When failure becomes the stepping stone to success

A failed experiment is not the end of nurturing an idea, but is the beginning of a new journey to think beyond the existing notions.

Ask any kindergarten child why things fall on the ground and just not fly away, he/she will enthusiastically answer, “the earth pulls it”. The concept has become so deep rooted in our minds that seldom do we think about the actual force or its impact in our day-to-day lives. But in 1600s, when English Mathematician Sir Isaac Newton hypothesized about a force that every object applies on each other for the first time, it mystified everybody. He postulated that this force applied by earth is so massive because of the humungous mass of earth which made the fall of any object to ground faster each split of a second. We know this as acceleration due to gravity now even off the top of our heads. But for Newton, the conventional mathematics of Algebra and Geometry of Euclid, Archimedes and Pythagoras continually failed to prove his hypothesis. Even after years of contemplating his idea, Newton met with harsh criticism from the contemporary scientific fraternity for lack of evidence for his work.  At this juncture, when any researcher could succumb and relent, he sat down to analyze why the Mathematics known to him that could define anything static with equations couldn’t get him evidence to support his strong hypothesis. Unprepared to reconcile, the genius in him developed the concepts of a new form of mathematics from abstract, the Calculus which could define change with equations. With differential and integral calculus, he beautifully explained his theories of gravitation and motion in his work Principia Mathematica. One cannot dismiss his thoughts and findings as momentary ramblings for the initial lack of evidential support as his theories hold true even after four hundred years and even paved way to the blockbuster Theory of Relativity by Albert Einstein in later years.

It is not unusual for researchers to ponder over a particular problem in such depth and get fixated on an outcome while designing and performing experiments. So when the observations and experimental results do not turn out the way anticipated the degree of dejection and dismay is tremendous. The question here is, is it always the positive evidence that matters? Following the popular argument that “absence of evidence is not evidence of absence”, it is equally valid to state that absence of evidence opens an array of new possibilities and scope for alternative hypotheses. Statistically, no alternative hypothesis can be asserted with full confidence as all our experiments only help us to reject null hypothesis. Moreover, Type II errors can limit the authenticity of significance observed in our studies. Nevertheless, when the required results are not obtained, the ideas should never be surrendered, but make it the well- born excuse to explore the way far beyond our stated hypothesis.  Preconceived notions and biases can curb the expanse of our imagination and perspectives. As Thomas Jefferson had once stated, “Do not be frightened from inquiry by any fear of its consequences”. Inventing a new division of Science like Newton couldn’t possibly be everyone’s cup of tea. But overcoming dejection when met with failure and thinking a new possibility is a quality that each of us should imbibe from a mastermind like him. It is only when logical arguments rule our toil can we push ourselves to be innovative and persuade us to never settle for just an ‘absence of evidence’.

Dr. A P J Abdul Kalam: inspiring, ingenious, insightful

“Dream is not that which you see while sleeping it is something that does not let you sleep”. 

                                         - Dr. A PJ Abdul Kalam in “Wings of Fire: An Autobiography”

Dr. A P J Abdul Kalam was the most discerning visionary India has ever seen. He rose from an insubstantial household in Rameswaram to be the ineluctable element of space, defense, legislature and education enterprise in India. One of the few scholars hand-picked and mentored by the father of Indian space programs, Dr. Vikram Sarabhai, he played the most crucial role in materializing Satellite Launching Vehicle-III (SLV-III), Polar Satellite Launching Vehicle (PSLV), ballistic missiles Agni and Prithvi, Pokhran-II nuclear tests raising India’s glory to unfathomable scale. He adored his life with simplicity even when accolades poured in from all over the world including thirty honorary doctorates and Bharat Ratna, the highest civilian award of the Republic of India.

Rajiv Gandhi Centre for Biotechnology had the honor to interact with Dr. A P J Abdul Kalam twice. Back in 2002, when the institution just flourished out from its incubator and started its independent journey in the new campus at Jagathy (where the Campus I: RGCB Discovery Research now exists), the then President of India, Dr. Kalam dedicated the institution and its facilities to the nation. It was a moment of great honor to the founders and scientists of RGCB. The visionary in him emphasized the need for “fully exploiting the rich biodiversity that the country was endowed with for the benefit of people.” He urged the scientists to “explore the possibilities of utilizing the indigenous knowledge in Indian traditional medicine” to produce more marketable drugs. Looking at the scientific profile of the institution, he called for untiring perseverance from biotechnology researchers to never stop their efforts at discovering and patenting therapeutic molecules but carry it forward to convert these molecules into drugs beneficial to mankind.

Taking his words in its true sense, it was with immense pride that RGCB welcomed him again in December 2005 for inaugurating the international symposium on “Translational Research: Apoptosis and Cancer”. It was the day after the Principal Investigators confirmed the positive results of a clinical trial to reduce radiation mucositis with a herbal mouthwash developed by RGCB and the Regional Cancer Centre. Professor M Radhakrishna Pillai, Director of RGCB reminisced the day when Dr. Kalam addressed the gathering at MR Das Hall in RGCB, “He spoke to us not as the ace scientist, not as the President of India but as a common man with fears and apprehensions about the deadly disease of cancer, emphasizing the necessity for a wholesome physiological and psychological approach to addressing this disease.” Calling for an initiative to uplift translational research through a consortium of research institution-industry- hospital, he put forth the dire need for Biotechnology discipline in India to rise up and provide affordable and accessible therapeutics to millions of Indians. “Ignoring the repeated cues from his aide-de-camp about running late and his forthcoming engagements of the day, he stayed back to directly interact with the more than three hundred students and scientists who gathered excitedly to meet him and talked vivaciously about his personal and professional lives and his visions and aspirations about India”, Professor Pillai shared his excitement with RGCB blog. Humility is the hallmark of greatness. “Professor Pillai, could you please grab me a chair as it is difficult for me to sit on the floor with my bad backache?” he reluctantly requested seeing the hundreds of students sitting on the floor of RGCB atrium waiting to interact with him

.

Today, as the nation mourns the loss of one of our greatest leaders, RGCB salutes Dr. APJ Abdul Kalam, the man who taught India to dream high, to be courageous to think different, to be creative to invent, to be righteous at heart to share knowledge, to be an ideal citizen, to be an unrelenting seeker of cognizance. 

Navigating through neuronal circuits in human brain

The Human Connectome Project is nearing its completion this year, casting light to the extensive structural and functional connectivity in brain.

Memories, speech, behavior, thoughts, emotions, experience, feelings; the quantum of functions managed by a human brain is tremendous. Deciphering the numerous neuronal circuits in brain has often left scientists and doctors equally puzzled. With more than 90 billion neurons and 150 trillion synapses, human brain has always been the object of awe and mystery over these years. When the Human Genome Project finally decoded the nearly 3 billion nucleotides of human DNA, researchers were energized to attempt a similar Herculean task to map the human brain. Two consortia of research institutions were formed in 2010, funded by National Institutes of Health (NIH) for The Human Connectome Project (HCP). Mapping of the long distance circuits of the whole brain (macro-connectome) is a five year $30 million project carried out by Washington University in St Louis- University of Minnesota- Oxford University (WashU-Minn) Consortium.  Simultaneously, mapping of every neuron, dendrite and synapse of the brain (micro-connectome) is a three year $8.5 million project executed by Harvard University- Massachusetts General Hospital- University of South Carolina (USC-MGH) Consortium. Discussing the progress of the HCP over the past five years with RGCB blog, David Van Essen PhD, the principal investigator of The Human Connectome Project remarked the extensive impact of HCP on neuroscience research.” The Human Connectome Project, now in its fifth and final year of funding, will soon complete its objective of acquiring high quality multimodal neuroimaging data from 1200 healthy young adults, along with extensive behavioral data.  By freely sharing these rich and complex datasets with the scientific community, we hope to accelerate analyses and improve our understanding of brain structure, function, and connectivity and its relation to behavior.”

The project utilizes cutting edge imaging techniques like functional Magnetic Resonance Imaging (fMRI) and Task MRI for analyzing functional connectivity and diffusion MRI (dMRI) for structural connectivity along with Magnetoencephalography (MEG) and High Angular Resolution Diffusion Imaging (HARDI) for crossing white fibers. 1200 healthy adults including twin and non-twin siblings were studied. The brain images at resting state and while undertaking different tasks like solving memory problems, playing gambling games, various physical movements were procured. The Blood Oxygen Level Dependent (BOLD) was used to represent the neural activity at each point and a dense functional connectivity matrix was recreated to show the spatial temporal orchestration of the brain.

One of the major challenges in the initial stages of compiling and making meaningful results out of the enormous amount of data was the inter subject variability in cortical folding pattern leading to blurring of images when population average is taken. This was solved by the perspicacious graduate student in Van Essen lab, Mathew Glasser. He developed Myelin maps by plotting heat maps of cortical region by calculating the ratio of intensity from T1 and T2 weighted images from the same individual. To tackle other challenges in the course of the HCP like noise and bias in the data, discordant results from different imaging modalities as well as subtle cortical boundaries, Salimi- Korishidi and Griffanti et al developed denoising by FMRIB's ICA-based X-noiseifier (FIX) and Robinson and Jenkinson et al developed inter subject alignment using Multimodal Surface Imaging (MSM), thus substantially reducing the average image distortion. The extensive and invaluable data procured over these years is analyzed by the Connectome Workbench and shared across the globe on the robust infrastructure XNAT developed by Marcus et al.

 “The improvements in data acquisition and analysis achieved by the HCP will have an impact on our understanding of brain development and aging and on the analysis of connectomes related to human disease, through projects soon to be funded by the National Institutes of Health”, David Van Essen PhD, the pioneer in neuroinformatics tools, shared with RGCB blog the impact of this much sought after venture and his pride in spearheading the project that unlatches the realm of neuronal circuits. ”The opportunity to help lead this exciting adventure and to work with an exceptionally talented and dedicated team of HCP investigators and staff has been a highlight of my scientific career.”

Neuroscience research in India has a long way to go. Studies in 2010 and 2013 analyze the status, flaws and refinements entailed for India to make our mark in Neuroscience research. Let the critical information newly available to us through the Human Connectome Project aid us in our mission to answer many questions in aging and diseases.

Tools, the lack of them and deploying resources

Many a time we forget how to turn our limitations into our privileges in today’s rat race.

Not many of us know Robert Evans. Some may know him as Reverend Evans because of his numerous books on the history of nineteenth century Evangelism. But he has a whole other dimension through his passion that defined him. His passion to hunt supernovae in the darkest nights. He holds the world record for visual discoveries of supernovae; yes the number is a whooping 42 with an added number of five photographic sightings. Though supernova by definition is a catastrophic stellar explosion ejecting most of its mass as energy as high as that emitted by a star like Sun in its entire lifetime, the universe being so expansive, this is sighted as a small twinkle in a spot in the sky, which was dark before. Imagine your king size bed with a black bedspread. Throw a handful of sand onto it so that the grains are scattered across it. That is one galaxy as viewed from earth with a high power telescope. Now imagine 2000 such beds arranged around the first bed. That’s the sky on a moderately moon lit night. If a single grain of sand is added anywhere in this, our hero Evans can spot it. Well, he calls it the average memory of a star gazer. The astronomical society could only envy his distinctive supernova spotting skill. It was quite a puzzle for them as to what robotic telescope he was using. To solve the mystery of that extraordinary telescope and the probable high end observatory he employed, Nobel Prize winning astrophysicist Adam Rises and his team visited his home once in the Blue Mountains of Australia. His wife Elaine received them with a smile and took them to meet Evans in his "observatory". In the domestic storage room at the back of his ranch house he had a simple 16 inch telescope that was much smaller in size than the fuel tank of an entry level car.  Reiss and his team was quite taken aback when he carried it to the deck next to his kitchen and set it on a homemade plywood mount facing sky against thick foliage of the Eucalyptus trees in his backyard. It was through a square-foot sized, foliage-free area, using this unsophisticated machine that he spotted 42 supernovae that mankind has known - when the automatic robotic 60 inch telescope of Corralitos Observatory in New Mexico spotted just 14 during the same time span. With a shy grin Evans would say, "There’s something satisfying I think about the idea of light traveling for millions of years through space and just at the right moment as it reaches the Earth someone looks at the right bit of sky and sees it. It just seems that an event of such magnitude should be witnessed".  Though Evans took it as his privilege to witness nature’s magnificence, to the thousands of physicists around the world, this imparted much more than mere wonder, it paved the way to various theories on expansion of universe and dark energy. Evans believes he had two advantages. When majority of telescopes were mounted in observatories in Northern Hemisphere, the half of sky spanning over the entire Southern Hemisphere lay vast before him. And while the gigantic robotic telescopes took a good half of an hour to set the field and focus on a galaxy, it took him a little more than a minute with his simple manual telescope anywhere on the face of earth. Clubbing these with his unique memory of star tracks, he made history.

It is not what tools we have, what facilities we are bestowed with, it is the passion with which we pursue our endeavor, the strong desire to strive forward uncompromisingly towards our goal and undoubtedly, understanding our advantages, strengths and limitations at the right time and mobilizing them towards a greater good that matters. Scientific research is an ever evolving, competitive discipline and as comrades-in-arms in this fight for the advancement of mankind, we cannot compromise, but even turn our flaws to our strengths, turn an Achilles’ heel into robustness in our onward expedition

Biotechnology, Law and Society

A quick peek into the Intellectual Property Rights, Patent Laws and Competition Policies guiding biotechnology research and industry in India.

June 1, 2015 was a much awaited day for biotechnology industry and many pharmaceutical companies, less followed by scientists and oncologists and least aware of by the millions of common people in India. The US based Biopharmaceutical Company Abraxis tying up with Biocon India was denied the patent for marketing its drug Abraxane by the Indian Patent Office (IPO) quoting Section 3(d) for lack of novelty and innovation. Abraxane is nanoparticle albumin-bound (nab) Paclitaxel for the treatment of metastatic breast cancer not responding to combination chemotherapy. Spanning from 2005-2013, Food and Drug Administration (FDA) has approved it for the treatment of advanced breast cancer, pancreatic cancer and non-small cell lung cancers. Phase III clinical trials carried out in India and US had shown that nanoparticle based preparation of Paclitaxel had 33% response rate when compared to the 19% given by solvent based preparations of Taxol because of the better target delivery which prompted scientists and pharmaceutical companies to push the drug to market. Upon denial of patent by IPO back in 2009, Abraxis appealed against the order to Intellectual Property Appellate Board (IPAB) based on which the patent application was reconsidered and the recent decision was taken relying on the Supreme Court verdict on the Glivec case of Novartis earlier.

On the bigger canvas, what does this mean to each of the parties involved? Stating the obvious, for Abraxis this caused a loss of their golden opportunity to market a chemotherapeutic drug in India where breast cancer is the second most common cause of cancer deaths among women. But for indigenous pharmaceutical companies in India like Cipla and Natco that are already producing nab Paclitaxel compounds; it opened a wide arena to market generic drugs at competent prices. For biotechnology industry and all those scientists involved, this was an eye-opener towards the section 3(d) of the Indian Patent Act of 1970. Mere discovery of a new form, component, property or use of a known substance or tool cannot be considered as a patentable invention. This drew crisp borders to the definition of innovation in biotechnology research. As for patients, though the majority in this picture due to the sheer number of people and the gravity of impact (as it definitely involves the quality of their own lives), but quite unaware of the legal battles involved, can expect to get generic drugs at an affordable cost in future.

As researchers in the booming field of Biotechnology in India, we should be aware of the legal guidelines defining, boosting and potentially dampening our works of effort. In this era of personalized medicine, Intellectual Property Rights (IPR) hover over diagnostic and therapeutic research sector augmenting quality, competition as well as rivalry at the same time. When scientific and industrial disciplines work shoulder to shoulder, the laws offer protection as well as limitations to the scope of knowledge in market. The functional competition policies in India, through tight guidelines on acquisitions and mergers have made a considerable gap between science and industry, increasing the extent to which basic science translates to practical use of biotechnological inventions in clinical science. Though the yardstick of success is high quality publications in science and economic turnover in industry, the ultimate aim funnels down to improving the quality of life of people, alleviating suffering, making the life of at least one patient better. Despite the numerous odds arising in the field, India is emerging to make a mark in the scientific map of the world. Let us join hands and work towards a productive tomorrow.

Message From Director

India’s engagement with biotechnology, life sciences and medicine is dynamic and constantly evolving. The Rajiv Gandhi Centre for Biotechnology (RGCB) sees itself a key player in this development process. Our research is focused on understanding disease biology and processing this knowledge for better management and therapeutics. The trademark feature of RGCB is the collaborative and interdisciplinary approach we bring to everything we do. This unique facet and the energetic atmosphere of the institute is our success, also creating by itself an ideal and fertile teaching atmosphere for graduate students and postdoctoral trainees. RGCB does innovative research in cellular and molecular mechanisms of human, animal and plant diseases. These programs are designed to lead discovery and innovation by integrating theory, modeling, simulation and experiential science encompassing disciplines such as cell biology, genetics, chemical biology, immunology and others. Our mission is to understand the underlying biology of human, animal and plant diseases, develop a unique training of individuals in fundamental & translational sciences and promote collaborations between medical, veterinary & agricultural professionals with basic biology scientists. This we hope will serve as a catalyst to translate discoveries effectively to eventual implementation for public benefit. RGCB has outstanding PhD and Post doctoral Programs in Basic, Interdisciplinary and Translational Sciences. The institute also conducts a unique Biotechnology Skills Development Program for engineering and science graduates to make them acquire skills in molecular diagnostics, instrumentation engineering, analytical sciences and bio imaging. Over the past 10 years, the ability of RGCB in making major contributions to understanding the fundamental mechanisms of disease has been greatly improved by support for our core facilities and research by the Department of Biotechnology, Government of India. We are also unique among other research institutions in the country, working out of three campuses, one concentrating on discovery, the second, an innovation focused research facility and the third a Bio-Nest for translation of research into applications and products. Please go through our informative website and visit us to find out for yourself why RGCB is the place to be for disease biology research and explore the wealth of opportunities that exist here.