Radiation induced by-stander effect (RIBE) is a poorly understood phenomenon wherein non-irradiated cells show evidence of DNA damage, genomic instability, mutation and apoptosis bothin vitro and in vivo. We have observed that chromatin fragments (Cfs) that are released from dead cells resulting from radiation treatment are one of the key factors responsible for RIBE.

Since our study shows that Cfs are DNA damaging agents with implications for diverse diseases associated with elevated Cfs levels, removal of Cfs could be of therapeutic value. We have developed pullulan-based histone antibody nanoconjugates for the removal of Cfs from circulation. Nanoconjugates were developed and various physico-chemical characterizations were carried out. The efficacy of these nanoconjugates on removing Cfs was evaluated both in vitro and in vivo.

There is a long held belief among medical doctors and scientists that metastatic tumours are histologically similar to the primary. This belief is reified because it supports the prevailing theory of cancer metastasis. The latter teaches that tumour cells detach from the primary site to intravasate into the blood stream reach distant organs where they extravasate into the target tissues and grow  to form a metastatic cancer.

Following our observation that circulating Cfs are DNA damaging and oncogenic agents, we investigated whether application of dead cancerous cells (dcCfs) to NIH3T3 cells will bring about similar pathological changes. We found that numerous dcCfs exiting from the dead cells rapidly entered into the recipients, integrated into their genomes and triggered genome-wide de-regulation of transcription. Whole genome sequencing of NIH3T3 cells treated with dead human cancer cells detected several hundred thousand human reads in recipient mouse cells.

Our research has shown that Cfs derived from cancer patients are biologically more potent than those derived from healthy volunteers. We have observed that treatment of NIH3T3 cells with Cfs isolated from sera of cancer patients trigger a genome-wide deregulation of transcription, chromosomal instability, inflammation and up-regulation of multiple cancer-related pathways encompassing 200 genes. In 30% of our experiments, oncogenic transformation was observed in the treated cells within 72hr - 96hr.

Whether nucleic acids that circulate in blood (CNAs) have any patho-physiological functions in the host have not been explored. Our lab has demonstrated for the first time that CNAs in the form of fragmented DNA and chromatin (DNAfs and Cfs) can freely enter into healthy cells, associate with their chromosomes and integrate into host cell genomes. The latter leads to activation of DDR and up-regulation of apoptotic pathways.