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Government of India

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May 2018

Putting More Life Into The Lifeline

Author: Ashwani Lohani (Chairman Railway Board)  untitled-13.jpg

The preceding four years have indeed been an eventful period for the railways. A rapid move forward in consolidating existing operations and energizing various growth-oriented projects is being witnessed. The realization that railways needs to restructure, reform and revitalize has indeed dawned on the national carrier. The need to enhance infrastructure at a pace that blends with the rapidly growing national expectations in so far as passenger and freight traffic is concerned has also started getting addressed. With the tremendous emphasis being laid on safety, an effort that has already started giving results, the impetus is also being given to expediting the much-needed reforms – cultural, process and structural reforms becoming the order of the day. Perhaps for the first time ever in history, very major strides are being made in the process of bringing reforms in the railway system. Delivery is indeed the primary focus of the organization.

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With 73  train accidents, the year 2017-18 has indeed been the best year in the history of the railways in so far as its safety record is concerned. It is also the first year ever to log double-digit figure of accidents and it is definitely not a freak achievement, but an achievement that the entire organization has worked for. Renewal of overaged unsafe rail-track has touched an all-time record of 4405 km, sharply up from 2597 kms in 2016-17. The last four years also witnessed an unprecedented high removal of 5469 unmanned level crossings, that are inimical to safety. The Government has also recently and wisely decided to fill up a huge backlog of almost one lakh safety related posts besides creating a fund (RRSK) with a corpus of one lakh crores to be spent on safety items.

 

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The sharp focus of the Government towards capacity enhancement, primarily narrowing the huge backlog of infrastructure deficit has also started paying dividends. The average annual capital expenditure during the last four years at over 98,000 crores is more than double of the spending achieved in the previous five. Our achievements in commissioning 9528 kms of new broad gauge line in the last four years as against 7600 kms during the previous five is indicative of our commitment to enhance the pace of building of infrastructure. And electrification, easily the most widely recognized symbol of development has also witnessed a spike of 4300 kms during 2017-18, a pace that we indeed intend to accelerate further. Manufacture of coaches and locomotives at railway production units has also touched new highs in 2017-18 with ICF manufacturing 2397 coaches, CLW manufacturing 350 electric locomotives and DLW 321 locomotives.

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The 14th of September 2017 will go down in the annals of history as a giant leap for the railways in our country, for it is on this day this year that the nation took a major step forward towards displaying its intent of moving away from the era of slow speed trains to real high speed ones. As a citizen of this nation and more so as a railwaymen, I indeed feel more proud than ever. The very thought that the journey from the heart of Ahmedabad in Gujarat to the heart of Mumbai in Maharashtra would be covered in a time frame much shorter than what air travel would entail, and that this is just the beginning, is indeed extremely exciting. Prime Ministers Modi and Shinzo Abe on this day laid the foundation stone of the Mumbai – Ahmedabad High Speed Rail (MAHSR) project, popularly known as the Ahmedabad-Mumbai bullet train in Ahmedabad. And the next five years shall witness frentic activity in the states of Maharashtra and Gujarat to complete this project and position India and also its railway system in the illustrious list of nations that run high speed trains. This first route marks the beginning of a new journey for the railways as well as for the nation. This first route that shall be fully commissioned in 2023 will be the front runner of many more such routes. This project apart from triggering a paradigm shift in how people travel within India and therefore facilitate travel and tourism, would also have a significant impact on the nation’s economy as it scores high on the “Make in India” front. “Make in India” and “transfer of technology” rightly figure in the project agreement between India and Japan, thereby enabling India to make the bullet train a pivotal part of connecting our remotest corners to the epicentres of urbanisation. Called in Japan as ‘Shinkansen’ which means ‘new trunk line’, the bullet train is almost a wonder that will script the most memorable milestone in our journey towards a ‘New India’.

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Construction of dedicated freight corridors has also picked up speed. With many administrative, managerial, contractual and legal hurdles having been resolved, this project is going to see the light of the day in March 2020, when both the eastern and western corridors would stand fully commissioned. This would also be a giant leap forward for the railways as from a mixed traffic configuration on our tracks, we would start moving to lines dedicated for freight with its attendant benefits.

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Major strides have also been made in one of the most fundamental missions launched in recent times – mission cleanliness. While a lot yet needs to be done, considerable improvements have been achieved in cleanliness of stations and trains. Other passenger interface areas like catering, passenger information regarding delayed trains, e-ticketing and introduction of PoS machines are also being aggressively handled and taken forward. A variety of new designs of coaches and trains in the form of products like the Tejas, Antyodaya, Deendayalu, Humsafar, Anubhuti have also been launched to enhance passenger satisfaction levels. Our sensitivity towards the commuters experiencing dense loads in the suburban systems at Bangalore and Mumbai is also reflected in the sanction of projects for upgradation of Mumbai and Bangalore suburban systems at an overall cost of 51000 and 17000 crores respectively thereby benefitting millions of our passengers.

And our commitment and role in integrating the nation can never be underestimated. With 970 kms of gauge conversion done in the last four years, the North East is now fully integrated with the broad gauge network that covers the entire nation. Rail connectivity has now been established with the states of Meghalaya, Tripura and Mizoram and direct train connectivity has been made between Itanagar and Silchar to Delhi.

Indian Railways indeed provides the wheels on which the nation moves. It is also aptly called the economic lifeline of the nation and the primary and the most economical mode of transport for the masses. The onset of the new government in 2014 has indeed led to the beginning of the unleashing of this gigantic monolith and a lot of action has indeed begun in the right direction with reforms being at the core of them. Yet the fact remains that internal contradictions within the organization due to it being a business enterprise and also a ministry leads to inadequate exploitation of its true potential. A gigantic leap forward within the realm of possibility would entail a major structural reform at some point in time, the sooner the better.

Change is always painful, yet it is the only constant an organization must have, if it is to progress by leaps and bounds and for a long-term gain, paying a price in the short term is inevitable. While the progress made in the recent past is indeed noteworthy, the fact remains that we run short of the national expectations and would continue to do so with the gap increasing at a rapid pace, unless major structural reforms are undertaken to ultimately run the organization truly on professional lines. Yet the pace of improvement witnessed in recent times and the commitment to the reform process makes one confident that the railways would always be the key player in the economic development of the country in times to come.

 

 

 

 

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Translating Basic Research towards the Development of Novel Malaria Vaccines & Drugs

Deepak Gaur*  deepak.jpg

Malaria remains one of the top killer diseases across the world accounting for around 200 million cases and half a million deaths primarily among young children, infants and pregnant women residing in some of the most impoverished countries of the world. Unfortunately, India is still endemic to this deadly disease that has plagued the human race for many centuries. The war against malaria has been fought on several fronts and while there have been some significant advancement in terms of developing novel malaria intervention strategies, it is crucial to continue these efforts with great vigor in order to counteract the different species of the highly complex malaria pathogen, Plasmodium.

Malaria control strategies have primarily involved the use of insecticide treated bed nets (ITNs), indoor residual spraying and therapy with anti-malarials such as chloroquine, artemisinin, which have led to a steady decline in malaria mortality during the past decade.

The discovery of Artemisinin was recognized in the award of the Nobel Prize for Medicine in 2015 to the Chinese chemist Youyou Tu. However, the continuous development of drug resistance by the parasite and insecticide resistance by the mosquito vector has proved to be a major challenge in achieving malaria elimination. It has been widely believed that an efficacious vaccine against malaria will be a major public health tool in combating the disease. However, the process of developing an efficacious malaria vaccine has been hindered by several obstacles that have thwarted its development. In fact, there is no successful vaccine available against any parasitic pathogen substantiating the complexity of these organisms and their ability to modulate human immunity. While, a successful malaria vaccine remains a big challenge, there have been several highly promising advancements in the recent past that provide hope for the development of a successful malaria vaccine.

The most advanced malaria vaccine, RTSS that targets the liver stage of the parasite life cycle has been developed through a three decade old association between the Walter Reed Army Institute of Research (WRAIR, US military) and Glaxo Smith Kline (GSK). The recent Phase III results have shown that the vaccine elicits a maximum protective efficacy of 50% against clinical malaria in young children (RTS,SClinical Trials Partnership 2015 Lancet). While, this is clearly not sufficient, the RTSS vaccine still does have the potential to save lives in Africa which carries most of the burden of global malaria mortality. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive scientific opinion for RTS,S (July 2015).

The World Health Organization (WHO) has issued a position paper for RTS,S (also knownmosquirix.PNG as MosquirixTM)in which it recommends large-scale pilot implementations of RTS,S. Importantly, recent clinical trials with fractionalization of RTSS dosage has increased its efficacy to 80%, which is highly encouraging (Regules, JID 2016).RTS,S does serve as a significant platform to further build upon and produce a vaccine with the higher optimal efficacy.

The fact that individuals residing in malaria endemic regions develop natural immunity against the disease does suggest that it should be possible to develop malaria vaccines that mimic natural immunity. However, the challenge remains for us to advance our understanding of malaria immunity and identify the correlates of protective immunity. In parallel to RTSS, there have several efforts to characterize novel target antigens at all three stages (liver, blood and mosquito) of the parasite’s complex life cycle and evaluate their vaccine potential in human clinical trials. Recently, a whole organism approach based vaccine, PfSpz, comprising of sporozoites attenuated by irradiation have shown remarkable efficacy in naïve human volunteers and is being taken forward for field efficacy trials (Hoffman 2015 Am. J. Prev. Med.).

India has been at the centre of malaria research as the landmark discovery of Sir Ronald Ross in 1897 describing the whole sexual cycle of Plasmodium through the Culex mosquito was made during his posting in India. Malaria research in India has been funded primarily by the Indian government agencies, the Department of Biotechnology (DBT) and the Indian Council of Medical Research (ICMR). ICMR has developed a network of malaria field stations across the countries to study malaria epidemiology and vector biology. DBT has provided special attention to basic R&D that has improved our understanding of the parasite biology as well as on translational research aiming to develop novel anti-malarials and vaccines.

One of the biggest success stories has been DBT funded efforts of the ICGEB Malaria group to develop recombinant blood-stage experimental vaccine (JAIVAC-1) and conduct a Phase I human clinical trial. JAIVAC-1 was the first ever malaria vaccine trial against Plasmodium falciparum in India with recombinant molecules produced in an Indian laboratory (Chitnis 2015 PLOS One). It was funded jointly by DBT and the European Vaccine Initiative. JAIVAC-1 was the culmination a strong public-private partnership between ICGEB and Bharat Biotech, a Hyderabad based Biotech Company that has developed vaccines against several disease including the recent Rotavac that has come through the support of DBT. Another vaccine formaulation against P. falciparum, JAIVAC-2 has been developed by ICGEB along with Zydus Cadlia that is being taken forward for a Phase I trial. Human malaria is caused by both P. falciparum and P. vivax, and ICGEB has also developed a sub-unit recombinant vaccine (PvDBPII) against P. vivax malaria that has also been clinically evaluated in a Phase I trial.

Importantly, DBT was quick to recognize that vaccine development steps beyond the bench requires an expertise that is lacking in academically oriented scientists and thus DBT in partnership with the Bill & Melinda Gates Foundation created a separate entity with translational expertise known as the Malaria Vaccine Development Program (MVDP). ICGEB and MVDP have partnered in conducting the JAIVAC-1 and PvDBPII trials.

In a recent highly noted effort supported by DBT, scientists at the School of Biotechnology (SBT), JNU and ICGEB have discovered a novel multi-protein adhesion complex which is essential for the malaria parasite P. falciparum to invade human erythrocytes (Reddy 2015 PNAS; Du Toit 2015 Nature Reviews Microbiology). This complex comprises of three proteins (RH5, CyRPA, and Ripr) and facilitates the interaction between the essential PfRH5 parasite ligand to its red cell receptor, Basigin. Abrogation of this key protein complex has been demonstrated to neutralize the parasite, which provides a paradigm shift in the mechanism of action of parasite neutralizing antibodies that instead of inhibiting ligand-receptor interactions are impeding key protein-protein interactions between parasite molecules (Reddy 2015 PNAS). This discovery has laid the foundation for the development of a new generation blood-stage candidate vaccine, JAIVAC-3 targeting PfRH5 and CyRPA, which is being spearheaded by SBT, JNU with DBT support through their vaccine Grand Challenge Program.

DBT initiated a strong collaborative program between basic and clinical researchers known as GLUE through which JNU, ICGEB and an ICMR institute, NIRTH Jabalpur undertook a partnership aimed at studying Plasmodium vivax malaria in Central India. The collaboration identified the functional domains of P. vivax RBP proteins involved in specific host cell (reticulocyte) invasion and demonstrated that naturally acquired human antibodies against the PvRBP proteins were functionally binding-inhibitory, thus substantiating their promise as key vaccine candidates against P. vivax (Gupta 2017 JID).

Another translational malaria project being supported by DBT is the development of curcumin as an antimalarial. Studies in the Indian Institute of Science have shown that curcumin synergizes with ART as an antimalarial to potently kill the parasite as well as primes the immune system to protect against parasite recrudescence (Padmanaban 2012 Curr. Science). Further, nanocurcumin has been shown to be superior to native curcumin in preventing degenerative changes in experimental cerebral malaria (Dende 2017 Sci Rep). The results indicate a potential for the novel use of ART–curcumin combination against recrudescence/relapse in falciparum and vivax malaria. In addition, studies have also suggested the use of curcumin, as an adjunct therapy against cerebral malaria. Steps for the further clinical evaluation of the ART-curcumin combinations with DBT support are being undertaken.

In yet another significant project funded by DBT through their nanobiotechnology program, scientists at Jawaharlal Nehru University (Special Centre for Molecular Medicine and School of Biotechnology) and National Institute of Immunology (NII) are working on producing nanoparticle based formulations of the drug acriflavin and targeting it to the parasite through specific antibodies. JNU has a US patent for the antiparasitic activity of Acriflavine (Dana et al. ACS Chem Biol. 2014), which it wishes to harness in the development of a novel and highly efficacious antimalarial drug.

DBT’s support has produced a critical mass of Indian scientists involved in malaria research and some significant contributions in our basic understanding of parasite biology that have been undertaken by leading institutions and universities across India.

In spite of this optimism, we need to take bigger strides towards understanding the complexity of the Plasmodium pathogen and finally producing tools for successful intervention of the disease. The war against Malaria is a long drawn one comprising of several battles that have still yet to be won. In this regard, the support of DBT in this endeavor is highly appreciated and remains essential for our country to overcome this debilitating disease.

Rapid fire:

  • DBT funded efforts of the ICGEB Malaria group to develop recombinant blood-stage experimental vaccine (JAIVAC-1) and conduct a Phase I human clinical trial.
  • JAIVAC-1 was the first ever malaria vaccine trial against Plasmodium falciparum in India
  • Another vaccine formulation against P. falciparum, JAIVAC-2 has been developed by ICGEB along with Zydus Cadlia
  • Through DBT support, SBT, JNU and ICGEB have discovered a novel multi-protein adhesion complex, which is essential for the malaria parasite P. falciparum to invade human erythrocytes
  • This complex comprises of three proteins (RH5, CyRPA, Ripr), which form the basis of the new generation candidate vaccine , JAIVAC-3
  • Development of curcumin as an antimalarial supported by DBT.
  • In another DBT project. JNU & NII are working on producing nanoparticle based formulations of the drug acriflavin and targeting it to the parasite through specific antibodies.
  • DBT’s support has produced a critical mass of Indian scientists involved in malaria research.

* Author is Professor at School of Biotechnology, Jawaharlal Nehru University, New Delhi.

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