pennsylvania

Prof. Sen’s US collaborator under SPARC, Prof. Warren D. Seider, a world renowned Professor of Chemical and Biomolecular Engineering at the University of Pennsylvania, who has written ground-breaking Chemical Engineering books, talked about the application of mathematical programming methods to optimize a biorefinery to make ethanol. Citing Prof. Rafigul Gani’s mathematical model, which appears in Prof. Seider’s textbook –“Product and Process Design Principles”, co-authored with several experts, including Prof. Gani, Prof. Seider showed how both India and Thailand were to gain immensely if they used their biomass-based feedstocks – wheat straw, sugarcane bagasse, hardwood chips among them – to produce ethanol products sustainably.

Prof. Ramkrishna Sen, Convenor of both the workshops and the Head of the Department of Biotechnology, talked of how his biorefinery helps in carbon-dioxide sequestration from point sources, wastewater remediation and biofuel production through strategic cultivation of green microalgae and valorization of biomass for various applications in a biorefinery model. Prof. Pinaki Bhattacharya, a well-recognized expert in Chemical Engineering and former Professor & Head, Department of Chemical Engineering, Jadavpur University and Emeritus Professor, Heritage Institute of Technology; Prof. Ranjana Chowdhury, Professor & former Head, Department of Chemical Engineering, Jadavpur University and Dr. Harshad Velankar, Senior Manager & Head Bioprocess Division, Hindustan Petroleum Green R & D Center, HPCL, Bengaluru were also the invited dignitaries of the event and delivered very interesting and insightful talks that stressed on the need for setting up of biomass based biorefineries and attempted to address the challenges in designing and operating such sustainable biorefineries.

The other speakers at the workshop were Prof. Debabrata Das, Visiting Professor, Department of Biotechnology, IIT Kharagpur, who has been researching into biohydrogen production processes for the last three decades, and Prof. B. C. Meikap, Professor, Department of Chemical Engineering, IIT Kharagpur, who presented his nice work on amine-based carbon capture in fluidized bed reactor operations.

Among Prof. Sen’s doctoral students, Dr. Geetanjali Yadav, who has worked with Prof. Seider in designing a commercial scale algal-to-biodiesel production plant that could produce 183 million gallons of biodiesel per year during her Fulbright-Kalam Climate Fellowship at the University of Pennsylvania presented her work and Mr. Romit Mitra presented his novel idea on metabolic engineering of yeast for biobutanol production in a biorefinery. A doctoral student of Prof. R. Chowdhury, Jadavpur University presented his work on bioethanol production using agro-wastes.

The Indo-Australia joint workshop on the ‘Recent Advances in Biocementation Technology’, which followed on January 4-5, too was held under the aegis of SPARC. The Australian collaborators of Prof. Ramkrishna Sen under the SPARC program from the Department of Civil and Environmental Engineering, Curtin University, Prof. Abhijit Mukherjee and Dr. Navdeep Dhami joined hands for the two day-workshop along with the experts from India, Prof. Devendra Narain Singh (Institute Chair Professor, Department of Civil Engineering, IIT Bombay), Prof. Brajadulal Chattopadhyay (Professor, Jadavpur University) and Prof. Debasis Roy, Department of Civil Engineering, IIT Kharagpur to make it a fruitful learning experience for all the participants. Prof. Sen and his research students, Piyush Nanda, Raviranjan Kumar and Ankita Debnath presented their research work in the relevant field.

Indo-Australia SPARC workshop participants

Biocementation is an emerging technology that leverages microbes and their actions for production of renewable and sustainable construction materials. The workshop aimed to give a bird’s eye view on biocementation from the perspective of biotechnologists, civil and environmental engineers.

Both the workshops were well organized by the members of the Bioprocess & Bioproduct Development Laboratory, Department of Biotechnology, which thankfully acknowledges Dr. Chinmay Hazra and Dr. Debasree Kundu for their tremendous efforts and ground level coordination. The workshops, inaugurated by the Hon’ble Director of IIT Kharagpur, Prof. V. K. Tewari, Dean (CE), Prof. S. Dasgupta and Associate Dean (SRIC), Prof. R. Mukherjee were well attended by more than 50 participants from within and outside IIT Kharagpur. SPARC, an initiative of the Ministry of Human Resource Development, helps improve the research ecosystem in India by facilitating academic and research collaborations between Indian institutions and the best and selected institutions across the world’s 28 nations. As the national coordinator, IIT Kharagpur has been coordinating this flagship program with other nodal institutes of India.

Innovating for Rural Healthcare

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Do you think compact discs are devices of the past? May be for your laptops, but not for researchers at IIT Kharagpur who have redefined the use of CDs for low-cost medical diagnostics. Researchers from IIT Kharagpur led by Professor Suman Chakraborty from the Department of Mechanical Engineering have recently innovated a simple low-cost motorized spinning disc-based kit to perform Complete Blood Count (CBC).

CBC is a collection of the most commonly required blood tests that is routinely suggested by the medical doctors, to assess a wide range of diseases spanning from common fever to cancer. The existing methods for this test are prohibitively expensive in the tune of ₹ 200 for the underprivileged population due to the requirements of sophisticated instrumentation and trained personnel.

“We have proposed a unique low-cost kit comprising a motorized device as a blood cell counting platform. The device is a simple spinning disc running on a small motor which is capable of performing the test whereby the parameters such as haematocrit (packed volume of red blood cells), haemoglobin, red blood cell (RBC), white blood cell (WBC), and platelet counts are estimated with an accuracy higher than 95 % as compared to an automated haematology analyser,” said Prof. Chakraborty.

This novel innovation which included Ph.D students Rahul Agarwal and Devdeep Mukherjee, and Post Doctoral Fellows Arnab Sarkar and Arka Bhowmik has recently been reported in Biosensors and Bioelectronics, a high-impact flagship Journal from Elsevier. [Download Paper]

Explaining the methodology, Ph.D students Rahul Agarwal and Devdeep Mukherjee said, “The method essentially exploits the difference in densities of cells for separation in a rotating disc due to centrifugal force and implements label-free imaging method for counting the separated cells within the spinning disc.”

The researchers highlighted on the biodegradability of the disc after using it for multiple sample testing.

“The design and fabrication techniques have been kept simple along with potential automation thereby making the device portable and eliminating the need of trained personnel. Most significantly, eliminating any need for downstream processing of the separated blood,” remarked Post Doctoral Fellows Arnab Sarkar and Arka Bhowmik.

This innovation is expected to bring down the cost of one Complete Blood Count test to about ₹10.

“Such an innovation of medical device may result in a paradigm shift in providing diagnostic services to the underserved rural population at large. The upcoming superspecialty hospital of IIT Kharagpur would operate in a hub and spoke model, and would use several of such devices to ensure improved reach of telemedicine and mobile healthcare to the last man of the society,” said Director V K Tewari.

Regarding commercial product development and availability, Prof. Suman Chakraborty reaching out to MSMEs.

“The Common Research & Technology Development Hub on Technologies for Affordable Healthcare supported by the Government of India’s DSIR aims to support growth & development of precision manufacturing of innovative technologies through MSMEs to reduce India’s massive import in healthcare technologies and their affordability and accessibility. The CBC kit will be a key product which could be licensed and be made market ready by MSMEs connected to this Hub,” he said.

More such healthcare technology commercialization is in the process confirmed Chakraborty.

Mentoring Startup for Industry 4.0

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The Center of Excellence in Advanced Manufacturing Technology at IIT Kharagpur is roping in MSMEs for collaborative R&D projects and consultancy to develop resources for Industry 4.0. In a recent initiative, the Centre, which is funded by the Department of Heavy Industry of Ministry of Heavy Industries and Public Enterprises, Government of India, has signed an MoU with a Kolkata-based startup Hemraj Infocom to promote industrial consultancy and industrial research internship for students.

Hemraj Infocom will be the first affiliate member in the industry consortium of the Centre which is currently led by top industries as Tata Motor, Tata Consultancy Services, Tata Steel, Tata Sons, BHEL, and HEC.

Prof. Surjya K Pal who is heading Centre said, “We are looking forward to more such startups joining the consortium whom we will offer mentorship in the area of Industry 4.0 applications. With Hemraj we will be mentoring them in the manufacturing applications in which our Centre has got a strong foothold. They will also have access to the facilities at our Centre both to the experts and infrastructure. We will also provide them with free training on cutting-edge industrial applications, research solutions for their typical industrial challenges such as cloud computing, real-time data processing, analysis and storage, networking and automation, real-time process monitoring.”

Students from various backgrounds including electronics and electrical communication, or mechanical or electrical engineering etc. would be able to work on problem statements shared by the startup.

Hemraj Infocom is working in combined areas of IoT, AIML, Robotics, Automation and which will prove to be revolutionary with a new industrial boom in India in the near future.

Soham Dasgupta, CEO of Hemraj Infocom confirmed the submission of projects for mentorship in voice-enabled survey devices, predictive maintenance for motors. He is hopeful such research internships will further boost MSME culture in the region. “We are also looking for upgrading the research skills of our human resources,” said Dasgupta.

Abhishek Saha, Head, Business Development of Hemraj Infocom said, “we are enthusiastic about seeking guidance on mission-critical projects from an academic institution of repute like IIT Kharagpur which will enable us to deliver proof of concept and projects thereby by implementing niche areas of R&D in our business operations.”

The Centre has been conducting several industry-aligned workshops, short-term courses, talks by industry experts for MSMEs and capital goods sector in areas such as computer numerical controls, composite manufacturing, metallography. The programmes are also open to students from other educational institutions. For affiliate members, such training workshops will be conducted free of cost and also a huge pool of student researchers in diverse areas of Industry 4.0 would be made available to work on problem statements.

Prof. Pal has been approaching FOSME, CII, EEPC to reach out to startups and MSMEs and connect them to the Centre’s consortium.

“It will diversify the Centre’s research goals through a different set of application-oriented industrial challenges with more tight timeline and product delivery schedule as against giant corporations which focus on broader R&D,” he remarked. More such MSMEs are in touch with the Centre for affiliated memberships, he confirmed.

The Centre aims to stimulate innovation to manufacture smart machines in the capital goods sector. This centre offers a unique platform for innovative and top-quality research focused on the industries on Specialty materials, Design and automation, Additive manufacturing, and Digital Manufacturing and Industrial Internet of Things. The centre will boost innovative interventions and collaborative research in the advanced manufacturing domain by enabling an ecosystem among Institutes of higher repute, heavy industries, and also the MSMEs and start-ups.

In the quest for the hidden past

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Indian researchers have for the first time connected the decline of Harappan city Dholavira to the disappearance of a Himalayan snow-fed river which once flowed in the Rann of Kutch. They have connected the dots between the growth and decline of the Dholavira, the most spectacular and largest excavated Harappan city in India located in the Rann with this river which resembles the mythical Himalayan River Saraswati. The study has just been published online in prestigious Wiley Journal of Quaternary Science.

Studies so far made were indirect attempts to find out the river courses, its connection to climate and civilization in areas far away from these ancient cities. But this research team from IIT Kharagpur, Archaeological Survey of India, Deccan College PGRI Pune, Physical research laboratory, and Department of Culture, Gujarat, dated archaeological remains from all the stages and also inferred climate shifts through time which led to the rise and fall of the Harappan city.

“Our data suggest that prolific mangroves grew around the Rann and distributaries of Indus or other palaeochannels dumped water in the Rann near southern margin of Thar Desert. This is the first direct evidence of glacial fed rivers quite like the supposedly mythological Saraswati, in the vicinity of Rann” said IIT Kharagpur’s Prof. Anindya Sarkar who led the research.

Dr. Ravi Bhushan and Navin Juyal from PRL, Ahmedabad dated the carbonates from human bangles, fish otolith and molluscan shells by accelerator mass spectrometer and found that the site was occupied from ~5500 years back i.e. Pre-Harappan period to ~3800 years before present i.e. Late Harappan period. The Dholavirans were probably the original inhabitants in the region, had a fairly advanced level of culture even at its earliest stage. They built spectacular city and survived for nearly 1700 years by adopting water conservation suggested the researchers. The study indicates that the city expanded till 4400 years followed by an abrupt decline nearly ~4000 years back, onset of the newly proposed Meghalayan geological stage.

Researchers Dr. R.S. Bisht and Y.S. Rawat from the Archaeological Survey of India who originally excavated the site concluded this based on degeneration of architecture, craftsmanship, and material culture.

Dr. Arati Deshpande Mukherjee of Deccan College pointed out at the climate evidence coming from high resolution oxygen isotopes in snail shells Terebralia palustris which typically grow in mangroves and was a source of food for the Dholavirans.

The lead author of the paper and a PhD student at IIT Kharagpur Torsa Sengupta said, “the early to Mature Harappan snail isotopes suggested that the mangrove was fed by Glacier River debouching in the Rann of Kutch. However, during late Harappan period the meltwater contribution and seasonality reduced coinciding with the fall of Dholavira.”

“Though the Dholavirans adopted excellent water conservation strategy by building dams, reservoirs and pipelines, but were pushed to the limit by a catastrophic Meghalayan mega-drought collapsing the city. Indeed Dholavira presents a classic case for understanding how climate change can increase future drought risk as predicted by the IPCC working group” added Prof. Anindya Sarkar.

The research indicates that the collapse of Harappan Dholavira was near-synchronous to the decline at all the Harappan sites in India as well as societal collapse of Mesopotamia, Greece, China and the Old Kingdom of Egypt.

Opening new vistas

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Curcumin, found in turmeric, and Ginsenoside, found in the roots of Ginseng, both known for their medicinal properties, could go a long way in treating blood disorders like thalassemia and sickle cell anemia. These two plant ingredients, together with approved drugs such as Valproate and Vorinostat were found to be “most suitable for future trials” by a team of genetic scientists at IIT Kharagpur. They are trying to see which drugs induce fetal hemoglobin production – which is known to ameliorate such blood disorders – and whether ‘repurposed drugs’ could be used. Repurposing of drugs, a new and exciting arena of scientific study, seeks to use approved drugs for clinical conditions other than those in which they are usually used for.

Blood disorders or hemoglobinopathies such as beta thalassemia and sickle cell anemia affect millions. They occur due to mutations in the β-globin gene, which leads to low or absent production of adult hemoglobin. Drug-induced increase in fetal hemoglobin – which constitutes a major percentage of the total hemoglobin in newborns, and which gets almost completely replaced by adult hemoglobin by 4 to 6 months of age – has been shown to improve the clinical features of those affected with sickle cell disease and beta thalassemia. Unfortunately, most of these drugs have serious side-effects and are therefore rarely used in therapy. Identifying new drugs could be a time-consuming and uncertain exercise. Hence scientists are trying to see whether ‘repurposed’ or existing drugs can be used to treat these disorders.

To find out which drugs could be investigated for possible repurposing to treat these specific blood disorders, scientists at the Regenerative Medicine lab of the School of Medical Science and Technology of IIT Kharagpur studied the working of microRNAs (miRNAs), and also which chemical molecules affect their expression pattern. MiRNAs, which are a small class of non-coding RNAs, have recently been identified as critical regulators of as much as 70% of the genes in the human genome.

The production of fetal hemoglobin in human body, much like other biological processes, is a “coordinated event under the control of genes and proteins encoded by the human genome”. Since miRNAs regulate the pathways along which the production of fetal hemoglobin is stimulated, how miRNAs work and how they regulate gene expressions have evolved into a major branch of study. Several miRNA databases, tools and algorithms have been designed by scientists all over the world to understand their gene regulatory mechanism. In fact, the Regenerative Medicine Lab at IIT Kharagpur has also devised a database called “miRwayDB” to provide comprehensive information of experimentally validated microRNA-pathway associations in various diseases. Additionally, the lab has also developed an interactive tool known as “miRnalyze” to unlock intuitive microRNA regulation of cell signaling pathways.

‘Messenger RNAs’ and ‘microRNAs’ are two important biomolecules found in our cells which are known to regulate cellular functions. Any abnormality in the production of these molecules may disrupt series of molecular events or pathways, which subsequently may manifest as critical diseases. Our lab has developed “miRwayDB”, a database which records information about the effects of these biomolecules on molecular pathways as observed in various diseases. The resource has many applications such as prediction of in silico models, integrative analysis, validation of computational analysis etc. In addition, we have also developed a prediction tool, “miRnalyze”, which can predict ‘messenger RNA’ targets of ‘microRNA’ in a molecular pathway. The tool can identify common ‘microRNAs’ that have more than one ‘messenger RNA’ targets. miRnalyze is a useful tool for hypothesis generation in ‘microRNA’ mediated molecular pathways. Both resources were published in ‘Database’ journal of Oxford University press.

The team at SMST used several bioinformatics tools to match differentially expressed miRNAs with differentially expressed genes (as found in publicly available datasets) and identify their pathways. As many as 19 miRNAs were found to be differentially expressed in those subjects who had high fetal hemoglobin levels in their blood. Next, using another database (SM2MiR), the team identified 13 unique small molecules that strongly affected the expression of those 19 miRNAs. An exhaustive analysis of these 13 molecules showed that only five were definitely associated with the pathways that reactivated fetal hemoglobin production and can be further investigated for repurposing.

Prof. Nishant Chakravorty, who heads the Regenerative Medicine Lab and the team at SMST, said, “In our study, a number of genes and miRNAs were identified as putative molecular marker for HbF (fetal hemoglobin) regulation. The identified markers expand our understanding of HbF regulatory mechanism and may have importance in designing new therapeutic strategies to reactivate HbF production in patients with hemoglobin disorders.”

Of the five, three – 5’-aza 2’-deoxycytidine, Valproate and Vorinostat – are known pharmacological agents. For example, Valproate is used to treat seizure disorders in childhood and Vorinstat is an anti-cancer agent. However, these have side-effects.

Prof. (Dr.) Anish Chatterjee (MBBS, DCH, MD-Paediatrics), Professor, Dr. B C Roy Post Graduate Institute of Paediatric Sciences, said, “Medical practitioners nowadays widely use repurposed drugs. For example, Sildenafil, which is used to treat impotency in males is used to treat neonatal pulmonary hypertension. Again, Hydralazine which is used to control blood pressure, is also used to treat leprosy.” He adds, “Research in repurposing of drugs, which is being carried out by the Regenerative Medicine Lab of IIT Kharagpur, with which I have been associated with for some time, has immense potential. It might lead to the discovery of new information about existing drugs. Not only that, it could lower the cost of medical treatment as cheaper drugs, instead of the costly ones presently used, could be used to treat diseases.”

The study at the Regenerative Medicine Lab was conducted by Prof. Chakravorty, his student at SMST, Mr. Sankha Subhra Das, and Dr. Rashmi Sinha of the B.C. Roy Technology Hospital. The work, which has been published in the April 2019 “Gene” and is available online, also identified natural compounds, such as Curcumin and Gensenoside, which have proven health benefits with minimal toxicity, which the team expects to be “of critical importance in future clinical trials for HbF induction”.

Mr. Sankha Subhra Das, a research scholar associated with this team, is already working on other facets of thalassemia treatment, and has done several other in silico studies using bioinformatics tools. Other PhD scholars, such as Mr. Motiur Rahaman, is working specifically on beta-thalassemia. “We are trying to classify HbE-beta thalassemia into different categories based on clinical severity and trying to see if there is correlation with HLA haplotypes,” said Prof. Chakravorty. The team is enriched by several scholars such as Dr. Suman Kumar Ray (post-doctoral fellow), who has a background in plant medicine, and helping it to see how plant based phytochemicals can help increase fetal hemoglobin. The researchers at the Regenerative Lab are also engaged in research on repurposing strategies for bone and cartilage regeneration. The team will be moving on to do further experimental in-depth studies particularly on thalassemia patients. An active collaboration with Prof. (Dr.) Tuphan Kanti Dolai’s clinical team at the Department of Hematology, NRS Medical College and Hospital, Kolkata holds promise to this.

A New Page in India’s History

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A breakthrough discovery by a study led by IIT Kharagpur has made the colourful Rann Festival of Gujarat a little more vibrant. The researchers have uncovered the earliest traces of the Old Iron Age which is older than 3000 years in the deep stretches of the Rann of Kutch and the Thar Desert. Most importantly the study reaffirmed the theories of human migration from the west to the east induced by climate change.

The region of Gujarat has been a part of many tales from the times of our mytho-history through various historical periods until modern times. Even the Harappan period can be traced to a few rocky islands in the Kutch region of Gujarat. However, till now the Rann which is a prominent geological feature of Gujarat was devoid of any sign of continued human settlement throughout the Early Iron Age to Early Historic Age (~3100 – 2300 years). The lack of evidence even led archaeologists term this period as ‘Dark Age of Gujarat’.

The recent explorations in the coastal settlement of Karim Shahi region of the Rann near Indo-Pak border, led by Prof. Anindya Sarkar from the Dept. of Geology and Geophysics at IIT Kharagpur, however, have unraveled the secrets behind this curtain of silence. The team has found the earliest evidence of human habitation dating back to 3000 years. They also found evidence of Historic to Medieval (~1500–900 years old) human settlement at Vigakot in the Thar Desert.

“We were conducting geological investigations for finding out the past climate change during and after the collapse of Harappan civilization funded by the INFOSYS foundation and IIT Kharagpur. During our explorations we came across numerous archaeological artefacts strewn over the surface of Karim Shahi and Vigakot,” said Prof. Sarkar.

The most intriguing finding is how the human habitation thrived in such water-deprived inhospitable terrain and survived from Iron Age to Medieval period although major Harappan cities were abandoned by that time, he opined. The researchers also did a total station survey to determine the landscape.

“What seems to be an arid landscape today have indications of an active river system and some amount of rainfall during that period as evidenced from the analysis of sediments, botanical remains like pollens and isotopes of oxygen in fossil molluscan shells,” said collaborator Dr. Navin Juyal from Physical Research Laboratory, Ahmedabad.

The researchers also referred to the historical travelogue of Al Beruni of 1030 AD which mentioned the presence of rivers in Kutch.

“Our study suggests that the Rann of Kutch and part of Thar desert were still a hospitable terrain for the sustenance of human settlements from the Early Iron Age till at least medieval times which led to the survival of the civilization under such climate threat situation following the Harappan decline,” he said.

It is long known that from Mature to Late Harappan period (5200 to 3300 years) the number of human settlements continuously increased from the Indus River valley in the west to the Ghaggar-Hakra in the east. This migration following the collapse of the old Indus Valley (Harappan) civilization has been attributed to the decline of monsoon or major droughts by many scientists. But what happened to the people after such collapse? Little is known about the people after the post-urban Harappan period. Some archaeologists believe that there was no demographic collapse as such. Rather populations persisted in smaller less complex settlements dispersed from the original river valleys of the Indus and Ghaggar-Hakra to more distant areas of the Ganga-Yamuna interfluves or Gujarat and Rajasthan until 3000 years before the present time. In northern India new kind of civilization rose afterward, namely, the Iron Age (or Painted Gray ware) between ~3000 and 2500 years before the present time that was followed by the Kushan period (~1900–1500 years).

“This was indeed a very critical transition, wherein human migration, as suggested by our findings, was far more expansive than thought before. We suspect that the gradual shift of Intertropical Convergence Zone, the main driver of monsoon from west to east over the last seven thousand years, forced people to migrate for greener pastures,” remarked Prof. Sarkar.

An earlier study by Prof. Sarkar on Haryana’s Bhirrana region had shown human migration from west to east due to the weakening of the monsoon. In a way, this created large climate refugees who took refugia were still some little rainfall was available.

“The United Nations framework convention on climate change and high commissioner for refugees in its report warned about such climate refugees due to impending climate change. If it could have happened in the past it will happen in the future too” reminded Prof. Sarkar.

Apart from the climatic conditions and sustenance of the settlements, the researchers have been successful in stitching a critical section of India’s Iron Age history which lay buried under the deep stretches of the Rann. The recovery of artefacts like pitcher, jars and bull figurines and also numerous animal remains like bones, teeth etc. have helped in reconstructing the social subsistence pattern of the region during the study period confirmed co-researcher Dr. Arati Despande Mukherjee from Deccan College PGRI Pune. The earliest evidence of Iron Age found in Gujarat till now was 2500 years old which has now been pushed back by several centuries in antiquity. At Motichher, a place close to Karim Shahi, iron objects, nuggets, and slags have been found and which would need further investigation. The researchers acknowledged the Indian Army for facilitating the explorations. The areas are so remote and close to an international border that no scientific investigation could have been carried out without the permission of the Indian army.

Talking about a probable occupation of those people, Prof. Sarkar remarked, “both Karim Shahi and Vigakot probably acted as trade centers during this time. In fact, at Vigakot we found 1100 years old Chinese Qingbai porcelain probably manufactured in Guangdong province of south China and Sgraffiato potteries of 10th century Persia suggesting it to be a part of long-distance trade between West Asia and China”.

Prof. M.G. Thakkar from Kutch University and a collaborator emphasized the fact that the multidisciplinary study has proven the near-cultural continuity after the Harappans which the experts till now only hypothesized. He also harped on the point that this finding is going to bring Kutch under international limelight.

The findings have been published online in the prestigious Elsevier journal ‘Archaeological Research in Asia’. Download Paper

Graphic Credit: Suman Sutradhar

Dance of the rain

The Hindu, Times of India (Kol), Times of India

Reduced rainfall was among the factors that created multicentennial-scale drier conditions that may have contributed to the Indus Valley deurbanization. Lack of rainfall is believed to have been among the reasons for the social upheaval and the eventual fall of the Tang, Yuan and Ming dynasties of China. Drought interspersed with violent monsoon rains sounded the death knell of the Khmer empire of south-east Asia that flourished between 802 and 1431 CE.

There can be no doubting the profound impact of the abrupt shifts of rainfall on human history – a fact we need to constantly remind ourselves in this day and age of irretrievable climate change. Abrupt shifts in the Indian summer monsoon (ISM) precipitation has similarly impacted history in India. For example, bad precipitation is known to have worsened the agrarian crisis that tore asunder the mansabdari system of the Mughals, thereby hastening their fall.

But linking of ISM’s variability to human history in the subcontinent has been limited by the scarcity of high-resolution paleoclimatic data for the period encompassing the last 1000 years or earlier. Researchers at IIT Kharagpur and Wadia Institute of Himalayan Geology, Dehradun have been able to present high resolution oxygen isotope proxy record from the Wah Shikar cave in Meghalaya that identifies abrupt shifts in the ISM that has had profound impact on human society in the region for the past 900 years.

Given that India has seen extreme precipitation in the recent years that has caused devastation such as the Kedarnath floods of 2013 or the recent floods in Kerala and Tamil Nadu, researchers also believe that we need to investigate the long-term spatio-temporal variability of the ISM in order to understand the complex mechanisms that drive this variability, and therefore help improve predictive capabilities of climate models that help future planning. The speleothem proxy from Meghalaya, believe the researchers, holds crucial answers.

A 233 mm long stalagmite sample (WSS-3) was collected from the Wah Shikar cave. The sample was split into two halves and as many as 465 subsamples were extracted from them at every 0.5 mm interval parallel to the central growth axis. Palaeoclimatic records using oxygen isotope proxy in speleothems from northeastern India have been widely used to understanding ISM variability on millennial time scales. But data have not been derived from such finely divided samples.

“This is what is most definitive in this study,” says Prof. Anil Gupta, who has led the research and pioneered speleothem study in the country. “We took samples from every half millimetre or sometimes even one-third of a mm, and we dated using uranium-thorium time series. Such fine sampling of less time interval means we are covering data at 2-3 years’ interval while most research collect data at 20-30 years’ interval. In fact, we have even captured the drought events of last few centuries,” he added.

The analysis of the data derived from the samples show marked changes in ISM strength over northeastern India during the past 900 years coinciding with intervals of severe droughts and floods in the Indian subcontinent. The data pertains to the three main time slices – Medieval Climate Anomaly (MCA), Little Ice Age (LIA) and Current Warm Period (CWP). The findings have been corroborated with other proxy time series.

The data shows strong ISM conditions during MCA which is attributed to the warming of climate due to high solar insolation, which pulled the Inter Tropical Convergence Zone, or ITCZ, northward and strengthened the tropic monsoon circulation (ITCZ is a belt of low pressure which circles the Earth, generally near the equator, where the trade winds of the Northern and Southern Hemispheres come together). Data collected from caves in central India, northwestern India and western Himalaya corroborate the research team’s conclusion about ISM conditions during MCA.

During LIA, there were three different phases of precipitation in the ISM – all of them related to the cooling of the atmosphere owing to a host of factors – reduction in the number of sun spots, leading to the decreased solar insolation, volcanic forcings, and resultant atmospheric cooling. Each atmospheric cooling interval coincides with dry ISM episodes and long droughts as well as famine in India. Contrary to the earlier record from the same cave, the data collected by the IIT Kharagpur research team suggests reduced rainfall conditions during LIA.

Kailash Cave, Chattisgarh, site of another speleothem study

The abrupt changes in the ISM during the last millennium had large socio-economic impact on Indian society. Several dynasties, such as the Sena in Bengal, Solanki in Gujarat in the mid-13^th century and Paramara and Yadav in the early to mid-14^th century – all of which flourished during abundant rainfall – declined during the drying phases of the ISM, suggesting role of the climate in the socio-political crisis. Weak monsoon meant decline in agriculture and trade, and thereby societal discontent that often resulted in upheaval and rebellions. The researchers suggest that the increase in rain-water harvesting structures in northern India during the period attests to the decline in precipitation.

From the beginning of the 19^th century, the changes in ISM became more abrupt with a rise in atmospheric temperature that coincides with the dawn of Industrial Revolution and enhanced societal developments along with long term astronomical changes. The study says, “An increase in the frequency of abrupt shifts in the ISM during the last three centuries, coincidental with a rise in atmospheric temperature, suggests occurrence of more climatic surprises in future consequent to future rise in the global temperature and subsequently more precipitation in the form of rain at higher altitudes.”

The data from the Wah Shikar cave also indicates increased frequency of extreme rainfall events in India during the Current Warm Period that portends further increase in near future with the rise in global atmospheric temperature. This has already been predicted by the 5^th Assessment Report of Inter-Governmental Panel on Climate Change, 2013. The study says that higher rainfall in high altitude regions in the Himalaya will increase the risk of flash floods and landslides as well as reduction in glacier extent that will affect Asia’s water resources and agricultural wealth, consequently harming south Asia’s economy in the decades to come.

Read the paper:

https://reader.elsevier.com/reader/sd/pii/S0031018219302974?token=4A82D920755F48CF72C2E4198AA4766EABD3286DF052C79C66D9D71CC0C27AD4287D44F160CF66F987247634D96165A1