Interview of Dr. D. Sundar

As part of the Research Café Seminar series on April11, Dr D Sundar will talk on the advances in genomics and biological computation to increase our understanding of life. Dr Sundar, a faculty member in the Department of Biochemical Engineering and Biotechnology at IIT Delhi, since 2008, has worked extensively on bioinformatics, especially in the design of tools that help in manipulating genomes. The inter-disciplinary Research Cafe Seminar series that started on March 10, is aimed at understanding the science behind some special research being done in the institute. In an interview with Vanita Srivastava, Dr Sundar speaks about genome editing, its importance in the current times and the future research terrain.

What is Genome Editing? What is its relevance in the current times?

Just as editing text involves adding, removing or replacing words, genome editing is an approach in which deliberate alteration of a selected DNA sequence in a living cell is carried out by adding, replacing or removing DNA bases. A zoo of genome editing tools exist today - zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALEN) and the latest CRISPR-Cas9. These can be used to make changes at targeted locations in the genome in a highly specific manner. While most gene mutations are detected and corrected by the cells themselves, a few become permanent. Human genomes contain various errors or mutations. Many are harmless, but some can cause life-threatening diseases. Genome editing can help us study and understand complex genetic conditions. Applying this in genomic medicine to specifically target human genes has been the ‘Holy Grail’ in modern biology. Likewise, in industrially relevant micro-organisms, plants or animals, most applications of genetic engineering have so far involved inserting new genes, termed as transgenes, rather than using editing to incorporate desirable genetic variations. This may all change now with the advent of genome editing...a revolution in our ability to modify living genomes.

How does your team deal with the efficiency and efficacy of genome editing tools?

Genome editing techniques are becoming powerful research tools for highly efficient and permanent site-specific modification of various types of cells, organisms, plants and animals. It must be emphasized that the efficiency of these genome-editing tools are directly determined by the specificity and affinity of these to targeted areas in genome. We are now on the threshold of understanding the specificity of two such genome-editing tools – zinc fingers and CRISPR/Cas9 systems. Over the past decade, considerable efforts have been made by us to develop strategies to understand the DNA-binding specificity in zinc fingers and to diminish the off-target effects of CRISPR/Cas9.

What will your future research focus on? What are the new collaborations in this field?

While genomics is revolutionizing modern biology, lack of computational algorithms and resources for analyzing the massive data generated by these techniques, has become a rate-limiting factor for important discoveries in biological research. The main focus of our current research is on developing resources and other tools for performing highly specific targeted genome editing that are robust and user-friendly. We will make these publicly available to academic scientific community, as we have been doing in the past.

Our lab has also been working on Big Data-based leads for drug development from traditional home medicine for cancer prevention and treatment. Ayurveda, the oldest and world-renowned system of home medicine is trusted for health benefits through centuries. However, it is not supported by laboratory evidence and hence has not developed to systematic medicine. The current era of industrialization of human life style, and rapidly expanding ageing societies (due to better standard of living and health care) has led to increasing incidence of cancer, a highly complex disease. Cancer treatment is complicated not only by its intricate etiology and diagnosis, but also by secondary undesired effects of chemotherapeutic drugs, their high cost and unavailability. Natural drugs, on the other hand could be economic and safe. Although several of herbal drugs are known to possess anti-cancer potential, their functional chemistry and biology have not been dissected. Furthermore, their efficiency in the complex landscape of cancer mutations and types has not been attempted. We have been studying Ashwagandha, a popular herb in Ayurveda, by taking advantage of Big data that has been generated for genomics, transcriptomics, epigenomics and proteomics of cancers.

Collaborations with the Department of Biotechnology of India (DBT), Govt. of India and National Institute of Advanced Industrial Science and Technology (AIST, Japan), has helped us set up a joint international research laboratory, named DAILAB (DBT-AIST International Laboratory for Advanced Biomedicine) at IIT Delhi. DAILAB is actively conducting research projects on integrated drug screenings for stress, aging and cancer intervention with prime focus on elucidation of functional mechanisms of traditional home medicine drugs, native to India.

The progress in genomics has also raised our expectations in personalized cancer research. Today, it is possible to combine information about potential disease markers, drug targets along with genomic insights to help clinicians make appropriate decisions. The need for collaboration between computational biologists like us and the clinicians are the need of the day. In one such joint work with the clinicians at the All India Institute of Medical Sciences (AIIMS), our group is developing a systematic pipeline to rapidly and effectively analyze genomic data to identify potential targets that could aid in developing correct treatment options. We are currently working on understanding the disease progression and resistance to chemotherapy in Chronic Lymphocytic Leukemia (CLL) and on Multiple Myeloma (MM).

The Department of Biotechnology (DBT), Govt. of India, awarded a Unit of Excellence (UoE) grant to our lab in 2016.