The dugong or sea cow (Dugong dugon) is one of the rarest and most threatened marine species alive today. Because it is elusive and difficult to study, knowledge of its global population status and distribution has remained limited. Now, a new study published in the journal PLOSone [ref] finds that dugongs have disappeared from 60% of their former range in the Andaman and Nicobar archipelago in the last 20 years.

The study published by Elrika D'Souza and colleagues at the Nature Conservation Foundation, Mysore is the first to combine historical (1959-2009) and current (2010-2012) data from the archipelago to estimate long-term dugong occupancy trends. Surprisingly, the authors found that remaining dugong populations, now restricted to some sheltered bays and channels, were not limited by the availability of seagrass, their primary food item. It doesn't seem to be habitat loss that's driving this reduction in numbers.

The study suggests that it is mainly anthropogenic factors-hunting, entanglement in gillnets- that have contributed to a decline in species numbers over the years. The tribes of the islands place a high totemic and heritage value on the dugong and are legally allowed to hunt the animal. This, combined with illegal hunting by settlers and incidental by-catch in gillnets has severely compromised population numbers over time, and led to their local extinction around some islands.

The authors suggest that an effective management strategy will have to incorporate the protection and monitoring of areas where dugongs still persist, with a strong enforcement of bans on illegal hunting and high gillnet use. Finally, it will be important to motivate indigenous communities to set harvest thresholds or self-impose bans on hunting to allow local dugong populations to recover. It is only with the implementation of these efforts that dugongs in this region will have a fair chance at survival.

Further reading:

D'Souza E, Patankar V, Arthur R, Alcoverro T, & Kelkar N (October 2013) Long-Term Occupancy Trends in a Data-Poor Dugong Population in the Andaman and Nicobar Archipelago. PLoS ONE 8(10): e76181. doi:10.1371/journal.pone.0076181

Researchers at the Indian Institute of Technology, Jodhpur have identified that the mahogunin ring finger protein–1 (MGRN1) promotes elimination of misfolded proteins; thus alleviating the cytotoxic risk posed by damaged proteins. The degradation of altered or misfolded proteins is a chief intracellular function to maintain homeostasis and survival. Unfortunately, this essential function is often hampered resulting in a diseased state. Misfolded proteins are observed in the pathology of a number of incurable neurodegenerative diseases and protein conformation disorders. They cause cellular toxicity and may eventually result in cell death. In living cells, majority of misfolded proteins are eliminated via two proteolytic systems i.e. autophagy lysosomes and the ubiquitin proteasome system. Researchers at IIT Jodhpur have conclusively demonstrated that MGRN1 is involved in the elimination of misfolded proteins via selective autophagy pathway.

Autophagy essentially means 'self-degradation', an activity performed by every cell in order to eliminate waste material. Chaperone-mediated autophagy (CMA) is a specialised pathway that is involved in the selective destruction of misfolded proteins in cells. In this pathway misfolded proteins having a particular motif i.e. KFERQ or a biochemically related motif are targeted by a cytosolic chaperone hsc70 for further destruction. A chaperone is a protein that helps with folding and assembly of nascent polypeptide chains. Amit Mishra et al found that MGRN1 is involved in the degradation of misfolded proteins via association with Hsp70 molecular chaperone. Although the mechanism for specific targeting of abnormal proteins by Hsp70 yet remains elusive, the involvement of MGRN1 has been demonstrated.

The IIT Jodhpur team experimentally proved that MGRN1 associates with chaperone-linked misfolded protein inclusion bodies and suppresses cell death generated by abnormal proteins. Loss of MGRN1 function develops age-dependent spongiform neurodegeneration (formation of vacuoles in neuronal cells) in mice. Exposing the cells to various stress inducing agents showed elevated endogenous levels of MGRN1, this result suggests it's active molecular role in cellular quality control pathway. Further Mishra's team observed a novel interaction between MGRN1 and Hsp70 molecular chaperone. Cumulative function of Hsp70 and MGRN1 additively enhances cytoprotection against cell death due to oxidative and endoplasmic reticulum stress. This study has, for the very first time, elaborated the quality control function of MGRN1 E3 ubiquitin ligase.

Insufficient or retarded abnormal protein elimination in neuronal cells leads to various neurodegenerative diseases such as Alzheimer's, Huntington, and Parkinson's, Amyotrophic lateral sclerosis and polyglutamine diseases. This reinforces the urgency for a therapeutic strategy against abnormal proteins. Probing further into this research, in order to decipher the entire process of misfolded protein elimination and most importantly of identification of misfolded proteins in the cell, could allow researchers in the future to modify the pathway and increase its efficiency. Another important consideration would be the implications of over-expressing MGRN1; apart from its "clearing" ability any possible negative impacts must also be studied. Overall this study suggests that in the near future a detailed understanding of the molecular mechanism of MGRN1 and efficient upregulation of its quality control function may generate a potential therapeutic opportunity with profound implications for neurodegeneration and aging.

Further reading:
Chhangani D, Mishra A. Mahogunin ring finger-1 (MGRN1) Suppresses Chaperone-Associated Misfolded Protein Aggregation and Toxicity. Sci Rep. 2013;3:1972. doi: 10.1038/srep01972.

Scientists at CSIR - Indian Institute of Chemical Biology (IICB), Kolkata have reported surprisingly high levels of arsenic in locally grown rice, resulting in genotoxicity. Genotoxicity can be explained as the damage to our genes caused by various chemical agents. Arsenic is a potentially genotoxic agent that may cause skin lesions, pigmentation, chronic bronchitis, liver fibrosis, chronic obstructive pulmonary disorder, hypertension, liver fibrosis, oedema of hands and feet, anaemia and most prominently malignancies or cancer. Arsenic is a very common component of various pesticides used in agricultural fields. The risk of increasing arsenic levels in ground water and soil, due to its prolonged agricultural use, has been known for a while now. However, arsenic levels in rice have only recently come into the picture. A.K. Giri at IICB and his team have conducted a thorough study in rural West Bengal and conclusively demonstrated genotoxicity as a result of high arsenic content in rice.

The researchers observed a vast variation in the arsenic content of locally grown rice. The concentrations varied between 100 μg/kg and 300 μg/kg. Hence depending on the concentrations of arsenic in the rice consumed, the cohort of 400 human subjects was divided into six groups. These groups were numbered from A through F. Further classification within each group involved men, women, different age groups, varying body weight, tobacco users and non-tobacco users. Each group was tested for the genotoxic effects due to over consumption of arsenic. It was observed that the groups where arsenic concentration was over 200 μg/kg, i.e. groups D, E and F, showed significantly higher genetic damage than groups A, B & C. A step-wise correlation was observed between the arsenic concentration and genotoxicity. Another important observation of the study was that arsenic concentration in water consumed by the families was such that water borne arsenic contributed to no more than 20 percent of the total arsenic consumed. This eliminates water as the source for arsenic induced genotoxicty.

The study was conducted in rural West Bengal primarily because of the uniform diet of the locals, common method of cooking rice, variation in the concentrations of arsenic in rice observed and most importantly rice being the staple crop throughout. Arsenic content was monitored in the rice consumed as well as drinking water by collection of cooked rice and water samples for each of 400 individuals. Arsenic content was estimated from urine samples and genotoxicity was tested using the micronucleus assay. (A micronucleus is a short DNA fragment that does not get incorporated into daughter genes during cell division; these micronuclei are indicative of genetic damage). The observations were uniform throughout the sub-groups, thus validating the claims that arsenic is responsible for genetic damage.

This is the first study that has brought to light the risk of arsenic consumption through rice. The provisional tolerable weekly intake of arsenic is limited to 2.1 μg/kg-body weight/day, which comes to 105 μg/day for an average body weight of 50 kg. This could result in severe genotoxic effects especially because rice is consumed almost daily in rural areas. The researchers also find that the risk posed to the rural population is much higher as they often suffer from folate, protein and fibre deficiencies, highlighting the severity of the situation. Arsenic toxicated rice is not a problem endemic to India, it is a problem faced worldwide by a population of about 3 million consuming rice on a daily basis. Yes, it is difficult to reach out to rural areas and regulate age old practices, but this study clearly calls out for immediate measures. Rice, being a staple food, has to be given absolute priority and returned to its original quality. Health officials must immediately take steps to curtail the arsenic concentrations and prevent severe genetic damage that could affect generations to come.

This article was co-authored by Dhwani Rupani, Dhruvika Chawalla and Vidhi Khanna

The mechanism of activation of the pro-apoptotic protein HtrA2 has been elucidated by researchers at the Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Mumbai. HtrA2 (high temperature requirement protease A2), a unique mitochondrial pro-apoptotic protein, conserved from prokaryotes to humans is involved in functions such as apoptosis, protein quality control, unfolded protein response, cell growth and metabolism of amyloid precursor proteins. It is also implicated in several diseases including arthritis, neurodegenerative disorders and cancer making it an important therapeutic target. The x-ray structure of HtrA2 could not explain clearly how crosstalk and plasticity of all domains, loops and linkers make it a fully functional molecule. As Dr. Kakoli Bose puts it, “Something triggers its activation and we wanted to know what.” Thus began a two year long research that has finally led to this.

HtrA2 has a trimeric pyramidal structure with short N-terminal region holding the oligomer together through intermolecular hydrophobic and van der waals interactions, thus playing a role in the stability of the trimeric ensemble. The core consists of three serine protease domains (SPDs) surrounded by three C-terminal PDZ domains restricting the entry of the substrate to the SPD active site. SPD is connected to PDZ through a flexible linker and it is hypothesized that PDZ-protease dynamics and their relative orientation modulate HtrA2 activity and hence functions. “It is the intermolecular interaction and not the intramolecular interaction that is essential here” quips Dr. Bose. She further adds that, activation of HtrA2 occurs allosterically, where the signal is relayed via a distal non-canonical substrate binding site i.e. the PDZ domain moves towards the adjacent SPD domain resulting in the formation of an oxyanion hole, or simply put ‘the catalytic site’. It is these structural reorganizations and conformational dynamics that lead through HtrA2 activation and confirm the need for a trimeric structure rather than a monomeric one where the catalytic site would not be appropriately formed.

FRET (Förster resonance energy transfer) studies were conducted by Lalith K. Chaganti, Ph.D. student in Dr. Bose’s lab, to determine the intramolecular PDZ-SPD interaction and the dynamics of the SPD-PDZ interface. It was observed that in case of HtrA2, the energy transfer efficiency was much higher and the distance between PDZ and SPD was lesser as compared to HtrA2 mutant or the monomeric form, thus confirming their hypothesis. A model was propounded where, as a function of temperature, the interface movement occurs such that the PDZ moves away from SPD in a V-shaped trajectory thus bringing the two FRET pairs in vicinity of each other. This model might also hold good for the activation of HtrA2 via substrate binding to PDZ. The team also performed studies using enzymology, in which FITC labeled b-Casein was used as a substrate to check the activity of the enzyme via fluorescence studies. Kinetic parameters like K_m, V_max, etc were also quantitatively studied to correlate the observations with substrate binding and catalysis. Additionally, they also performed far UV-CD studies to understand the effect of deletions and mutations on HtrA2 secondary structure and stability. These studies highlight importance of N-terminal region, oligomerization and intricate intermolecular PDZ-protease interaction in proper active-site formation, enzyme-substrate complex stabilization and hence HtrA2 functions. The fact that this study involved a number of advanced research techniques rather than just one, definitely gives it an edge over the others. It has experimental data such that one experiment backs the other. Next in line, Bose et al. are looking at HtrA2 homologues, specific substrates and also inhibitors, apart from HtrA2 they are also working on another human papillomavirus protein E2.

Ask Dr. Bose, why she chose this particular protein for her research and she elaborates that she wanted to work on a pro-apoptotic molecule with a complex structure-function relationship that is implicated in cancer. With HtrA2, that fulfills all these criteria, she seemed to have found her match. “More than anything else, HtrA2 acts via non-classical apoptotic pathways and has an extremely intriguing structure which pushed me to pursue this”, she says. HtrA2 has been implicated in a number of cancers, namely breast and prostate cancer; making it a promising therapeutic target. If the intricacies of how apoptotic pathways via HtrA2 are shut-down in case of cancer, its inhibitors can be identified, the re-establishment of these pathways will not be far away. This could provide a disease targeted rather than a symptom targeted solution to millions of patients suffering from cancer all over the world.

ROTAVAC, developed by Bharat Biotech in collaboration with the Indian government and other Indian and international partners was launched on May 14^th, 2013. Dr. VijayRaghavan, the secretary of the Department of Biotechnology (DBT) announced that the low-cost vaccine against rotavirus exhibited good efficacy and an excellent safety profile in its phase III clinical trials. ROTAVACwill be available at about Rs. 54 per dose, for three doses (Total Cost = Rs. 162) i.e. almost one-fifteenth the cost. Apart from the cost issue, this vaccine is a landmark for many more reasons too.

Need for a new vaccine

WHO global statistics (January 2012) recorded about 453,000 child deaths (under 5 years) in 2008 attributed to rotavirus infection, of which about 22 percent occurred in India. Rotavirus infection is transmitted via the faecal-oral route causing severe diarrhoea accompanied by vomiting and fever; eventually death results due to dehydration in the absence of treatment. Management of the infection requires oral rehydration therapy and zinc supplements which are available to less than one-third of the Indian population. Rotavirus infection abounds in societies with poverty, considering the hygiene and sanitation conditions that prevail. The families are unable to care for their sick children due to the expenses involved in treatment, inappropriate recuperation facilities and the losses they sustain staying home from work to take care of the child. Thus, in a developing country like India where resources are limited, prevention is definitely better than cure.

Despite the number of deaths reported as a result of rotavirus infection and WHO recommendation in 2009, rotavirus vaccines do not figure in the National Immunization Program of India. High prices cause an essential vaccine to fall under the category of "vaccinations given with parent consult", resulting in almost 2 million cases of rotavirus diarrhoea each year.

ROTAVACv/s other rotavirus vaccines

RotaTeqÔ (Merck & Co.) and RotarixÔ (Glaxo Smith Kline) are the two currently available vaccines against rotavirus infection. RotaTeqÔ is administered in three doses, each costing about Rs.900 (Total Cost = Rs. 2700) and RotarixÔ is administered in two doses, each costing about Rs.1000 (Total Cost = Rs. 2000). Even the GAVI Alliance (a non-profit organization that funds vaccines for poor countries) negotiated a price close to Rs. 200 per dose, for two doses (Total Cost = Rs 400).

ROTAVAC on the other hand will be available at about Rs. 54 per dose, for three doses (Total Cost = Rs. 162) i.e. almost one-fifteenth the cost. This will help the Indian government to provide the vaccine to its citizens without any external help. Even if it is not included in the National Immunization Schedule, ROTAVAC will be accessible to the common masses and not to a few well-off families.

Another point of significance is that ROTAVAC was developed in Indian laboratories, utilizing an Indian strain, tested on Indian subjects and thus can be expected to be more effective in the Indian population.

The journey

The vaccine originated from a new strain of rotavirus, 116E, isolated from an Indian child at the All India Institute of Medical Sciences in New Delhi in 1986. The viral strain 116E showed exceptional promise because children infected with this strain manifested strong immunity against subsequent infections. It is important to note that rotavirus infection from a particular strain is capable of providing immunity from other strains as well. The Phase I studies began after almost two decades , in 2001.

The randomised, double-blind, placebo-controlled phase III clinical trial that began in March 2011, enrolled 6,799 infants (aged six to seven weeks) at three sites - the Centre for Health Research and Development, Society for Applied Sciences, in New Delhi; Shirdi Sai Baba Rural Hospital, KEM Hospital Research centre in Vadu; and Christian Medical College in Vellore. The principal investigators were Dr. T. R. Chandola, Dr. G. Kang and Dr. A. Bhavdekar. The results of this trial demonstrated good efficacy and a good safety profile; the trial was also approved by a Data Safety Monitoring Board (DSMB). Additionally, the vaccine was also compatible with the oral polio vaccine.

Looking forward

Bharat Biotech is expected to file for the registration of ROTAVACsoon. Once licensed by the Drugs Controller General of India (DCGI), the vaccine will be available as a more affordable alternative to the currently available rotavirus vaccines. ROTAVACcould be available in the market as early as the end of 2013. Apart from India, ROTAVACis expected to improve the healthcare scenario worldwide, especially in developing countries.

Conclusion

It is a mark of pride that India, a country known for its exceptional success with generics has now taken a step towards innovative products; an amazingly economical one that too. ROTAVACis the result of a collaboration of partners from India as well as USA. This success paves the way for many such future Indo-US endeavours in the interest of public health.

Let's not bank upon ROTAVACto be a panacea for rotavirus infections, but yes, let's applaud Bharat Biotech in the accomplishment of this task and hope that ROTAVACis able to reduce the massive infantile mortality rates that plague our country.

Researchers from Rajiv Gandhi Centre for Biotechnology, Kerala have identified Curcumin as a potent chemo-sensitizer to 5-fluorouracil (5-FU), an anti-cancer drug. This suggests that curcumin’s use in combination with 5-FU may lead to significant improvements in the therapeutic index of the drug and in breast cancer treatment outcomes.

Breast cancer is the second most common form of cancer and one of the leading causes of cancer deaths. This disease shows great variability in the drug regimen, prognosis and treatment outcomes, depending on the type of mutation involved in the disease. Mutations generally occur in the BRCA gene, or the estrogen receptor gene, progesterone receptor gene, or as a deficiency in Her2 expression. A rare form of the disease involves mutations in all three genes (triple-negative disease) and generally does not respond to conventional hormonal therapies, or Her2-targeted therapies. These approaches fail because they cannot target ER/PR/Her2/Neu receptors, demanding the need for more research and novel treatment strategies.

Of the many drugs currently available in the market, 5-fluorouracil (5-FU) is an anti-metabolite that is used to treat many different forms of cancer, including breast cancer. This compound inhibits the activity of a key enzyme, Thymidylate synthase (TS) in cancer cells. This slows down growth of cancer cells and causes cell death by apoptosis. A wide range of in vivo and in vitro studies have shown that over-expression of the TS enzyme is strongly associated with chemo-resistance to the drug, 5-FU.

This study shows that using 5-FU and Curcumin in combination has a synergistic effect, by enhancing cytotoxicity and cell death in breast cancer cell lines. There was no such toxic effect on a normal, immortalized cancer cell line, MCF10A. The combination of 5-FU and Curcumin showed an increase in the number of cells dying by apoptosis. This effect was achieved by significantly enhancing the cleavage of cell death proteins, procaspase-8 and procaspase-9, to their active fragments. Another hallmark of apoptotic cell death, DNA fragmentation viz. a hallmark of apoptosis was also observed with the drug-Curcumin combination used on cancer cells.

In the next step, the authors attempted to identify the signaling pathways in cancer cells that were associated with this synergistic effect. 5-FU showed a dose-dependent activation of the transcription factor, NF-κB. But curcumin down-regulate activation of NF-κB. Activation of NF-κB induced by 5-FU is down-regulated by curcumin. Other key pathways, such as AKT and MAPK also upregulated by 5-FU, and downregulated by curcumin were not involved in synergism.

In order to pinpoint crosstalk between the drug target, Thymidylate synthase and the signaling pathway molecules, the transcription factor, NF-κB was inhibited using SN50, and by IκB double-mutant (DM) transfection. Interestingly, inhibition of NF-κB did not prevent inhibition of TS by 5-FU, suggesting that it worked downstream of the TS signaling pathway. Curcumin was also capable of sensitizing breast cancer cell lines that differed in their receptor status, highlighting its potential as a chemo-sensitizer.

This specific study has provided new insights into current chemotherapeutic regimen used in breast cancer treatment. While more in vivo studies are necessary to improve our understanding of breast cancer chemotherapy, it appears that Curcumin, with its cost-effectiveness and insignificant toxicity effects, could be established as a conventional chemo-sensitizing agent in chemotherapy.

Researchers at the Madras Diabetic Research foundation and Dr. Mohans Diabetes Specialities centre, Chennai, India have established a link between Diabetes and adipocytes(fat cells) in our body. Under induced oxidative stress fat cells switch over to a senile (aged) phenotype characterised by increase in generation of Reactive Oxygen Species (ROS), DNA damage and shortened telomeres. Finny Monickaraj et al. point out that it is the switch of these stressed fat cells to a senile phenotype that leads to glucose uptake impairment, thus insulin resistance.

Off late, the role of adipose tissue is not only being implicated in energy storage but also in longevity, inflammation, metabolic dysfunction and genesis of age related disorders. Experiments carried out in animal models indicate that an excess of fat cells impels onset of metabolic dysfunction. In obese conditions (state of aging) adipocytes secrete pro-inflammatory cytokines which make the cell micro-environment deleterious leading to inflammation and insulin resistance. This implies that metabolic disorders like diabetes are in harmony with the aging process. Aging of cells, is thus a critical contributing factor in metabolic imbalance.

Adipocyte cells were treated with hydrogen peroxide (H₂O₂) externally, glucose oxidase to generate H₂O₂ in-situ, asymmetric N^G, N^G-dimethylarginine (ADMA) and fluctuating glucose concentrations (to mimic diabetic conditions) for a fortnight. The cells were then assayed for molecular changes due to the induced oxidative stress. Researchers found a substantial increase in ROS in cells that were treated compared to the control cells. This increase could also be the reason for DNA damage and shortening of telomere length. Besides up-regulation of p53, p21 and TNFα (senescent proteins), adiponectin, a protein responsible for glucose regulation and fatty acid breakdown, was found to be down-regulated. Insulin stimulated 2-deoxyglucose uptake in stressed cells compared to the control appeared to be low, giving a clear connection between fat cells and insulin resistance in the body.

Research done by Finny Monickaraj et al. has expanded our knowledge in the field of diabetes. However detailed studies are required to prevent insulin resistance arising from fat cell signalling. There is an indispensable need to further study the molecular mechanisms that determine alteration of fat cell function due to oxidative stress. These studies can lead us to the cause of many age-related disorders that are still muffled.

This article was co-authored by Dhwani Rupani, Dhruvika Chawalla and Vidhi Khanna

The antimony-resistant form of Leishmania donovani (LD), a protozoan parasite that causes “Kala Azar” has been found to show unique glycans, with N-acetylgalactosamine as the terminal residues, which leads to a surge of Interleukin-10 and in turn multi drug resistant protein (MDR) 1. Leishmaniasis is transmitted by the bite of phlebotomine sand flies and may be cutaneous, muco-cutaneous or visceral in nature. Visceral leishmaniasis, also known as Kala Azar, may be fatal if left untreated for over two years. Treatment involves the use of antimony compounds such as meglumine antimoniate and sodium stibogluconate. An increasing cause of concern for Kala Azar has been its re-emergence in recent times, attributed primarily to resistance of the parasite to antimonials. Mukherjee et al have highlighted that over expression of the N-acetylglycosamine glycoconjugates in amastigote as well as promastigote stages of antimony resistant LD have an important role to play in drug resistance.

The researchers traced the molecular mechanisms following infection of macrophages with antimony resistant LD (since protozoa entering the body are phagocytised by macrophages). They observed that antimony resistant LD acts via the toll-like receptors in our body. These toll-like receptors are proteins found on macrophages, responsible for regulating innate immune responses. Over activation of the toll like receptors by antimony resistant LD is followed by a number of intricate mechanisms eventually causing induction of Interleukin - 10 (IL-10). IL-10 is known to "deactivate" the infected macrophages, thus allowing disease progression. Apart from the action of antimony resistant LD on toll-like receptors, it also causes up regulation of the multi-drug resistant protein 1(MDR1). Up regulation of MDR1 takes place only in the presence of the IL-10 surge. MDR1 is an ATP dependant efflux pump that has been implicated in the resistance of a large number of chemotherapeutic drugs. MDR1 causes an efflux of antimony compounds from the macrophages, terminating their action and eventually causing resistance.

Considering that LD is a "master of manipulation of the host cell"; Mukherjee et al have performed laudable work by elucidating its evasive mechanisms of resistance. The researchers have compared experimental results from antimony resistant LD with antimony sensitive LD and knocked down antimony resistant LD. By this approach the possibility of any exogenous factors being involved in the development of resistance stands eliminated. Yet a few questions remain; in order to curtail the resistance mechanisms it is essential to decipher pathways involved (putative targets) and the role of the terminal N-acetylglycosylamines.

Leishmaniasis is an endemic disease found mainly in developing countries like India and Africa, where healthcare facilities are not up to the mark. Thus availability of effective drugs in such countries is a crucial deciding factor for the mortality rate. Recently, there has been an increase in the number of Leishmaniasis cases due to increasing resistance of the protozoan to first line agents i.e. the antimony compounds. Supplementary drugs may be used to combat the infection but do not give the success rate observed in case of antimony compounds, they can only enhance the effect of the first line agents. The research by Mukherjee and his team is a step towards re-enforcing the reign of antimony compounds in the treatment of Leishmaniasis. If it is possible to identify the susceptible steps of the resistance mechanisms it could be possible to modify the antimonials such that they remain unaffected by the "manipulation" of the protozoa or even identify novel agents for the treatment of this dreaded disease.

Indian Association for Cancer Research (IACR)’ annual conference was held at Dr. B.R. Ambedkar Centre for Biomedical Research (ACBR), from 13-16^th Feb. ACBR situated in University of Delhi, North Campus is a premier institution conducting research in cancer biology, infectious diseases, immunology, functional genomics, epigenetics and natural products. The conference had a stupendous gathering of Cancer researchers both, from abroad as well as from India. Prof. N. K. Ganguly a renowned scientist and Former Director General, Indian Council for Medical Research, New Delhi chaired the conference.

The grand inaugural session featured dignitaries’ including- Dr S. K. Bramhachari - DG CSIR, Prof. N. K. Ganguly- Former DG, ICMR, Prof Dinesh Singh- Vice Chancellor, DU, Dr. S. V. Chiplunkar- President IACR, R Prasad- V. P. Chest Institute, Dr. B. C. Das- ACBR and Nobel Laureate Prof. Harald zur Hausen. In his introductory note, Prof. Bramhachari stressed the importance of inter disciplinary research and the need to develop mathematical models for solving complex biological problems like cancer. Prof. Ganguly in his presiding note explained the current status of cancer therapeutics, pipeline of new drugs; ups and downs in HPV vaccine development in India and the journey towards effective HPV vaccine. Dr. Chiplunkar as the president of the society welcomed the delegates and highlighted the vision of IACR to bring scientists and clinicians on a common platform to form a better bond, facilitate exchange of innovative ideas and the wealth of knowledge available and ultimately help finding cures.. Delivering the keynote address Prof. Hausen talked about “The search for a causative role of infection in human cancer”. He talked about his pioneer work on cervical cancer and HPVs, colon cancer and its association with bovine viruses and red meat linked model for Leukemias.

The highly energetic and motivating inaugural session was followed by cultural night having bombastic, mind boggling performances of students in the form of Panjabi bhangra, contemporary dance style. Some of the show stealing performances were by students from north east in the form of their traditional folk dances.

On second day of this convention a daylong International Symposium on Infection and cancer dwelt on science establishing the link between infection and cancer. Basic, translational and industrial research developments in the field of HPV vaccine and its future prospects were highlighted. Prof. Harald zur Hausen also delivered a public lecture, “Are we losing the war against cancer?” which was open for outsiders and all students of the university. His talk was an appropriate amalgamation of the successes and the loopholes in the path of vaccine development. He also explained the importance of global programme of HPV vaccination for boys along with girls which will result in a better coverage and drastically reduce cervical cancer incidence. The major concern about HPV vaccine is its high cost; future insights for a developing country like India demands a state of art research for a better, cheaper and safer vaccine.

Right before the talk in the free time we students had a great time interacting him learning about his research that established the link between colon cancer, red meat consumption implicating the involvement of bovine viruses in colon cancer development, the two hit model for acute lymphoblastic leukemia and role of infection in it etc. It was an indeed a great opportunity and an encouraging experience for us to talk with a Noble laureate in person.

DBT and ICMR representatives talked about funding opportunities to pursue research in frontier areas of translational cancer research and emerging cancer research areas. Apart from talks, the conference featured a vibrant poster session by students. Smt Mangala Bamane award and Shri Sitaram Jogelkar award for oral presentation and Young scientist awards further encouraged young participants to take part in this conference.

If food for thought wasn’t plenty enough, exquisite Indian and continental food with appetizing beverages at Indian Habitat Centre lightened the scientific atmosphere. All in all, IACR2013 was an immense success that involved Cancerians from research as well as clinical sides.

Have you ever relied on a shot to prevent infections? I am sure the answer is an astounding yes. Now if we were to list the characteristics of an ideal vaccine, it would probably read

• Addresses an immediate and pressing need
• Single dose confers lifelong protection
• Leaves serological trail post immunisation i.e. at any point one can detect what one has been immunised with
• Effective in children, adults and elderly
• Cheap
• Amenable to local conditions

The last point in the wish-list is especially important in a large part of the world where refrigeration or maintaining a cold chain poses problems due to lack of electricity, frequent power cuts, high cost, transportation, etc.

"Made in India" vaccine for meningitis, MenAfriVac is a viable effective vaccine that overcomes resource poor settings addressing an epidemic at very low cost.

The need: 1997 saw the largest meningitis epidemic sweep across sub Saharan Africa, in worst cases in Sahel killing upto a third of the affected population. Remaining survivors were left deaf, dumb and visually impaired. Repeated outbreaks of meningitis in the "Meningitis Belt" led to the formation of Meningitis Vaccine Project – an alliance between PATH, WHO, GATES foundation committed to developing a vaccine against Nesseria meningitis, the major cause of meningococcal infections. The vaccine had to be priced at less than $0.5 per dose in order to be sustainable in low income countries.

Serum Institute of India Limited steps in: Exercising frugality and prudence right from the start, Serum developed the vaccine at 1/10th of current vaccine development cost, in less than $ 0.5 million. However, a bigger challenge lay in easing its adoption. Maintaining a vaccine in cold chain (2-8^oC) requires continuous power supply, equipments, ice pack manufacturing - a challenge in resource poor settings. The only way left is to produce and clinically test the vaccine at higher temperatures. Serum rose to the challenge by manufacturing the world's 1st vaccine that could be kept unrefrigerated. MenAfriVac can be stored at 40^oC for as long as 4 days. This means that the vaccines only need to be cold and stored at a central node before adoption at rural areas. In similar vein relooking at heat stability data for current vaccines might yield more cost effective solutions.

The Arduous Journey and the fitting finale: 2005 saw the vaccine clearing Phase I clinical trials in healthy individuals in India demonstrating safety. Phase II trials in 2006 in Africa coincided with an epidemic wave in which the vaccine proved its efficacy. In 2010, the Drugs Controller General of India gave the regulatory approval for the export and use of the vaccine.

December 2012 saw this revolutionary vaccine being administered to the 100 millionth person, a significant milestone. In 2 years of its adoption now stretching out to 10 countries, the vaccine has drastically reduced meningitis in administered regions. Burkina Faso where MenAfriVac was first administered has shown the lowest rate of meningitis in 15 years.

Perhaps more than anything the MenAfriVac Public Private Partnership shows realisation of commitment by Governments, Industry, Organisations of mission they all believed in.

Further reading:

http://www.sciencedirect.com/science/article/pii/S0264410X11020226

http://www.path.org/menafrivac/about-mvp.php

http://www.path.org/news/pr121203-menafrivac.php

http://apps.who.int/immunization_delivery/optimize/Optimize-newsletter-April-2012.pdf

http://www.who.int/immunization/newsroom/menafrivac_20121114/en/index.html

http://www.eurekalert.org/pub_releases/2012-11/bc-mav111212.php

http://www.meningvax.org/files/PressReleasePATH_WHO_MVP-14Nov2012.En.pdf

This piece was co-authored byDhwani Rupani, Dhruvika Chawalla, Malhar Khakharia, Vidhi Khanna

A team of researchers at the Tata Institute of Fundamental Research, Mumbai shed light on the collective forces produced by motor proteins driving intracellular transport in a recently published a paper in Cell. Rai et al describe how as a team, dyneins are able to carry a much higher load than a team of kinesins. This is despite the fact that a single dynein motor is able to carry a much smaller load than kinesin.

Kinesins and dyneins are motor proteins present in cells, and facilitate the transport of viruses and organelles such as mitochondria throughout the cytoplasm via microtubules. Transport processes involved in day to day functions of the cell require large forces which are likely driven by multiple motors, as single motors are unable to provide sufficient force. This transport is characterised by step – like motion of these motor proteins over microtubules. In a fascinating description, Roop Mallik whose team led the research says, “The cell may have its own ways in which motor proteins adapt to do the required amount of work. How these motors generate force as a team is what our research is all about.”

Roop Mallik’s team found that dyneins have the ability to change step size depending upon the load being carried, as opposed to which kinesins take fixed steps. In case of kinesins moving a load, they are unable to “fall back” and work as a team, i.e the leading kinesins do not slow down for the lagging kinesins, concentrating the load on a single kinesin, and ultimately leading to its detachment. On the other hand dyneins have the ability to change their step size according to the load, just like a self-regulating gear. This capacity allows dyneins to work as an integral part of a larger team, distributing the load and supporting each other.

Researchers introduced latex beads into cells to form latex bead phagosomes (LBPs) that became the motor proteins’ cargo inside cells. Movement of LBPs over microtubules was studied using a precisely calibrated optical trap. An optical trap is a device that makes use of converging laser beams to exert a restoring force on LBPs, which can be used to measure the displacement of LBPs by direct proportionality. A clear increase in the magnitude of force with increase in the dynein number was observed, supporting the hypothesis.

Roop Mallik’s Laboratory has further moved onto understanding the role of motor proteins in other cellular processes. They have begun experiments to test the role of motor proteins in the accumulation, fragmentation and change in size of fat droplets in cells. Studies of motor proteins also have implications in neurodegenerative diseases like Alzheimer’s disease and Lissencephaly where point mutations of the amino acid sequences in motor proteins are observed. We hope that this unusual subject is carried further, so in the future it could also be used as a target for therapy in cases of such fatal diseases.

This article was co-authored by Geoff Hyde and Swetha Suresh

Padma Shri Prof. VijayRaghavan’s appointment as the new Secretary of Department of Biotechnology (DBT) has met with a unanimous cheer from the life-sciences community. With his rare combination of scientific reputation, cross-disciplinary background, track record in building excellent institutions and the “can-do” spirit, Vijay has is bound to keep the momentum initiated by his predecessor Dr MK Bhan going full throttle. Despite his stature, setting directions for the future no doubt remains an immense challenge given the rapidly changing life-sciences scene in India.

We at IndiaBioscience and NCBS News asked veteran centre heads, senior scientists at universities and academic institutions, industry representatives and young PIs* – What changes would they like to see Vijay’s leadership bring? If there was just “one thing” that Vijay could do to make a big change, what would it be?

The wishlist included (in no particular order)

1. Promoting collaborative models and fund multidisciplinary/scientists from other disciplines to work on problems in biology. Promoting foreign collaborations and academia-industry dialogue.

2. Balancing funding to ensure that bioscience works to address problems of mass-benefit at the same time encouraging cutting edge science. Support risk taking, innovative and path breaking projects.

3. Improve the quality of teaching, infrastructure and human resources in all set-ups whether a research institution or university by attracting talent and managing resources. Encourage in-depth subject training with cross disciplinary exposure.

4. Encourage entrepreneurship and innovation by bringing in new policy measures.

Strikingly amongst all the replies we got, there was one common wish - Streamlining DBT's administrative processes to ensure timely actions to ensure transparency of funding and, closing the gap between grant sanction and release of funds.

In his response to the community’s comments, Vijay outlines his plans for the future –

“Thank you all for your generous best wishes: They mean a lot. Even more important is your wish list about what needs to be done. This is really of incredible value and I will get the main points of it printed out and we at DBT will not only go through it, but we will focus on addressing the list in a prioritized manner. I have been at the DBT for the third day now, as I write this. I have also been working to collect views from within about what can and should be done. If we look at the urgent needs of the scientific community and the nascent biotech industry, and if we look at the boundary conditions from within, we get a list of problems which need attention and we can move to working on solutions.

The state of the Life Sciences in India

Before we see what directions the solutions could take we need to get an idea of the initial -and boundary- conditions, and our limitations. India has a modestly sized scientific community, but for a country of our size this is clearly far too small. We have already established foundations in many areas of biology, yet we need to develop the depth and breadth of these foundations if we are to nurture excellence. There are pockets of excellence: Individuals who have done well in globally competitive areas. But for the Life Sciences in India to enjoy significant international recognition, we also need to define new problems, perhaps from our context, that the world recognises -through the quality of our work- as problems of importance. Amongst us there are excellent basic scientists, who see red when they are asked about the practical benefits. And, there are others who feel that working on an applied question is a sufficient metric of quality. Then, there are yet others who have worked to solve problems through quality science, not worrying about the labels they wear. Industry for its part is exponentially growing, yet innovative entrepreneurs feel hamstrung by obstacles of every kind. The University system feeds the best into research, yet it justifiably feels neglected. Finally, despite a growing budget for science, we are going through a tough patch which will last for a year or so.

The DBT, till now

The picture I have outlined above is fuzzy, it’s the view from outside the government, where I was until three days ago. For some it seems depressing, but that would be the wrong attitude to have. From within, one is exposed to the harsh reality of performance indices and budget numbers. When we sit and analyze these in the offices of the quintessentially early 20th century-style bureaucratic abodes of New Delhi, you might expect even greater pessimism: You could not be more wrong. It is simply amazing what a can-do set of officers the DBT has now, nurtured by its past dynamic Secretaries. You all know Dr. M. K. Bhan, and his predecessor, Dr. Manju Sharma too. They have developed a cadre of Scientist-officers who have a sense of responsibility and pride in the tasks they have. Led by them, DBT has built and expanded its foundations hugely: Lesser people could have let things be. The optimism, capability and hard-work of DBT officers deliver what good we see. The listing of problems that we as users write down is also seen by those at DBT every day. An approximately 20-fold increase in the budget of the DBT since its start has not been matched by an improvement in management structures and office infrastructure. Despite this background, the DBT's efforts over the past 25 years have transformed Indian biology and biotechnology.

The future

If the DBT now transforms its internal processes and facilities it can do 100 times more. All of us at DBT see this. We are working hard, I assure you to define our goals for the coming 18 months to fix ourselves to serve you better. So, patience for a while, impatience then, but please, constantly hit us with your views, suggestions and feedback. The fix cannot be done by bunkering down but only by working with you all. This fix will also involve the granting process. Here, while the main roadblocks are obvious, the solutions too are blindingly obvious. We can list what we want to see: Better quality proposals, better reviews, better analysis by the task-force, followed by timely approvals and timely release of funds. Our officers work within the existing systems and do the very best they can. Who then are the ones to improve and update processes? If we are swamped by the chores of the day, we can never attend to important tasks well. If DBT's granting mechanisms are to be transformed and the working environment modernized, we must have a dedicated team from within for this task. The good news is that such a team can be formed from the DBT’s own officers and from the Information Technology ministry working at the DBT.

And what about the finance procedures specifically? Some would call them the elephant in the room. All of us love to blame them for our woes. But, the finance systems at DBT were designed for a small budget organization. Here too, within the Government Financial Rules many structural changes are possible.We will work on these. Finance regulators play a key role: They approve the expenditure of public money, following the rules in place. The team at DBT is small, excellent, approachable and responsive and they are our partners in making processes smoother.

Major efforts in restructuring the granting processes had begun and, with feedback and testing, important lessons have been learnt from the efforts of the past year. I think is reasonable to expect changes across the board in about 18 months, again, through a very interactive process with you.

Finally, my colleagues and I are determined not to let a tight budget keep us down. By trimming fat and re-prioritising we will ensure that there is support where it is needed. As our partners in a shared purpose, we ask that each of us, in our institutions and labs, do the same. Doing this calmly and properly, partnering with others here and abroad, my colleagues at DBT are sure that Indian Life Sciences can demonstrate innovation in adversity. We can even take on new projects -that some of you have listed- despite the trying times. In sum, there are opportunities for transformation on the foundation that has been built by you, by DBT and through the efforts of publicly funded science. We need to have a system of interactive functioning to address our pressing concerns: But we have no cause to let these concerns press us down.”

Thank you all again!

Cheers,

Vijay

This piece was co-authored by Dhwani Rupani, Dhruvika Chawalla, Malhar Khakharia, Vidhi Khanna

Withania somnifera (Ashwagandha) extracts have been found to act peripherally to reduce b-amyloidplaques in the brains of transgenic Alzheimer’s mice, presenting a new possibility in the treatment of Alzheimer’s disease. Alzheimer’s is characterised by increased concentrations of b-amyloid in the brain, resulting from improper cleavage, increased expression, decreased degradation or altered homeostasis across blood brain barrier of the amyloid precursor protein (APP). b-amyloid aggregation results in the formation of insoluble plaques which inhibit the functionality of neurons. Current treatment options target the activation of amyloid destroying enzymes, restoring proper cleavage mechanisms and immunotherapy. Receptors controlling the entry and exit of b-amyloid between brain and periphery, peripheral destruction of b-amyloid are viable and relatively untouched targets for the reversal of Alzheimer’s pathology. In this study researchers have successfully tapped these mechanisms by demonstrating that the increase in low density lipoprotein receptor related protein (LRP) in the liver of transgenic mice, eventually leads to improved b - amyloid clearance and cognitive functions.

In healthy people, products of the improperly cleaved peptide are cleared by membrane bound LRP, a low density protein found on brain capillaries. LRP isoform in the liver takes up the abnormally cleaved, toxic b-amyloid leading to degradation by proteolytic enzymes. A subunit of this protein, soluble LRP (sLRP) binds to b-amyloid in plasma, preventing its access to the brain. It has been proven that lower levels of LRP in the liver and sLRP in the plasma also contribute to Alzheimer’s disease pathology. Sehgal et al have reported increased levels of liver LRP and plasma sLRP following administration of Withania somnifera for 1 week to transgenic mice. This was followed by decrease in the brain β-amyloid levels, increase in plasma b - amyloid levelsand eventually improved performance of the mice at behavioural tests. Additionally they reported increased expression of neprilysin, an enzyme that degrades b-amyloid protein in the liver and decreased expression of the receptor for advanced glycation end products (RAGE), which is responsible for the influx of amyloid - b into the brain. The ability of the extract to act peripherally, without having to penetrate the blood brain barrier is a significant advantage over available drug therapies.

The study was conducted in two mice models, APP/PS1 and APPSwInd J20, both showing similar results. The scientists conclusively eliminated the possibility of the extract to influence improper cleavage mechanisms of the brain by simultaneously studying the expression of mRNAs for LRP concentrations and also for concentration of the cleavage enzymes. They then confirmed the improved brain pathology to be a primary result of increased liver LRP, independent of neprilysin concentrations. This extensive and very precise study deals with the effects of the extract on the brain, eliminating other plausible theories, providing exact time-frames and testing the results on two different models, giving due consideration to age and sex.

Yet, a few questions remain unanswered such as the active components of the extract, the possibility of LRP binding to other essential proteins in the body, its long term toxicity and most importantly its potential results in humans. It has also been reported that LRP at the blood brain barrier stimulates uptake of APP, which could worsen the condition of the patient. Furthermore, Withania somnifera eliminates only the β-amyloid plaques in Alzheimer’s, leaving other pathological hallmarks like oxidative stress, change in the metal homeostasis, etc unhindered.

The blood brain barrier has consistently been a major dampener for the various drugs tested for Alzheimer’s due to its intricate restrictive mechanisms. This study is novel in that it deviates from conventional theories and provides agents that do not require penetration into the brain to be effective. If scientists are able to determine the active agents of the extract, a reduced, sophisticated dosage form may be designed.Efficient pharmacological reagents can also be developed that mimic the role of LRP in the brain. Withania somnifera, also known as Ashwagandha, is an important component of Ayurvedic medicine. Thus, the research done by Sehgal at al leaves open a wide stage for the use of Ayurveda in treating Alzheimer’s disease, possibly providing some hope to the millions of people suffering from this dreaded senile disease.