By Kalpana Palkhiwala : The world is observing ‘World TB (Tuberculosis) Day, today to commemorate the day in 1882 when Dr. Robert Koch announced the discovery of the cause of Tuberculosis, the bacillus, Mycobacterium tuberculosis. In 1982, the International Union Against Tuberculosis and Lung Disease (IUATLD) proposed March 24 as the official World TB Day. This day is meant to focus attention on TB and generate public awareness that TB till today remains a global epidemic causing the deaths of several million people each year, mostly in developing countries. In 1996, the World Health Organization (WHO) joined with the IUATLD and a wide range of other concerned organizations to increase the impact of World TB Day.TB is one of the leading causes of morbidity and mortality worldwide as over 1.7 million people die due to TB every year which amounts to one death every 20 seconds. India has the world’s largest TB epidemic in terms of incidence and mortality and the disease remains the largest killer of Indians between the ages of 15 and 45. In India, it causes over 1000 deaths in a day. India harbors 1/5th of the world’s incidence (largest of any single country) of TB. TB spreads through TB germs from infected people when they cough, sneeze, talk or spit into the air. Inhaling these TB bacilli can infect any person. Each infected person with active TB disease, if not treated, can infect on an average of 10 to 15 people every year. But every person infected with TB bacilli will not necessarily become sick with the disease.
In quest of evading this deadly disease, WHO recommended Directly Observed Treatment Short course, better known as the DOTS, is a combinatorial therapy of bacteriocidal and bacteriostatic drugs which comprises of Isoniazid, Rifampin, Ethambutol and Pyrazinamide.
The bacterial antibiotic isoniazid developed early in 1950’s is a prodrug which requires Mtb catalase peroxidase katG to get activated and bind MtbInhA (enoyl acyl carrier protein reductase), affecting fatty acid synthesis. Another bacterial Rifampin, affects the transcription consequently preventing translation by inhibiting beta subunit of DNA-dependent RNA polymerase in bacterial cells. Ethambutol is bacterisotatic which affects the cell wall arabinogalactan by inhibiting the enzyme arabinosyl transferase, and the pro drug pyrazinamide alters Mtb fatty acid synthase via more highly acitive metabolite pyazinoic acid. One of the major obstacles with DOTS is the lengthy treatment duration of 6 to 9 months resulting in patient non-compliance leading to emergence of more fatal forms, namely Multi Drug Resistant TB (MDR-TB) and Extensively Drug Resistant TB (XDR-TB). Drug-resistant TB requires a stretch of period up to two years of treatment with second-line anti-TB drugs which often produce adverse drug reactions.
All these processes points to the need for new drugs. In order to find new drugs for TB, CSIR had initiated the Open Source Drug Discovery (OSDD) project, which was launched on 15th September 2008.
Open Source Drug Discovery (OSDD)
OSDD has established a web-based platform (www.osdd.net), which enables the best minds around the globe to collaborate. In the past two years OSDD has gathered momentum as an internationally recognized open innovation model. Today, OSDD has more than 4500 registered users from over 130 countries. OSDD has leveraged the distributive power of internet to tap the hitherto untapped human potential towards drug discovery. The offshoot of OSDD is a new model of imparting higher education to young aspirant scientists in remote areas of India and of nations less endowed with scientific opportunities.
OSDD brought Science 2.0 to drug discovery. Its scientific portal has a semantic search facility with an RDF data store driving it. OSDD has been able to create a semantic search facility with an RDF data store driving it. OSDD has been able to create a semantic-web architecture that seamlessly integrates social networking with various steps of implementing scientific projects in drug discovery. This portal thus connects complementary expertise in order to facilitate projects demanding varied skill sets and infrastructure. This portal was developed in collaboration with IT giant Infosys.
Data intensive scientific discovery has been made possible in OSDD using the crowd-sourcing model involving students and young researchers willing to voluntarily solve problems for the sake of the satisfaction of solving challenges than for any monetary reward. OSDD’s crowd sourcing approach has successfully curated most extensive annotation on Mtb which served as primer for the identification of potential drug targets. As per published estimates, this innovative approach packed nearly 300 man-years into 4 months.
OSDD has private partners actively engaged in collaborative projects like lead optimization of two molecules with renowned contract research organizations (CROs).
OSDD has integrated the insilico or computer based approaches with the actual laboratory experiments with researchers sharing data in the open portal and receiving feedback from the open, collaborative community thought of wary of open collaboration to work in the open source mode.
Biological research often requires access to physical biological materials. OSDD has set up open access repositories to facilitate such access. These are a Biological Repository of strains, clones etc. and a Chemical Repository of small molecules
OSDD: Attribution and Intellectual Property
OSDD community is built around a set of rules that lays down the basic principles of collaboration through a clickwrap license. The license mandates attribution and sharing of scientific data online with a commitment to give back improvements to the community. Its intellectual property approach is highly novel and innovative in as much as it believes in patents but uses patents to ensure:
i. Affordability, by ensuring that the drugs are licensed non exclusively
ii. For ensuring quality control of downstream drug manufacturing, by licensing to only those entities who employs quality processes
iii. That the subsequent innovations which follows on the existing patent developed in open source also in open source through its viral clauses.
OSDD policy is to ensure that the molecules are available on non exclusive basis to patients in developing world. These drugs will be manufactured by the generic drug industry. Thus what OSDD offers is a sustainable innovation model for diseases without market.
OSDD offers as innovation model that de-risks the drug discovery for neglected diseases. It de-risks early stage drug discovery which is a high risk endeavor through its open collaborative model. OSDD approach to late stage development is to utilize the expertise of CRO’s who have demonstrated capability for such work and the public sector laboratories with such skills. It openly advocates public funding of clinical trials to de-risk this activity.
Government of India has released a sum of Rs. 46 crores for the OSDD project during the 11th plan. Out of this an expenditure of Rs. 9.7 crores has been incurred so far.
OSDD follows a system of open peer review for evaluating projects for funding. The projects are posted on the OSDD portal (http://sysborg2.osdd.net) and are open for community review both in terms of its scientific merit and fund requirement. A committee of experts for approval of funds reviews projects receiving positive comments from the OSDD Community. All the comments and details of these activities are posted online and visible to all the community members. This workflow ensures transparency in the project approval and fund release process.
Initiatives of DBT
The Department of Biotechnology (DBT) funds about 120 tuberculosis researchers for development of diagnostics, novel vaccines, booster to the existing vaccine BCG, Drug Development and creating appropriate infrastructure. The research includes clinical trials for increasing the efficiency/cure-rate of existing Anti Tuberculosis (ATT) Drugs. DBT has been supporting immuno-modulation clinical research using some known immuno-modulators i.e. Mycobacterium indicus pranii (Commercially available as IMMUVAC) for increasing the cure rate of ATT in Category II TB patients who are most difficult to treat. Initial results show apriori defined improvement in cure-rate. Other well-known immuno-modulators that work at the cellular level such as Vitamin D & Zinc are being clinically tested to shorten the ATT regimen in Category I patients with encouraging early results. Scientists at University of Delhi South Campus (UDSC) have identified several proteins produced and secreted specifically by Mycobacterium tuberculosis (Mtb) during growth. They have developed high affinity monoclonal antibody pairs to detect several of these Mtb-specific proteins called MTCAg. These antibodies have been used to develop a test to detect the presence of two MTCAgs in the cultures of specimens from suspected TB patients. The presence of both or any one of the MTC specific antigen in the sample confirms the presence of Mtb. The test is specifically designed as a rapid immunochromatographic format that allows easy and rapid screening of specimens for confirmation of growth of Mtb. It can be performed with minimal training and provides results in less than 20 minutes. This visual test for detection of tubercle bacilli in culture has been developed and is available with trade name ‘Crystal TB confirm’.
A team of scientists at ICGEB led by Dr. Kanury V.S. Rao has made an important breakthrough in TB research. About 20 Mtb-derived antigens presented in the early stages of the infection have been identified and are now under evaluation as potential vaccines for TB. The rationale is to supplement immune memory of the host to improve protective efficacy. Understanding the biology and immunology of Mycobacterium tuberculosis infections, ICGEB, New Delhi, the team is aiming to use the knowledge generated for the development of new therapeutic strategies for tuberculosis. The scientists are collaborating with a pharmaceutical company to translate these leads into candidate drugs that can be tested in the field.