Structural and Computational Biology Group
International Center for Genetic Engineering and Biotechnology (ICGEB)
New Delhi, India
AsianScientist (Mar. 17, 2017) – The malaria parasite (Plasmodium spp.) has afflicted the human race since the dawn of civilization. Malaria-like symptoms—episodic fevers and an enlarged spleen—were described in Nei Ching, an ancient Chinese medical text that dates to 2700 BCE, showing that we have been aware of the disease for at least 4,700 years.
As the centuries rolled on, we gradually began to unveil the unseen foe. The first breakthrough was the identification of the malaria parasite as the causative agent of the disease in 1880, displacing the previous notion that it was caused by bad air—mal aria means bad air in Latin. Less than 20 years later, a British officer in the Indian Medical Service demonstrated that the malaria parasites could be transmitted by mosquitoes.
Today, half the world’s population lives in areas susceptible to the disease which affects more than 200 million people each year, costing an estimated US$12 billion. Taking up the mantle in the continued fight against malaria is Dr. Amit Sharma, a structural biologist with the International Center for Genetic Engineering and Biotechnology.
Sharma studies malaria parasites at the molecular level, using crystallography and other methods to identify weak spots on parasite-specific proteins that could be targeted by drugs. One of India’s most well-regarded scientists, he has been recognized with the 2015 Infosys Prize and the 2011 Shanti Swarup Bhatnagar Prize for Science and Technology, India’s highest science award, among others.
In this interview for Asia’s Scientific Trailblazers, Sharma tells Asian Scientist Magazine more about his latest work and where we stand in the battle to defeat malaria.
- Malaria has plagued humans for a very long time. Why has the disease been so difficult to eradicate?
- What perspectives do structural biologists like yourself bring to the study of malaria?
- In 2016, your group published a paper in Nature describing a single dose malaria drug. Could you tell us how it was discovered?
- What stage of development is the drug currently at? What impact do you hope it will have?
- What other projects do you have going on in your lab?
- What breakthroughs in malaria research do you hope will happen in the next ten years?
- What is your opinion about the state of science and technology in India?
- What practical steps can be taken to improve the quality of scientific output from India?
- What advice would you give to young scientists hoping to establish their careers in Asia?
Malaria is caused by a eukaryotic parasite that has been around on earth for millions of years, from much before primates started to evolve. This parasite seems very adept at surviving biological pressure in terms of drugs or host immune responses. Human struggle with the malaria parasite has even left its footprints in the human genome.
Indeed, the parasite is very resilient and may remain so unless very disciplined, scientific, international and coordinated steps are taken worldwide to contain it. All national and international stakeholders will need to synergize in order to contain and eliminate the malaria parasite.
The molecular functioning of biomolecules like proteins is governed by their structural and chemical characteristics. Specifically, in order to understand whether given sets of parasite proteins can be targeted by drugs or for vaccine development, structural information is vital. This is exemplified by the success in the field of HIV drug discovery where structural biology has contributed tremendously to outwit the virus.
There are similar success stories with parasites as well, and therefore structural biology of malaria parasite proteins remains a vital component of research for us and many others in the field. Structural biologists reveal details of atomic interactions that occur between proteins and drugs and/or between host and parasite proteins. These molecular insights then guide translational research that aims at targeting the malaria parasite.
This discovery was made at Broad Institute in US by Dr. Stuart Schreiber and his team. They first synthesized and then screened a 100,000 compound library to identify candidate molecules which can target malaria parasite at multiple developmental stages. At the outset, the experimental objective was set at a very high threshold in terms of single dose clearance and potency against multiple parasite stages.
We and others contributed to Broad’s groundbreaking efforts by addressing the biochemical basis of action of the candidate drugs. This study was a tour-de-force in malaria, and represents an astounding achievement of first rate international science and linkages.
Along with Broad and Medicines for Malaria Venture we plan to take the candidate molecules forward in development so that they are more specific for the parasite and show reduced toxicity to hosts. This is a very significant on-going research thrust in our lab, and we are hoping to identify more potent and selective anti-malarials that can be taken forward for clinical development in coming years. We hope that this work will not only impact positively in terms of attracting sustained funding for basic/translational research but also potentially deliver new drug arsenal in coming years.
Using funding from international agencies, we are actively working on exploring and validating additional candidate drug molecules that can serve as new generation anti-malarials. In addition, our structural studies have revealed striking similarities in eukaryotic pathogen tRNA synthetase active sites—an enzyme family which continues to fascinate us. Hence, some of the candidate drugs that are being explored for malaria seem to be of high utility against other human parasites as well.
In addition, we have initiated a program to dissect and understand the role of host microbiome in human communicable and noncommunicable diseases. We rely heavily on our wonderful national and international collaborators from Japan, UK (Oxford and Cambridge), US (Boston and California), France (Grenoble) and India (Pune and New Delhi) for these studies.
I do hope and feel that two central problems of malaria biology may be better understood within the next decade. The first is the molecular basis of the development of drug-resistant malaria parasites. This is not only a very intriguing and challenging phenomena from a public health perspective, but also ultimately a deeply frustrating facet of anti-malarial drug development.
The rate of development of drug resistance is alarming when compared to the success rates of launching new drugs. An intensely combative situation exists presently: on one side is human ingenuity that drives drug discovery while on the other side is the natural proclivity of malaria parasites to outwit drugs. The outcome of this battle will likely decide the future of malaria on earth, and still several breakthroughs are required to fully address this issue.
The second major black box where breakthroughs are expected is the unraveling of the complex interplay between the host microbiome, its biomolecules/metabolites and malaria prognosis. I do feel that another decade of fundamental research will reveal the identity and extent of host molecular factors that are vital modulators of the course of malaria infection. Revelation of linkages between host microbiome and infectious diseases like malaria may in future guide therapeutic options as well.
Like in many other developing countries, there are pockets of excellence in science and
technology in India. In some fields like space technology, India is clearly top rated. In other fields including in crystallography and chemistry India has tremendous strengths and legacy of achievements—again several individuals are top rated scientists internationally. In my opinion, while competing with the best worldwide, Indian science should remain context-based in terms of addressing nation’s problems.
Quality in scientific output stems from several inter-dependent factors including substantial funding, human resources, infrastructure support, scientific temper and proactive scientific administration. Since independence, India has established very impressive scientific infrastructure throughout the country. In addition, human resources for science in India are immense, and indeed await full empowerment.
Already, numerous pockets of excellence in India produce high quality science depending on the exact discipline. Scientific output, including its quality, seems correlated with percent of GDP that a country decides to dedicate to science. I feel that doubling or tripling of the present GDP commitment in India will provide a huge fillip to Indian science, its quality and its throughput.
I do not particularly feel that its apt for me to advice our young, independent and bright generation of Indians or Asians. The present generation is blessed with unprecedented access to scientific information, worldwide virtual connectivity and unparalleled evidence of the benefits of scientific method to advance human civilization. There are essentially no more physical or metaphorical boundaries between Asia and rest of the world. Humanity is one and its science is owned by all.
Asia is and has been a powerhouse of cutting-edge science. Countries like Japan, China, India, Korea, Taiwan and others are very dominant players on the world stage. So, if Asia remains invested heavily in Science its youth will inevitably shine. However, given a wide choice of scientific problems, young scientists may consider to focus on pressing national problems that plague all countries including those in Asia.
This article is from a monthly series called Asia’s Scientific Trailblazers. Click here to read other articles in the series.
Copyright: Asian Scientist Magazine; Photo: Amit Sharma.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.