Overview

(Research Contribution Over 100 Years)

Foreword

Indian Institute of Science (IISc) was founded in the year 1909 at Bangalore and it started functioning from 24 July 1911 with three departments: General Chemistry, Applied Chemistry and Electrical technology. Gilbert Fowler, a professor at the Applied Chemistry Department, was appointed as the first Chair of Biochemistry on 16 February 1921, almost nineteen years after Benjamin Moore was appointed as the first Chair of Biochemistry in U.K. at the University of Liverpool in England in 1902. It is interesting to note that the Biochemical Journal and the Journal of Biological Chemistry were started in 1906 and 1905 respectively. Thus, Biochemistry as a distinct discipline was gaining momentum in the first quarter of 20th century. Gilbert Fowler served as Chair of the Department of Biochemistry until 1924 and he was succeeded by R. V. Norris (1924-1929), V. Subrahmanyan (1930-1949), K. V. Giri (1950-1958), P S Sarma (1959-1970), H R Cama (1970-1976), J Ganguly (1976-1981), N R Moudgal (1981-1984), C S Vaidyanathan (1984-1986), T Ramasarma (1986-1989), N Appaji Rao (1989-1992), P S Sastry (1992-1995), P V Subba Rao (1995-1996), R Maheshwari (1996-1998), M R S Rao (1998-2003) K Muniyappa (2003-2009), H S Savithri (2009-2014), C Jayabaskaran (2014-2019) and PN Rangarajan (since 2019).

 

 

Since 1921, the Department of Biochemistry at IISc has been carrying out investigations in diverse areas of Biochemistry and Molecular Biology. The department served as the nucleus for creation of other centres/departments in IISc as well as establishment of new institutions and industries as described elsewhere. The Department celebrated its Golden Jubilee and Platinum Jubilee in 1971 and 1996 respectively. The year 2021 is a new milestone in the history of the Department as it completes 100 years of existence. While acknowledging the contribution of faculty members, students, postdoctoral fellows, project staff, technicians and office staff of the Department, both past and present, a glimpse of the wide spectrum of research activities of the Department during the last 100 years is presented here.

The early years

During its initial years, research in the Department was primarily focused on societal problems of India at that time such as malnutrition, anemia, fluorosis, low agriculture yield, sandal spike disease among others. Societal relevance, rather than journal publication, was the primary goal of research of Prof. Fowler as well as several others who succeeded him. Prof. Fowler demonstrated the need of oxygen by bacteria and he found that the removal of sludge from sewage was counterproductive to decomposition. He devised a system for aeration that retained the sludge and introduced the idea of activated sludge. He was much sought out by cities across the world including New York, Shanghai, Cairo and Calcutta. He was a regular visitor to India from 1906 and became a permanent resident in 1916 after taking up position as a Professor of Applied Chemistry at the Indian Institute of Science in Bangalore. He demonstrated the value of sludge as organic fertilizer and feed supplement to poultry. His research in the fermentation of mahua flowers to produce alcohol and then to produce acetone for use in the manufacture of ammunitions led to the establishment of a factory at Nasik under his supervision.

 

 

To address the issue of rampant malnutrition at that time, nutrition research was started in the Department under the leadership of Prof. Subrahmanyan. Methods to fortify oil and Vanaspati with Vitamin A were developed. Techniques to detect adulteration in milk and ghee were established. Nutritive value of traditional South Indian food items was investigated. Extraction and processing of Soymilk were achieved, which was used as a part of Bangalore School Feeding Programme to feed 6000 children.

To support research activities in the field of Agriculture focussed on electroculture of plants, decomposition on cellulosic material and Photosynthesis, the Department received generous funds from Imperial Council of Agriculture (subsequently named as Indian Council for Agricultural Research) for several years. In 1943, the compost work developed in the Department became the basis for an All-India scheme under the direct auspices of the Imperial council of Agriculture Research for the conversion of municipal wastes into organic manure. To control the spike disease of sandal wood, the Department developed 'tree killer' solution. Optimal conditions for the long-term storage of fruits were developed.

Medical research was also an integral part of the Department's research activities. Fluorine in drinking water was identified as the cause for mottling of teeth in certain regions, and methods to remove fluoride from water were developed. An epidemiological study established a link between a cheap variety of tobacco and oral cancer in Indian West coast region. Attempts were made to treat anemia and infantile cirrhosis of liver using polyglandular extracts. When insulin for diabetes and antibiotics for infections were discovered in West, the Department immediately developed cheaper methods to produce them so that a common man can afford these medicines.

With the establishment of institutions such as CSIR and ICMR, the focus of research in the department shifted to basic research. Vigorous schools of research were established to study vitamins and trace elements, lipids, plant biochemistry, enzymology, endocrine biochemistry, carbohydrates, nucleic acids and cytogenetics. Newer separation techniques such as circular paper chromatography and agar plate electrophoresis were developed and allohydroxy-L-proline, a new non-protein amino acid in sandal leaves was characterized. Structure of the plant antibiotic morellin was elucidated. The toxic principle of kesari dhal (Lathyrus sativus) which causes neurolathyrism was identified as Oxalyldiaminopropionic acid. The role of Vorticellids in the process of sewage purification was established. Other significant findings include: understanding the mechanism of intestinal absorption and transport of vitamin A, characterization of oxidative enzymes involved in the metabolism of aromatic compounds in plants and microorganisms, demonstration of the role of ubiquinone in regulation of cholesterol biogenesis, study of structure and function of pancreatic ribonuclease and Sorghum acid protease, structural studies on DNA using antibodies raised against nucleosides, identification and separation of unusual bases in tRNA, isolation of a galactolipid and sulphur-containing sphingolipid from plants; characterization of retinyl ester hydrolase, cholesteryl ester hydrolase, acyl-CoA-GPC acyltransferase and phospholipases of rat intestine and demonstration of the presence of lysolecithin transacylase in pancreas; absorption of retinol and retinoic acid through the portal route; study of effect of malnutrition on the absorption of vitamin A from intestine and oxidation of retinal to retinoic acid; study of role of vitamin Ain reproduction and steroidogenesis using a retinoic acid-fed rat model; study of biosynthesis of ubiquinone and demonstration of its ability to lower serum cholesterol levels in limited human clinical trials; demonstration for the first time, the presence of free hydroxyproline in a plant (sandal tree leaves).

The advent of Molecular Biology and Recombinant DNA Technology as well as the discovery of DNA structure and genetic code dramatically changed the landscape of research not only in the Department of Biochemistry but also laboratories across the world. It became clear the biological phenomena can be understood better with the use of molecular biology tools. Thus, purification of enzymes from cells and tissues using classical chromatography techniques paved way for the synthesis of recombinant enzymes in heterologous hosts with epitope-tags which can be quickly purified in a single step by affinity chromatography. Chemical modification of active site residues to understand enzyme function was replaced by modification of amino acid residues by site-directed mutagenesis. Thus, the classical enzymology paved way for molecular enzymology and this transformation happened in almost every other area of Biochemistry. The use of molecular biology tools for understanding biochemical phenomena became a necessity. The initial resistance to embrace molecular biology slowly disappeared and the metamorphosis of biochemists into molecular biologists became complete in the beginning of the 21st century.

endocrinology, plant physiology, vitamins, minerals, food and nutrition, research in the next fifty areas focussed on the study of enzymes, nucleic acids, transcription, translation, bioenergetics, immunology, vaccines, allergy, parasitology, yeast genetics, chromatin biology, DNA repair, recombination, plant secondary metabolites, host-pathogen interactions and computational biology. The diverse research activities of the Department in the last fifty years are described below:

Reproductive Biology and Molecular Endocrinology

Research in endocrine biochemistry was initiated in the department in 1963 with a research grant from Ford foundation to study the biochemistry of pituitary gonadotrophins. Research on the role of pituitary and gonadal hormones as well as vitamin carrier proteins in mammalian reproduction was initiated in the early sixties which continued for several decades leading to the establishment of a Primate Research laboratory as well as Centre for Reproductive Biology and Molecular Endocrinology (CRBME) at IISc. Research on macaques led to the discovery of sialidase from the kidney that acted as an inhibitor of follicle stimulating hormone (FSH), a hormone responsible for pubertal development. The molecular mechanism of Luteinizing Hormone (LH), a hormone which has significant role in ovulation and testosterone production was elucidated. Neutralizing LH was shown to result in neutralization of several reproductive functions such as ovulation, implantation, and gestational progress and this discovery opened a new methodology in immunocontraceptive technology. The presence of Luteinizing hormone/choriogonadotropin receptors on tumor cells in the testicles was reported for the first time. The role of steroids in the regulation of placental proteins and gonadotropins in the differentiation of Leydig cells was investigated. Using human placental cells and cells from testis and epididymis as models, trophic hormones such as Follicle Stimulating Hormone, Leutinizing Hormone, Gonadotrophin Releasing Hormone and Estradiol 17β were shown to stimulate proliferation only when the cells are fully differentiated. With the development of facilities for animal and plant tissue culture, monoclonal antibodies to a variety of antigens were prepared and used for the study of antigenic determinants of proteins.

The phenomenon of specific carrier proteins mediating trans-placental delivery of vitamins like riboflavin, thiamine and biotin during gestation in female mammals, including primates was discovered in the Department. The biochemistry, immune-topology as well as hormonal induction and regulation of vitamin carriers, which were also synthesized in testis to become sperm components were shown to be required for vitamin transport through testis-blood barrier to support spermatogenesis. Antibodies against these carrier proteins were shown to cause termination of pregnancy in rodents and non-human primates.

The differential action of trophic hormones was shown to be the basis for the hormone-independent forms of some of the cancers, such as prostate cancer. Estradiol 17β which is traditionally considered as a female hormone was shown to have an important role in sperm maturation which is prerequisite for the fertilizing capacity of the sperm. It was demonstrated that by interfering with the action of estradiol 17β at the epididymal level, one can interfere with sperm maturation and thus block male fertility without any adverse effect on the libido.

Enzymology and Bioenergetics

Enzymology was a major thrust area in the Department right from the beginning and research in this area became molecular and sophisticated as newer techniques and equipments became available. A variety of techniques were developed for the study of kinetics of enzyme action. Research carried out in the Department on dialatometry and calorimetry for the quantitative measurement of volume and heat changes in biochemical reactions is widely acclaimed. A vibrant research group on bioenergetics carried out research on cellular thermogenesis, oxidative modifications of enzymes by H2O2, oxidative properties of metal-oxy radicals and peroxovanadium radicals. Notable advances were made in energy metabolism such as discovery of a novel mechanism involving lipid peroxidation for cellular thermogenesis. The parasitic plant cuscuta was used as a model system to study a variety of biochemical processes such as trehalose toxicity, regulation of shoot and haustoria development by cytokinins. Research on the recognition processes in biological systems and chemical specificity led to a model for measuring the specificity using free energy of association of amino acids of proteins with nucleic acid bases. Supernumerary nuclei in filamentous fungi were shown to serve as store house for nitrogen and phosphorus in the form of DNA to be degraded by regulated autophagy.

Mechanistic studies were carried out on enzymes such as aspartate transcarbamylase, serine hydroxymethyl transferase (SHMT) and xylanase. In addition, studies were initiated on the study of enzymes involved in the microbial biodegradation of aromatic compounds as well as those involved in triglyceride biosynthesis in plants. The complete amino acid sequence of SHMT and xylanase was determined. Insights into the origin of substrate and reaction specificities of several pyridoxal phosphate dependent enzymes were obtained by structural and functional characterization of site directed mutants of these enzymes and their ligand complexes. Molecular biology techniques were rapidly adapted for the study of structure and function of various enzymes. For example, site- directed mutagenesis was extensively used to understand the function of various amino acid residues of SHMT.

Restriction-Modification (R-M) enzymes, especially the Type III R-M enzymes which recognize specific DNAsequences but cleave away from the recognition sequence were used as model systems to understand how proteins recognize, cleave, and modify DNA. Phase variable DNA methyltransferases of Helicobacter pylori were studied. H. pylori was shown to possess extremely diversified R-M systems and new R-M systems evolve by random mutations, and by inactivating the old ones. Methylation dependent epigenetics was shown to play a key role in the biology of H. pylori. DNA mismatch repair (MMR) proteins of Haemophilus influenzae and Neisseria gonorrhoeae, were studied and their role in the regulation of mutation rates, which can alter the fitness and virulence of the pathogens was studied. The acetylome of H. pylori and acetylation in different biological and pathological processes are being studied.

Plant Viruses

Studies on molecular characterization of plant viruses led to determination of complete genomic sequences and characterization of non-structural proteins of different plant viruses and development of plants resistant to plant viruses. For the first time, a non-structural protein (NSs) from a negative strand RNA virus was shown to function as an RNA helicase. The mechanism of assembly of viruses established through structure-based mutagenesis demonstrated that virus particles can accommodate foreign peptides as large as 50-60 amino acids without hindering the assembly process and such virus like particles had the potential to be used as nano carriers for intracellular delivery of antibodies/drugs and for imaging.

 

 

Biochemistry of lipids

Extensive studies were carried out on malnutrition and brain development, biosynthesis of myelin lipids, the process of myelination; synaptogenesis, receptor ontogeny in the developing human brain and signal transduction mechanisms in brain. Studies aimed at understanding lipid metabolism and signal transduction in plants led to the discovery of a novel, soluble pathway of synthesis of triacyl glycerol. Phosphoinositide-specific Phospholipase C (PLC) in plants was shown to be soluble and the C2 domain alone is capable of targeting plant PLC to the membrane in response to a Calcium signal. Oleosin, a structural protein was shown to have catalytic activities essential for the biosynthesis and mobilization of plant oils.

Consanguinity, autosomal recessive disorder, fecundity and post-natal mortality in Karnataka, South India

The screening of 120,00 newborn children from Bangalore and Mysore showed that consanguinity (uncle-niece, first and second cousin marriages) had no significant effect on the incidence of inborn errors of amino acid metabolism. Similarly, it had no effect on the survival of children. Community genetics showed that heterozygosity index was not significantly altered in a group practicing marriage among close relatives.

Transcriptional, Post-transcriptional and Translational Regulation of Gene Expression

Key research contributions were made in the areas of transcriptional, post-transcriptional and translational regulation of gene expression, mRNA trafficking and storage as well as chromatin organization. Drugs such as phenobarbitone and 3-methylcholanthrene were shown to activate the transcription of specific cytochrome P-450 genes and heme was shown to play a key role in the transcriptional activation. Studies on the regulation of carbon metabolism of the methylotrophic yeast, Pichia pastoris led to the identification and characterization of several transcriptional and post-transcriptional regulators such as Mxr1p, Rop1p, Trm1p and Rtg1p. Rtg1p was shown to function as a nuclear, retrograde transcription factor in Saccharomyces cerevisiae and cytosolic, post-transcriptional regulator in Pichia pastoris.

A combination of genetic, biochemical, imaging and genomic tools is being used to the study of movement of RNA within cytoplasm as well as RNA decay. Arginine methylation was shown to promote translation repression activity of repressors Scd6 and Sbp1 by promoting interaction with conserved translation initiation factor eIF4G and self-association of RGG-motif proteins were found to regulate their repression activity by competing with eIF4G binding. Efforts are being made to understand the role of RGG-motif proteins in endocytosis and trafficking as well as decipher the role of RNA granules in translation control and mRNA decay.

Studies on translational readthrough or stop codon readthrough have led to the demonstration of translational readthrough in AGO1 (encodes Argonaute 1) which results in a longer isoform that acts as a global inhibitor of miRNA pathway thus unravelling a novel function of miRNAs. MTCH2, a mitochondrial carrier protein was shown to undergo double translational readthrough resulting in a novel isoform that affects the membrane potential and ATP synthesis. Advanced computational tools are being employed to identify novel translational readthrough candidates and these studies can pave way for the induction of readthrough across disease-causing stop codon mutations.

Chromatin structure and function

Investigations on chromatin structure and organization during meiotic prophase and mammalian spermatogenesis led to the demonstration that the C-terminal 34 amino acids of Histone H1 containing SPKK is essential for the maintenance of the higher order structure of eukaryotic chromatin. H1 variants (expressed in testis) lacking this motif generated a less condensed chromatin structure. A molecular model of the chromatosome particle (166 bp DNA containing the four core histones and histone H1) was constructed. The testis specific basic, zinc finger protein, TP2 was shown to condense GC rich DNA in a zinc dependent manner. A meiotic recombination hot-spot locus in the mouse genome was shown to encode a novel non-protein coding RNA.

Studies on SMC (Structural Maintenance of Chromosomes) protein complexes which are essential for maintenance of various aspects of chromosome organization led to the demonstration of a new role for cohesin in subtelomeric silencing. Cohesin was shown to repress telomere proximal gene expression in a SIR-independent manner. Key components of Smc5/6 complex such as Mms21/Nse2, a SUMO E3 ligase, and Nse1, a RING domain containing putative ubiquitin E3 ligase were characterized in detail. A functional interplay between Mms21 and Topoisomerase 1 in maintenance of longer chromosomes was demonstrated and sumoylation of Mms21 targets coupled with Topoisomerase 1 function were shown to be required for accurate inheritance of such topologically challenged chromosomes. Studies on the mechanism of partitioning of genome into transcriptionally active and inactive (silent) domains led to the demonstration of barrier activity in a fragment containing a tRNA(Gln) gene and the Ty1 long terminal repeat. The barrier activity was dependent on Pol III transcription of tRNA(Gln), the cohesin protein Smc1, the SAS1 and Gcn5 histone acetyltransferases.

DNA Repair and Recombination

Conceptually important and widely cited contributions were made to the areas of meiotic chromosome synapsis, telomere structure and function, RecA biology, higher complexity to homologous recombination and DNA repair. These findings had significant implications for the transmission of genetic information and maintenance of genome stability. A negative regulatory mechanism of homologous recombination that prevents deleterious effects of genomic rearrangements and induction of genotoxicity by inappropriate recombinational DNA repair was discovered. DNA damage response proteins were shown to be directly involved in telomere length homeostasis, cell senescence and cell cycle checkpoint control and this work has had important implications in understanding the relationships between genome instability and cancer. The mechanism of homologous recombination was deciphered in TB bacilli and a unique type of homing endonuclease encoded by RecA inteins of pathogenic mycobacteria was discovered.

Studies on mammalian RAD51 paralogs led to the identification of novel functions in DNA damage responses and tumor suppression. RAD51C was identified to have distinct roles in DNA repair and DNA damage signaling. XRCC3 was shown to be a novel phosphorylation target of ATM and ATR kinases which are crucial for the execution of DNA repair and intra-S-phase checkpoint. RAD51 paralogs in distinct complexes was shown to protect and restart the stalled replication forks. XRCC2 was shown to regulate replication fork progression during dNTP alterations thereby providing insights into development of precancerous lesions due to replication stress. RAD51 paralogs were shown to be involved in mitochondrial DNA replication and maintenance of mitochondrial genome stability. In addition, a novel photo-inducible DNA ICL molecule was developed for cancer therapy. Studies on non-homologous end joining (NHEJ), non-B DNA structures such as G-quadruplexes, triplexes, RNA-DNA hybrid, cruciform DNA etc in the generation of chromosomal translocations and thus cancer led to the discovery of non-canonical role of Recombination Activating Genes (RAGs) in these processes. A novel miRNA was shown to mediate regulation of RAG expression. Microhomology-mediated end joining (MMEJ), a sub pathway of NHEJ was shown to operate in both normal and cancer cells in human and other mammals and this contributes to mitochondrial DNA deletions seen in several human diseases in a Ligase III dependent manner. The mechanism of side effects caused by Endosulfan, a pesticide widely used in India was elucidated. A specific inhibitor of NHEJ that works in a ligase IV dependent manner, named as SCR7 was discovered and its potential use in cancer therapy was demonstrated. SCR7 was shown to improve CRISPR/Cas9- mediated precise genome editing. Another small molecule inhibitor, Disarib, that can specifically target BCL2, an anti-apoptotic protein was demonstrated to be more efficacious than ABT199, the only FDA approved BCL2 inhibitor currently in use in cancer therapy.

Allergy, Immunology and Infectious Diseases

Research in allergy, immunology and infectious diseases led to several interesting findings. Certain carbohydrate-containing IgE-binding epitopes of extensins (soluble plant glycoproteins) were identified as the major allergens among specific pollens and foods while tropomyosin was found to be the major shrimp allergen.

The role of Cytotoxic T Lymphocytes (CTL) in mediating protection against infection with JEV was demonstrated in the mouse model. In contrast to mouse cell lines, JEV was shown to induce the solubilization of MHC molecules in human endothelial and amniotic cell lines. The gene induction and subsequent release of soluble MHC molecules from JEV infected human cells was dependent on Matrix metalloproteinases in the case of HLA-E. While the HLA-F gene was induced, it neither resulted in upregulation of surface molecules nor its solubilization. Using lentiviral shRNA mediated knockdown of Rel A, it was demonstrated that the TNF-α mediated induction of HLA-F was dependent on the activation of NF-κB. It was concluded that JEV infection leads to significant alterations in anti-viral innate immune responses.

Glycodelin A (GdA), a progesterone-induced endometrial glycoprotein was shown to induce apoptosis in T helper cells and natural killer cells. GdA inhibits the activity of the cytotoxic T cells and macrophages as well as proliferation of B cells and monocytes. The potential of GdA for use in the treatment of graft vs host conditions was demonstrated. Abrin, a ribosome inactivating protein from the plant, Abrus precatorius was shown to induce apoptosis in cells and an immunotoxin constructed by conjugating the toxin part of the A chain with antibodies specific to receptors on breast cancer cells was shown to be useful in specific cell targeted killing.

The efficacy of DNA vaccines for JEV and rabies viruses were investigated in a mouse model and the efficacy of rabies DNA vaccine was shown to be enhanced by the addition of a small quantity of inactivated rabies virus paving way for the possible development of combination vaccines consisting of DNA and inactivated virus vaccines. Several JEV- and rabies virus-inducible mouse genes such as those encoding VINC, a novel virus-inducible nuclear noncoding RNA and ApoL9 (Apolipoprotein L9), a phosphatidylethanolamine binding protein were characterized.

Studies on the identification of novel microbial genes involved in stress led to the discovery of Peptidase N (PepN), a major aminopeptidase, in Escherichia coli and Salmonella enterica serovar Typhimurium. Further studies uncovered the roles of Lon protease, MarA transcription factor and the AcrAB-TolC efflux pump during phenotypic antibiotic resistance in E. coli. Recently, the roles of CspE, a member of the cold shock family of proteins, in bile resistance has been shown in S. Typhimurium. Further studies to decipher the roles of other novel genes during stress and virulence are being pursued. Studies on mouse CD4+ T cells lead to a better understanding of the roles of the strength of signal in modulating T cell activation. These approaches were extremely useful in deciphering the mechanism of anti-tumor action by heat killed Mycobacterium indicus pranii, which has adjuvant effects. Currently, host responses to infection by S. Typhimurium, an intracellular pathogen, is being actively pursued with regard to thymic atrophy and inflammatory responses. The differential sensitivity of various thymic sub-populations during atrophy has been shown using multi-color flow cytometry. The identification of molecules that can lower thymic atrophy and boost cellular immunity is being pursued. Our initial studies with Interferon-gamma, an inflammatory cytokine, identified the critical role of nitric oxide in modulating some responses. Recently, an in vivo mouse model of sepsis, an inflammatory disorder, mediated by Salmonella Typhimurium has been developed. Nos2-encoded nitric oxide has been shown to be crucial for host resistance in this model of infection.

In the area of molecular parasitology, the malaria parasite was shown to synthesize its own heme and enzymes of this pathway were found to be essential for parasite survival in mosquito but not in the intraerythrocytic stage of mammalian host. Curcumin was shown to prevent parasite recrudescence and cerebral malaria in the mouse model. A human clinical trial was initiated to examine the efficacy of curcumin-based combination therapy in comparison with the standard therapy. Inhibitors of the parasite heme-biosynthetic pathway were shown to have the potential as parasite transmission blockers.

Key contributions were made towards understanding the roles of molecular chaperones in acclimatization and virulence of neglected infectious disease-causing organisms including those causing amoebiasis, babesiosis, candidiasis, giardiasis, malaria, theileriosis, trichomonosis as well as trypanosomosis. By employing tools of genomics, proteomics and metabolomics, unique mechanisms of heat shock protein gene expression as well as functions in early branching eukaryotes were unravelled. Anovel, trans-splicing based expression of Hsp90 gene was discovered in Giardia lamblia. The heat shock response pathway of malaria parasite was investigated in detail. Novel methods of diagnosis and treatment of neglected diseases of human and animal origin are being developed. Nuclear organization of uniquely trans-spliced genes in Giardia and analysis of flagellar motilities of pathogens such as Trichomonas, Giardia and Trypanosoma are being examined.

Biology of Mitochondria

Research on uncovering the pathways of mitochondrial protein translocation, biogenesis, and turnover and understanding key regulatory mechanisms of redox homeostasis, protein trafficking & folding and organellar life cycle have led to the identification of three different translocase machineries for protein import across the mitochondrial inner membrane, two of which have constitutive functions while the third was found to be oncogenic in nature. One of the components of the pre-sequence machinery was found to be involved in regulating apoptotic pathways, thus imparting chemoresistance in cancer cells. Two novel classes of ubiquitous redox-sensitive proteins (P16 and DJ-1) which plays a critical role in ROS homeostasis in higher eukaryotes were identified and their role in ROS sensing and protection of organellar functions is being investigated. Potent biocompatible nanoparticles that can scavenge elevated ROS under pathological conditions are being developed.

Systems Biology & Metabolomics

Studies involving integration of systems biology with structural bioinformatics can pave way for navigation across the breadth of genome-wide molecular networks with the depth offered by atomic- level information. Focus on a molecular systems view of Mycobacterium tuberculosis has resulted in (a) the discovery of a new promising drug combination for MDR and XDR TB, that reverses isoniazid resistance, made through the identification and tackling of a global molecular mechanism that arises as an emergent vulnerability in drug-resistant mycobacteria (b) new blood-based biomarker signatures of host genes, for diagnosing tuberculosis and for detecting response to antitubercular therapy, obtained through an analysis of the host molecular networks perturbed in tuberculosis, (c) a structural view of the mycobacterial proteome, characterizing its pocketome and identifying druggable targets as well as repurposable drug candidates. An RNA-based biomarker for discriminating metastatic from primary melanoma has been identified and a strategy for enhancing the efficacy of sorafenib in hepatocellular carcinoma has been demonstrated.

Plant secondary metabolites

The Department has been engaged in discovery, validation and development of known and novel anti-cancer and anti-thrombotic agents as well as other drugs of clinical importance such as tropane alkaloids, vinca alkaloids, vinblastine, vincristine, and taxol. Major focus is on finding alternative microbial sources for their production as well as biotechnological, genetic and process engineering approaches for their enhanced production in the plant cell cultures or via fermentation of their endophytic fungi or marine algal resources. The in vivo animal model studies for testing the preclinical efficacy, biodistribution, bioavailability and toxicity studies for the novel and/or FDA approved anticancer drugs is actively being followed as a future trend.

 

 

 

Contributions to human resource development, institution building, liaison with industry and funding agencies and other outreach activities

Over the years, the Department has trained large number of PhD students and postdoctoral fellows who have occupied key positions in Academia and industry across the globe. Some of them have turned into successful entrepreneurs as well. The faculty of the Department played a key role in the establishment of National Biotechnology Board (NBTB) and its transformation into the Department of Biotechnology (DBT). In addition to carrying out research in diverse areas of Biochemistry and Biotechnology, the faculty of the department played an active role in the establishment of Society of Biological Chemists, India in the year 1930 with its headquarters at IISc. The department was the first in the country to be recognized as the Centre for advanced study in Biochemistry in 1968 by the University Grants Commission and this status has been maintained during the subsequent years. The faculty served and continue to serve as Chairman/members of various task forces of science departments (DST, DBT, ICMR, CSIR, UGC, DAE etc), science academies (INSA, NASI, IASc) and research advisory committees of various research institutions. Many faculty are/were coordinators/members of Ramalingaswamy re-entry fellowship program and Innovative Young Biotechnology Associate programs of the Department of Biotechnology, Biotechnology Industry Research Assistance Council etc.

 

A faculty member of the Department conceived and served as the founding coordinator of the first National structured Postdoctoral/Research Associate program in Biotechnology & Life Sciences (and a similar program dedicated for the Northeast region) on behalf of the Department of Biotechnology, New Delhi. The faculty have occupied key administrative positions in IISc such as Deputy Director, Dean, Divisional/Department Chairs, coordinators of new centres, undergraduate and Integrated PhD programs. It is a matter of pride that some of the faculty/alumni went on to becomeheads of institutions such as IISc (G Padmanaban), CSIR (Girish Sahni), JNCASR (M R S Rao), CFTRI (V Subrahmanayan, Ram Rajasekharan), CIMAP (Ram Rajasekharan) and CDRI (TapasKundu). Within IISc,the Department playedan active role in the creation of Centre for Reproductive Biology and Molecular Endocrinology, Primate Research laboratory, Centre for Genetic Engineering and more recently the Centre for Infectious Disease Research. Some of our alumni have served/continue to serve as faculty and chairman of academic departments in Universities outside India, Presidents of biotech companies such as Chief Biotechnologist, Monsanto, USA, Chief Biotechnology Officer, DuPont & CEO, Malaysian Life Science Capital Fund (Ganesh Kishore), CEO, InveniAI Corporation, USA (K. Nandabalan), Head, Alliance Management, Editas Medicine, USA (Varavani Dwarki), Head, Biopharma External Innovation, EMD Serono Inc., USA (Ravi Kiron), Director of Cancer Research Center, Arkansas, USA (N Dhanasekaran), CMD, Xcyton Diagnostics, India (B V Ravikumar), Bhat Biotech, India (Shyama Bhat) Chief of Lipid Research, VA Medical Center, Washington, D.C. USA (Raj Lakshman) to mentiona few.

The faculty have interacted with industries and contributed for the development of several innovative/indigenous technologies. For example, in 1943 alone, the total income of the Indian Institute of Science from Royalties and Profits from different undertakings in the Department of Biochemistry were Rs. 99,384. As early as 1922, an activated sludge plant of ~6000 gallons capacity was installed in the institute for the treatment of sewage from residential quarters and to utilize the sludge in agriculture. Activated sludge and cellulosic waste when fermented together was shown to produce an excellent manure. An activated sludge plant was established in 1938 at the Gun and Shell factory near Calcutta and Voricellid protozoa were shown to produce clear effluent. The faculty have played a key role in the establishment of factories for production of glue, acetone, alcohol and soap in Madras, Nasik, Hyderabad and Bangalore respectively. A group from the Department established the Lac Research Institute at Ranchi, which is now known as Indian Institute of Natural Resins and Gums. The department faculty have played a key role in the establishment of Central Food Technological Research Institute (CFTRI) at Mysore and the Paddy Processing Research Centre at Tanjore, Tamil Nadu. The latter is currently known as the Indian Institute of Food Processing Technology (IIFPT). When the Swedish Pharma company Astra Zeneca decided to establish an R&D centre, it approached the Department and thus was born the Astra Research Centre India. An indigenous recombinant Hepatitis B vaccine developed in the Department is being manufactured by at two companies in Hyderabad and millions of children are being immunized with this vaccine under the National Immunization Program of the Government of India. A company was established recently by a faculty member as part of entrepreneurial initiative of the Institute and is focussing on development of novel veterinary diagnostics. The Department migrated to a new building recently and is forging ahead with 100 years of history behind, constantly adapting to the changing research environment, never deviating from its original objective of carrying out high quality basic research and contributing to the needs of the country.