The Shanti Swarup Bhatnagar Prize for Science and Technology was instituted in the year 1957, in the memory of late Sir Shanti Swarup Bhatnagar, FRS, the founder-director of the Council of Scientific & Industrial Research (CSIR). The SSB Prize is awarded each year on the basis of conspicuously important and outstanding contributions to human knowledge and progress, made through work done primarily in India during the five years, preceding the year of the prize.
The SSB Prize, comprising a citation, a cash award of Rupees five lakh and a plaque, is given in the following disciplines:
• Biological Sciences
• Chemical Sciences
• Earth, Atmosphere, Ocean and Planetary Sciences
• Mathematical Sciences
• Medical Sciences
• Physical Sciences
• Engineering Sciences
This year, Science Reporter invited the Shanti Swarup Bhatnagar Prize awardees to share their award-winning work with our readers.
Understanding How the Brain Instructs the Body to Move
PROF. VATSALA THIRUMALAI
Neural Circuits and Development Laboratory
National Centre for Biological Sciences
Bengaluru 560 065
Dr Vatsala Thirumalai has made fundamental discoveries in exploring communication and modulation of neuronal function, uncovering how single cerebellar neurons alter computation in the circuitry that generates neural commands for movement.
The brain is science's last frontier. In my lab, we are focused on one of the most basic functions of the brain: its role in generating movement. Animals, including humans, need to move around to find food, reproductive partners and to escape from threats. Several brain regions are involved in selecting the type of movement (such as walking or running) and in planning how it is to be executed.
Nevertheless, we do not understand how the brain does these functions. We only know that when something goes wrong with these brain regions, as happens with a stroke or a tumour, the person loses the ability to move the limbs and becomes paralyzed. A greater understanding of the brain’s involvement in movement generation will help us work out therapies for these conditions.
Zebrafish are small fish that are found in shallow streams all over India. These fish are very useful in brain research because the eggs and the larval hatchlings are transparent and all the internal organs, including the brain, can be seen from outside. We can mark specific types of nerve cells and observe them in action in intact fish larvae, while they perform simple tasks. We can also insert very fine electrodes into the fish brain and monitor the electrical signals coming from single nerve cells.
The cerebellum or ‘little brain’ is one region that is very important for movement generation. Purkinje neuron is the main nerve cell type in the cerebellum. By recording electrical activity patterns from single Purkinje neurons, we showed that these neurons fire electrical signals in two modes: a constant ‘hum’ or an intermittent ‘burst’. The two modes are like two languages the Purkinje neuron is able to speak. We showed that the individual syllables or ‘spikes’ of the Purkinje neuron mean different things to downstream motor circuits in these two modes.
This discovery underlines how versatile single neurons are in processing information. We are currently investigating how Purkinje neurons choose between the hum and burst mode. In more recent work, we showed that the signals from these Purkinje neurons help the larva respond quickly to expected environmental stimuli.
The speed with which an animal moves is critical for its survival, whether to catch prey or avoid predators. Earlier work showed that based on an animal’s momentary needs, brain circuits select a suitable course of action and set the frequency of motion. Then, just like engaging gears in an automobile, spinal ‘speed’ modules are selectively activated to achieve a certain speed.
Recently, we showed that this is not the whole picture: speed can be set at the level of the motor neurons, which are the last command stations of the nervous system. Dopamine, a chemical produced by some nerve cells, is released at multiple sites including onto motor neurons. We discovered that when dopamine is present, zebrafish larvae swam faster not by changing how fast they beat their tails but by bending their tails more. This was possible because dopamine activated more motor neurons, including those that typically fire only during fast frequency rhythms. This study shows that even after the brain has issued the command for a movement, changing the properties of motor neurons can alter the final behavioural outcome. Such mechanisms can be exploited for rehabilitation after spinal cord injury or stroke.
I have highlighted a couple of studies from my lab that show the computational complexity even at the single neuronal level. In the coming years, we hope to be able to reveal more such interesting phenomena involved in the generation and control of movement.
Implications for Bacterial Disease Management
DR SUBHADEEP CHATTERJEE
Laboratory of Plant-Microbe Interactions
Centre for DNA Fingerprinting and Diagnostics
Hyderabad 500 039
Dr Subhadeep Chatterjee has made brilliant and sustained investigations, discovered reversible non-genetic heterogeneity in bacterial social communication systems that coordinate virulence and lifestyle transitions during plant disease. The fundamental findings have implication for bacterial disease management, including those of medical importance, and they give key insights on microbial evolution.
My laboratory has been studying the molecular mechanism of pathogenesis using Xanthomonas group of phytopathogens as a model system. These pathogens communicate with each other using a unique fatty acid signaling molecule known as Diffusible Signal Factor (DSF) by a process known as quorum sensing (QS). My laboratory at the Centre for DNA Fingerprinting and Diagnostics, Hyderabad has used molecular genetic methodology to identify a number of novel virulence functions which are regulated by DSF mediated QS. These include: a novel outer membrane adhesin XadM; chemotaxis and motility functions required for epiphytic (leaf) infection; iron uptake and utilization functions; an extracellular polysaccharide (EPS) which is involved in suppression of innate immunity, etc.
The work has provided important insights into the mechanism by which QS regulates Xanthomonas virulence-associated functions in a coordinated manner to promote infection and growth within the host plant. My group has shown that Xoo utilizes DSF QS signals to switch between the planktonic and biofilm lifestyles. This switching plays an important role in disease development, particularly during pathogen entry and colonization.
We have demonstrated that xanthomonads produce Xanthoferrin, a carboxylate type of siderophore, which plays an important role in pathogen growth under low iron conditions and in promoting virulence. We have also shown that ferric uptake systems are important for virulence in certain Xanthomonas pathogens but not in others wherein their role in virulence is supplanted by ferrous uptake systems.
We are studying the dynamics of cell-cell signalling (quorum sensing) in bacteria to understand how a single cell in a population integrates QS-signals and performs social behaviour. Our investigations discovered reversible non-genetic heterogeneity in bacterial social communication systems that coordinate virulence and lifestyle transitions during plant disease. The fundamental findings have implications for bacterial disease management, including those of medical importance, and give key insights on microbial evolution. Our work has also shown for the first time that the DSF class of quorum sensing signalling molecules can act as a pathogen-associated molecular pattern (PAMP) to elicit plant defence responses.
Our laboratory has identified and characterized a novel ferric iron-binding transcription factor, XibR (Xanthomonas iron-binding regulator), which is required for the regulation of iron metabolism and virulence-associated functions. This is the first report of a ferric binding transcription factor that is involved in iron homeostasis in bacteria.
In recent work, we have identified a novel function of cyclic β-(1,2)-glucan, an intrinsic component of Gram-negative bacteria, that is involved in iron homeostasis and protection against iron-induced toxicity by sequestering iron. This is the first work that reveals a critical role of glucan in intracellular iron homeostasis in several Gram-negative bacteria.
Our lab has also contributed to the fundamental mechanism of light-sensing by non-photosynthetic bacteria. We have discovered the mechanism of light-sensing in bacteria and how social behaviour in bacteria is regulated by day and night cycle which influences the cellular physiology and coordination of gene expression in important plant pathogens.
Nucleic Acids for Therapeutics and Bio-inspired Devices
DR JYOTIRMAYEE DASH
School of Chemical Sciences
Indian Association for the Cultivation of Science
Kolkata 700 032
Dr Jyotirmayee Dash has elegantly applied principles of chemical biology to modulate structure and function of nucleic acid targets in biological systems leading to new therapeutic tools for anticancer research.
Nucleic acids play important roles in living systems. The most abundant nucleic acid, DNA is largely double helical. DNA can also adopt a variety of secondary structures including four-stranded G-quadruplexes and i-motifs. The formation of four stranded DNA structures requires specific conditions: guanine rich DNA sequences fold into four-stranded G-quadruplexes in the presence of metal ions, Na+ and K+; while the complementary cytosine rich sequences fold into i-motifs under acidic conditions. It is believed that these four-stranded structures are involved in a variety of biological processes, such as telomere maintenance, regulation of oncogene expression, DNA repair, etc. Therefore, targeting these structures with small molecules is considered as an emerging area of research in medicinal chemistry.
Our group has done extensive research in the development of selective ligands for nucleic acid secondary structures using dynamic combinatorial target-guided approaches. The target-guided synthesis (TGS) using azide-alkyne cycloaddition (in situ cycloaddition) is a powerful fragment-based drug design strategy in which the target directly templates the ligation of appropriate reactive fragments to generate high-affinity target-specific compounds.
This methodology offers several advantages. First, it reduces the time required for the conventional laborious chemical synthesis of potent candidates and their biological screening assay. Second, it provides a large surface with more number of local DNA catalytic sites for better interaction of the reacting fragments. Third, it enables efficient isolation of the in situ lead compounds by simple magnetic decantation and lastly, it prevents the wastage of commercial DNA sequences by allowing the recovery and reuse of DNA magnetic nano-templates. The resulting ligands have been found to modulate gene expression and kill cancer cells thereby providing novel therapeutic approach for cancer as well as neurodegenerative diseases. We have developed small molecular probes that detect quadruplexes and can also be used for diagnostic applications.
In recent work, we have shown that the in situ cycloaddition can be used to develop binders for the transactivation response (TAR) RNA found in the human immunodeficiency virus type-1 (HIV-1) genome. We have identified a new class of thiazole based peptidomimetics capable of binding to TAR RNA. Small molecule TAR RNA binders are considered as antiviral agents.
We are also working on biomimetic systems. In our work, we have used four-stranded DNA to make devices to identify square numbers and transport metal ions across biological membranes. We have prepared nucleosides based hydrogels with potent antibacterial activities. Our goal has always been directed to the discovery of new tools which may give a new direction in the field of medicine.
Towards Recyclable, Self-healing Materials
DR SUBI JACOB GEORGE
New Chemistry Unit
Jawaharlal Nehru Centre for Advanced Scientific Research
Bengaluru 560 064
Dr Subi Jacob George has provided remarkable insights into Materials Chemistry at various length, energy and time scales which help not only in regulating the factors that govern the size, shape and chirality of supramolecular moieties but facilitating their applications like light emission, sensing, and ion transport to design novel autonomous devices like bio-molecular motors.
Our group has been working on supramolecular chemistry, a branch of chemistry, which deals with ensembles of molecules with weak intermolecular interactions like most biological assemblies such as proteins and nucleosides, and classes of biomaterials. The complex nature of this branch of chemistry intrigued us to investigate some of the most emergent materials called supramolecular polymers.
These dynamic systems are complementary to classical polymers in terms of their long-chain structure but differ in their intermolecular linkage which is non-covalent in the case of supramolecular polymers. Since these materials deal with non-covalent interaction where bond making/breaking are responsive to subtle changes in the environment, they exhibit unique reversible, adaptive, dynamic, and self-healing properties that are not possible with covalently linked classical polymers. The adaptive nature of supramolecular polymers brings a variety of applications in the sustainable use of polymers, biomedicine, electronics and self-healing materials.
Biological systems are home to complex adaptive networks with precise spatio-temporal control, coupled with sophisticated functionality. Mimicking these complex systems synthetically with time as an extra dimension is a remarkable challenge for the supramolecular chemist. In recent years, our group has made significant inroads towards elucidating the synthetic strategies towards a material realization of these concepts. Extracting the gist of out-of-equilibrium, fuel-driven networks from the biological world, chemical fuel-driven supramolecular polymerization strategies have been pioneered in his research laboratory, fundamentally advancing the frontiers of constructing controllable and adaptive materials with mono-disperse structure and predictive sequence. This control pans from growth kinetics to dimensional control on one end, to lifetime of materials on the other.
Our group is involved in the study of life-like synthetic materials by synthesizing materials away from equilibrium and is credited with the creation of a new category of self-assembled materials called transient materials which can have potential applications in sensing, security and drug delivery. Such a temporally controlled living and transient self-assembly approach is not only a conceptual synonym to a much bigger and complex biological relative, but also provides primed precursors of complex active materials in the years to come.
Earth, Atmosphere, Ocean & Planetary Sciences
Groundwater Analyses Reveal Alarming Scenarios
DR ABHIJIT MUKHERJEE
Department of Geology and Geophysics
Indian Institute of Technology-Kharagpur
Kharagpur 721 302
Dr Abhijit Mukherjee has made interdisciplinary, field and laboratory based numerical studies to understand the decadal scale changes in ground water quantity and quality in India. This work of social relevance quantified geological and human influences on groundwater chemistry, elucidated manmade and geo-genic pollutants and measured ground water-sea water interactions in two major river basins. He has provided estimates on ground water sourced drinking water availability across India and his studies have informed national water missions and policies.
Groundwater is regarded as the largest freshwater resource of this planet, and at present, India is specifically going through its worst groundwater crisis in history. I have been involved in studying the physical and chemical aspects of groundwater sciences. My research on quality and quantity of groundwater-sourced drinking water availability in India and eleven other countries has significantly contributed to the recent advancement of applied research on groundwater.
I have studied regions suffering from geological and human influences on groundwater pollution (e.g. arsenic, fluoride, sanitation-borne and emerging contaminant pollutions) on a country-scale, as well as in in-depth field-based studies in the Indus-Ganges-Brahmaputra river basin. This work provides input in understanding India’s drinking water and food security.
The study area stretches from Ladakh to Jorhat to Sunderbans. For the first time, my students and I have delineated the high and low arsenic zones across the entire river basins using artificial intelligence on several environmental, geological and human usage factors to develop probabilistic models of arsenic occurrence and human health risk. Our AI models predict the occurrence of high arsenic in groundwater across more than half of the Ganges River delta, covering more than 25% areal extent in each of the 19 out of 25 administrative zones. For instance, Nadia (93%) and Murshidabad (82%) are found to be the worst-affected. A total of 30.3 million people are estimated to be exposed to severely high As-hazard within the Ganges River delta alone.
The outcome of the study is particularly important for policymakers and administrators as this knowledge would provide a vital input in identifying safe drinking water sources in arsenic affected areas of India and other countries with similar pollution.
I have also extensively worked on groundwater insufficiency (e.g. Gujarat, Rajasthan) by understanding decadal-scale groundwater quantity changes over the Indian subcontinent by using hydrogeological methods as well as advanced computational and Artificial Intelligence techniques. For the first time, we were able to estimate the volume of existing usable groundwater across Indian states. The estimates show rapid depletion of usable groundwater storage during 2005-2013 in Assam, Punjab, Haryana, Uttar Pradesh, Bihar, and West Bengal. In these areas, increase in agricultural food production has resulted at the cost of non-renewable loss in groundwater volume at an alarming rate.
Observed and satellite-based estimates show highest groundwater storage depletion rates in Assam, Rajasthan and Uttar Pradesh between 2005 and 2013. A northeastern state like Assam, which was always regarded as water-affluent, has lost ~2% of its usable groundwater resource between 2005-2013, and is on the brink of suffering drought and famine in coming years. The work has significantly contributed in supporting and evaluating the Government of India (GoI) missions like MNREGA on groundwater rejuvenation in India, which potentially influenced country-wide artificial recharge programs.
In our recent studies on drying and pollution of Ganga river using a combination of in-situ and satellite-based measurements of river water and groundwater levels, chemical analyses of Ganges river and groundwater, simulation results from global hydrologic models and regional groundwater flow models, for the first time, we showed that the present-day summer drying of the river Ganges is also dependent on the well-documented groundwater depletion in the Gangetic aquifers of north India. We demonstrate that the present-day baseflow (groundwater inflow) to the Ganges from the adjoining aquifers, which may be up to a third of total river volume during pre-monsoon months, might have decreased by 59% from the beginning of irrigation-pumping age in the 1970s. Future analyses of Ganges river water-groundwater interactions, without effects of climate change or human interferences, provide an alarming but conservative scenario that in the forthcoming summers for the next 30 years, groundwater contribution to Ganges river water flow would continue decreasing, up to ~75% of the 1970s.
Also, recent study of sanitation-sourced groundwater faecal pollution to address the UN Sustainable Development Goals (SDG) has been instrumental in evaluating the efficiency of the Swatch Bharat Mission. We evaluated the role of economic improvement on the decrease in groundwater pollution; we studied across India datasets of water-borne faecal pathogen concentration in groundwater and satellite-based nightlight. Other studies include the delineation of groundwater-seawater interactions at coastal areas of the Bay of Bengal to understand the groundwater discharge and influences in Sunderbans and adjoining coastal areas.
Additionally, I am also leading one of the first Indian urban geoscience projects to investigate the future of the city of Varanasi. The work, involving subsurface geo-exploration and risk assessment along with studying river Ganga, has been one of the foremost comprehensive geosciences work for future urban development of India.
Understanding Evolution of Plant Terpenoids
DR SURYENDU DATTA
Department of Earth Sciences
Indian Institute of Technology Bombay
Mumbai 400 076
Dr Suryendu Dutta has made outstanding contribution to our understanding of evolution of plant terpenoids. His path-breaking research spans the study of hydrocarbon biomarker signatures of complex eukaryotic life in the Neoproterozoic, finding sesquiterpenoid biomolecules that play significant role in plant and animal interactions and preservation of nitrogen-bearing macromolecules like collagen and melanin under different geological conditions.
Prof. Suryendu Dutta has made invaluable contributions in the fields of organic geochemistry and molecular palaeobiology. He has made outstanding contributions to our understanding of the evolution of plant-terpenoids. Plants display rich biochemistry that includes the production of a vast array of terpenoids. These diverse natural products have been associated with a large range of important primary and secondary metabolic processes. His research reveals crucial information on the biosynthesis of many enzymes in ancient angiosperm trees. He has made original contributions enriching our understanding of the earliest appearance of tropical rainforests of Asia.
He has been looking at how some plant-derived terpenoids evolved through the continental drift of the Indian continent, before which India was part of Gondwanaland. He is also engaged in research related to plant metabolites that play active role in plant-animal interactions and facilitate plant-plant communications. He has also made noteworthy contributions in understanding the evolution of complex eukaryotic life on Earth during Neoproterozoic times. At present, he is investigating the diagenetic fate of proteins under different geological conditions.
Prof. Dutta also specialises in the application of organic geochemistry in petroleum exploration. His innovative research demonstrates how plant-derived organic matters are major sources of liquid hydrocarbons in many petroliferous basins of India. He is also using organic geochemical proxies to locate unconventional hydrocarbon prospects like shale gas and shale oil in Indian sedimentary basins.
Towards Continuous, Efficient Chemical Processes
DR AMOL ARVINDRAO KULKARNI
Chemical Engineering and Process Development
CSIR-National Chemical Laboratory
Pune 411 008
Dr Amol Arvindrao Kulkarni has made outstanding contributions in understanding of transport phenomena and reaction engineering for designing various flow reactors. He has successfully transformed complex batch processes into continuous processes including the first ever scalable process for silver nanowires.
Microreactors of continuous flow reactors have a distinct advantage over conventional batch or semi-batch operations carried out in the chemical and allied industry. Some of them include: consistency in product quality, continuous operation, very large values of transport coefficients (needed to achieve mixing, heat transfer and mass transfer), relatively much smaller amount of inventory in the reactor, possible significant reduction in the use of solvents and smaller overall footprint of the chemical plant.
While the buzzword of microreactors has been around for the last two decades, CSIR-National Chemical Laboratory was the first to bring this concept to India and demonstrate it to the Indian chemical industry at several scales of operation. Dr Amol Kulkarni, who has been spearheading this activity for the last 15 years at CSIR-NCL, has succeeded in developing the design procedures for flow reactors for laboratory scale, pilot scale and commercial scale.
Typically, the laboratory scale operations are for proof of concept and for generating useful data for moving to pilot scale operations (usually 100 times bigger than laboratory scale). The pilot plants are used to evaluate the effect of the scale of operation on the performance and the fine-tuning needed to take a process to commercial scale (100 to 1000 times the pilot scale).
At CSIR-NCL, Dr Kulkarni’s group has indigenously designed, patented and fabricated continuous flow reactors. The reactors designed by him are used by over 59 industries at different scales of synthesis and production. The designs of metal microreactors are licensed to Amar Equip. Pvt. Ltd., while those of glass-lined flow reactors for corrosive reactions are licensed to GMM-pfaudler Ltd. (Mumbai) to manufacture and supply globally.
These novel designs are based on fundamental chemical engineering principles. They are highly efficient, superior in performance while being much less expensive in the capital as well as operating costs. Understanding of detailed 3D multiphase flow, analysis of unstable reactive interface and its coupling with chemical reactions have helped systematize the design approach. He has also developed a pressure equalization approach for uniform flow distribution in 2D and 3D network of channels and multiscale coupling of transport phenomena with the kinetics of nanomaterial synthesis for their scale-up.
A notable example includes continuous process for the production of nanowires (0.1 to 1 kg/day) in suspension form. This is an Import Substituting Development and has helped save imports of over Rs. 200 Cr while the continuous processing has increased the efficiency of processes by a factor of 100 to 1000.
Synthesizing Carbon Nanotubes
DR KINSHUK DASGUPTA
Bhabha Atomic Research Centre
Mumbai 400 085
Dr Kinshuk Dasgupta has developed the lightest and the most economical AK-47-HSC bullet-resistant level III+ bullet-proof jacket – Bhabha Kavach – using carbon nanotubes and boron carbide composites. This indigenously developed and low-cost jacket is an import substitute and has been inducted in the Central Armed Police Forces.
Dr Kinshuk Dasgupta has made significant contributions towards the large-scale synthesis of carbon nanotubes (CNTs) by fluidized bed and floating catalyst chemical vapour deposition (CVD) techniques. The single-walled CNT, multi-walled CNT and CNT aerogels developed by Dr Dasgupta have been successfully deployed in various strategic and societal applications. This has been achieved through a detailed understanding of the structure-property correlation in these complex nanostructures at the molecular level. Additionally, a comprehensive engineering database has been created for the scale-up of these technologies to the commercial level.
The most significant application of CNT developed by Dr Dasgupta is the Bhabha Kavach, which is considered to be the lightest and the most economical bullet-proof jacket (BPJ) in India that is resistant to AK47 Hard-Steel-Core (HSC) bullets. It has been approved for deployment in Central Armed Police Forces and State Commando Forces. The indigenously developed Bhabha Kavach costs substantially less than the equivalent imported BPJs and, therefore, could potentially save the Government exchequer several thousand crores of foreign exchange.
He has developed ballistic grade CNT-boron carbide and CNT-polymer composites with improved fracture toughness and flexural strength and used them in Bhabha Kavach to obtain the lightest Indian body armour. The technologies of CNT and Bhabha Kavach manufacturing have been transferred to several industries.
Dr Dasgupta is one of the few researchers in the world whose group could successfully synthesize high-performance CNT wool by floating catalyst CVD. He could also control the chirality of CNTs in the wool and selectively synthesize metallic or semiconducting CNTs. Additionally, Dr Dasgupta has doped the CNTs with nitrogen and boron in order to improve the hydrogen storage capacity by five times compared to the bare nanotubes. He has functionalized the CNTs for selective separation of actinides from high-level waste, recovery of rare earths from lean solution and water purification. His recent work on CNT-graphene hybrid structures has shown tremendous potential in supercapacitor and desalination applications.
Dr Kinshuk Dasgupta with his team, for the first time in India, has developed the technology for preparing Sm-Co magnetic alloy powders from indigenous rare-earth oxides by the reduction-diffusion method. These alloy powders could be converted into permanent magnets having properties at par with international products (Recomma-18 grade). He has not only studied the effect of different pyrometallurgical and hydrometallurgical operations on the magnetic properties of these alloy powders, but also scaled-up the technology for producing 10 kg batch of the finished product. This work has made the country self-reliant and the technology has been transferred to Indian Rare-Earths Limited.
Contributions to Langlands Program
DR U.K. ANANDAVARDHANAN
Department of Mathematics
Indian Institute of Technology Bombay
Mumbai 400 076
Dr U K Anandavardhanan has made significant contributions in the field of distinguished representations in the Langlands programme, especially for his contributions relating to base change, distinction, root numbers and the Asai L-function for the linear group.
I work in an area of mathematics called the Langlands program which connects number theory with other areas of mathematics such as analysis and geometry. More specifically, my work is centred round what is called group representation theory. They typically deal with infinite-dimensional representations of certain matrix groups. There are a few subtle arithmetic invariants associated with such representations and some of my works are about relating properties of these representations with their corresponding arithmetic invariants.
Such questions have typically a long and rich history, for instance, what is known as determining the sign of the quadratic Gauss sum is one such problem investigated by Carl Friedrich Gauss more than two hundred years ago. Several of my results involve similar invariants called epsilon factors which typically take the values 1 or -1 in interesting situations and the hard part is to determine the precise sign. The epsilon factors show up in several important conjectures and results in the Langlands program. For example, they play a key role in the “local” Gan-Gross-Prasad conjectures, due to Wee Teck Gan, Benedict Gross, and Dipendra Prasad, one of the guiding lights in the so-called relative Langlands program. There are also “global” versions of most of these results and conjectures, and a few of my results involve these global counterparts.
Key Insights into Treatment for Prostate Cancer
DR BUSHRA ATEEQ
Department of Biological Sciences & Bioengineering
Indian Institute of Technology Kanpur
Kanpur 208 016
Dr Bushra Ateeq has made pathbreaking research on the resistance to androgen deprivation therapy, mainstay treatment for prostate cancer patients. She showed that anti-androgen drugs used for treatment of advanced stage prostate cancer patients are actually detrimental in the long-term, and Casein Kinase 1 inhibitors could be included as an adjuvant therapy for SPINK1-positive and neuroendocrine prostate cancer patients.
Prostate Cancer (PCa) is considered a hormone (androgen)-dependent malignancy, wherein cancer cells express the androgen receptor (AR) and are dependent on the AR-signaling for their survival. Hence, the primary treatment for the advanced stage prostate cancer is to chemically or surgically ablate androgen signalling, a procedure known as Androgen Deprivation Therapy (ADT). Although therapies targeting androgen signalling are well-established for PCa, and are highly effective initially, resistance ultimately ensues.
The other challenge in PCa treatment is its heterogeneous nature, marked by disparate genetic or epigenetic abnormalities in tumour cells. Earlier, our efforts in targeted molecular subtyping of Indian PCa patients revealed that about half of the patients from Northern India harbour a gene fusion known as TMPRSS2-ERG, while ~14% show many-fold higher levels of SPINK1, who also endure aggressive disease and poor survival. We examined the effect of androgen signalling on the regulation of SPINK1 oncoprotein, and unlike other androgen driven genes namely, PSA or TMPRSS2-ERG fusion, we found that stimulating PCa cells in culture with synthetic androgen results in reduced SPINK1 levels.
On the other hand, when PCa cells were treated with anti-androgen drugs, a robust increase in SPINK1 was observed. By immunostaining PCa patients’ specimens for the presence of SPINK1 and AR, the master regulator of androgen signalling, we noted an inverse association between SPINK1 and AR expression, which confirms SPINK1 as an androgen repressed gene. Contrary to common belief, we discovered that upregulation of SPINK1 in PCa is due to the loss of AR-mediated repression.
By using multiple strategies, we showed that AR, the master player of androgen signalling along with REST, also known as RE1-silencing transcription factor, suppresses the transcription of SPINK1. It was quite surprising to see that the long-term blockade of androgen signalling in SPINK1-negative PCa cells, triggers change in the lineage of these cells, manifested by increased neuroendocrine features and SPINK1 level owing to reduced AR and REST. We found that the switch of SPINK1-negative PCa cells to SPINK1 positive under long-term androgen signaling blockade was manifested due to increased levels of SOX2, a lineage reprogramming transcription factor, which positively modulates SPINK1 expression. The effect of anti-androgens was also tested in mice engrafted with human PCa tumours, and to recapitulate the ADT strategy used for PCa patients, these mice were surgically castrated and treated with anti-androgen drugs, namely Enzalutamide or Apalutamide. Surprisingly, at the end of the study, many folds increase in the levels of SPINK1 and neuroendocrine markers was observed in the tumours excised from mice.
Using enzalutamide-resistant PCa cell lines, we showed that SPINK1 plays a critical role in the maintenance of neuroendocrine features. Interestingly, high levels of SPINK1 in the tumour specimens of ADT-induced neuroendocrine PCa patients were detected. We highlighted the detrimental effects of ADT, which was confirmed by ADT-induced upregulation of SPINK1 and neuroendocrine-like features. Importantly, we discovered a strategy to restore the REST levels (SPINK1 repressor) by treating PCa cells with Casein Kinase 1 inhibitor, leading to downregulation of SPINK1 and neuroendocrine features, subsequently reduced stemness and cellular plasticity. Our findings shifted the paradigm about ADT. We found that anti-androgen drugs commonly used for treating advanced-stage PCa patients are actually counterproductive.
Currently, clinical trials using Umbralisib, a Casein Kinase 1 inhibitor for Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia, are underway. It will be worth carrying out well-planned clinical trials of Casein Kinase 1 inhibitor in SPINK1-positive prostate cancer and neuroendocrine prostate cancer patients, which so far remains undruggable.
Lower Doses of Steroids Treat ABPA Better
DR RITESH AGARWAL
Department of Pulmonary Medicine
Postgraduate Institute of Medical Education and Research
Chandigarh 160 012
Dr Ritesh Agarwal has made outstanding contributions in the field of Allergic Broncho Pulmonary Aspergillosis (ABPA). His research showed that lower doses of glucocorticoids are sufficient. Through well conducted randomized controlled trials, he also showed that Azole Monotherapy is useful in treatment of ABPA.
Asthma is a chronic respiratory disorder that affects about 2% of the Indian population. Patients with asthma are often allergic to pollen, pets, and several other environmental agents. In general, allergies to most of these inciting agents are not serious and do not cause permanent lung damage. Allergic bronchopulmonary aspergillosis (ABPA) is a severe form of an allergic reaction to a fungus called Aspergillus fumigatus. The early diagnosis and appropriate treatment for ABPA are essential to prevent permanent lung damage, which is medically known as bronchiectasis (holes in the lung).
Our group at PGI-Chandigarh is actively involved in the research of ABPA for the last 16 years. We first documented that ABPA is highly prevalent in the Indian subcontinent. The presentation of ABPA can be non-specific, and the disease can masquerade as poorly controlled asthma. As many as one of ten asthmatic patients attending chest clinics were found to be afflicted with ABPA. Our research emphasized the need for actively screening all asthmatic patients for ABPA so that the illness can be diagnosed before it causes lung damage. A major lacuna in the care of patients with ABPA was the lack of standard fashion for diagnosing the disorder. Research from our team evaluated and clarified the role of various diagnostic tests for diagnosing ABPA. Our efforts were instrumental in the formulation of international consensus-based diagnostic criteria for ABPA.
After that, we started investigating advanced diagnostic techniques in ABPA. We demonstrated the clinical utility of recombinant A. fumigatus antigens in the diagnosis of ABPA and identified specific threshold values for use in the clinic. Of note, these pure fungal antigens obtained using recombinant technology can simplify the identification of this disease.
The treatment for ABPA in the past was mainly the use of high doses of steroids, which is associated with various side-effects, of which some can be severe, like the occurrence of diabetes, hypertension, weakening of bones, and susceptibility to infection.
The most significant work of our group is in the treatment of ABPA. Our group’s research revealed that lower doses of steroids effectively treat ABPA, thus identifying a less harmful way to treat this condition. Importantly, our group evaluated the effectiveness of antifungal drugs, which have lesser side effects than steroids. In two different randomized controlled trials (RCTs), the quintessential experiment in clinical medicine, we showed that antifungal drugs (namely itraconazole and voriconazole) are as good as steroids in treating patients with ABPA. The use of antifungal drugs alone is a novel approach to treat an allergic condition. Our policy altogether avoids the use of steroids and its attendant side-effects.
In the future, we wish to evaluate why only some patients with asthma develop ABPA. For answering the question, we plan to perform genetic analysis in patients with asthma.
Understanding Colloidal Suspensions, Amorphous Solids & Crystallization of Glasses
DR RAJESH GANAPATHY
International Centre for Materials Science
Jawaharlal Nehru Centre for Advanced Scientific Research
Bengaluru 560 064
Dr Rajesh Ganapathy has advanced the frontiers of our understanding of mechanical response, memory formation, instabilities and arrest in colloidal suspensions, amorphous solids and crystallization of glasses using high precision direct imaging techniques, optical micro-manipulation and sophisticated analysis of colloids, challenging the theoretical frameworks.
Prof. Rajesh Ganapathy’s key scientific contributions have largely been the outcome of the novel, innovative and decisive experiments probing the physics of out-of-equilibrium soft matter. These experimental contributions span a range of topics that include driven soft materials with an emphasis on the yielding of crystals and glasses, the formation of mechanical memories and sheared suspensions; glass transition; surface directed colloidal self-assembly; and active matter.
A key experimental/technical achievement by Prof. Ganapathy was in the successful integration of a customized commercial rheometer with a confocal microscope. The confocal-rheometer apparatus allows access to three-dimensional structural information at the sub-micron length scale when soft materials are subjected to controlled mechanical deformation. This in-house developed apparatus, the first of its kind in the country and one among the few in the world has been exploited in gaining microscopic insights into how colloidal polycrystals flow [Proc. Nat. Acad. Sci U.S.A.109, 20314 (2012)], the yielding behaviour of amorphous solids [Phys. Rev. E 89, 062308 (2014)] and the shear-thickening behaviour of dense suspensions [under revision (2020)].
In a similar vein, Prof. Ganapathy’s recent experiment on bubble rafts subject to an oscillatory shear found memory formation to be maximal at the yield point. This is perhaps the most convincing demonstration of yielding, memory and non-local flows being intertwined even in the simplest of models for a soft glass [Phys. Rev. Lett. 122, 158001(2019)].
Perhaps the most fundamental contributions to emerge from Prof. Ganapathy’s research group have been towards uncovering the true nature of the glass transition. Whether the transformation of flowing liquids into rigid glasses is a purely kinetic phenomenon or a thermodynamic phase transition remains one of the biggest unanswered questions in condensed matter physics. Prof. Ganapathy has carried out the first experiments aimed at critically evaluating two leading and competing theories of glass transition – Dynamical Facilitation, a kinetic framework, and the Random First Order Transition (RFOT) theory, a purely thermodynamic framework [Nature Comm. 5, 4685 (2014), Nature Phys. 11 403 (2015), Phys. Rev. Lett 116 068305 (2016), Adv. Phys. 65, 363 (2016)].
By using in-house built holographic optical tweezers to experimentally realize the random pinning and amorphous wall and analyzing particle dynamics in colloidal liquids in detail, Prof. Ganapathy showed for the first time in experiments the existence of a growing static correlation length accompanying the transition to the glassy state. This was accompanied by a change in the nature of cooperative relaxation process seen for the first time in experiments. Building on these findings, Prof. Ganapathy led a study that measured for the first time the growing surface tension of amorphous-amorphous interfaces on approaching the glass transition [Nature Comm. 9, 397 (2018)]. This prediction unique to RFOT had remained untested in both simulations and experiments for over three decades. These seminal findings tilt towards a thermodynamic origin of the glass transition.
Prof. Ganapathy’s research has also highlighted for the first time the role of particle shape and interaction anisotropy in glass transition phenomena [Phys. Rev. Lett. 110, 188301 (2013), Proc. Natl. Acad. Sci. U.S.A. 111, 15362 (2014), Phys. Rev. Lett. 114, 198302 (2015)]. More recently, Prof. Ganapathy led a team of researchers to capture for the first time in experiments the transformation of glass to a crystal (Nature Physics 2020).
Prof. Ganapathy has also made significant contributions in exploiting atomic and molecular surface growth concepts to steer colloidal self-assembly. In two studies [Proc. Natl. Acad. Sci. U.S.A. 113, 12094 (2016), Science Advances 6, EAAY8418 (2020)], his research has uncovered striking similarities between atomic and colloidal thin film growth. This similarity has been exploited to achieve both site-specific nucleation and hierarchical organization of colloidal crystals on surfaces. Such ordered arrays of colloidal crystals find application as photonic bandgap filters and optical switches.
Prof. Ganapathy’s most recent forays have been in the area of active matter. He played a vital role in the experimental realization of a micrometre-sized colloidal heat engine that was powered by bacterial activity [Nature Phys. 12, 1134 (2016)].
To be published in Science Reporter December issue 2020