MFCEM: Hi Shantanu! At the onset let me congratulate you and your mentor Prof. Sandeep Verma, on this immensely relevant study, and for the many recognitions for this spectacular innovation.

The figures are alarming- according to the IDF, currently, 537 million adults are living with diabetes, and every 3 in 4 adults with diabetes live in low- and middle-income countries. Worse is the fact that these numbers are predicted to rise further. With this in mind, could you please highlight for our readers the relevance of your study, after which we would talk about the science that went into it.

Shantanu Sen: Thank you for recognizing our contribution and providing us with this wonderful platform to talk about it. The relevance of our study lies in addressing a critical gap in the storage and transportation of commercial insulin, a life-saving medication for diabetic patients. Current insulin formulations require continuous refrigeration, which is challenging in low- and middle-income countries with unreliable power supply and limited cold-chain infrastructure. This dependency not only affects underprivileged communities but also poses challenges for privileged users. Our work on thermostable insulin, enhanced by protein conjugation technique, aims to eliminate these constraints, ensuring insulin remains effective for longer duration even under non-refrigerated conditions and thus providing independence for their carefree usage. This innovation has the potential to revolutionize insulin storage and distribution globally, making it more accessible and reducing wastage.

MFCEM: The thermostable phenylalanine-conjugated insulin, termed FHI in your study was one of the many modifications that you tried; could take us through the thought process behind the choice of the modifications; what were the experimental challenges you faced? How did you overcome them?

Shantanu Sen: The choice of modifications was driven by the need to improve insulin's thermostability while preserving its biological efficacy. The chemical synthesis of this novel human insulin derivative involved conjugating a phenylalanine amino acid to the side chain amine of the B29th lysine residue of human insulin. This strategic incorporation of an additional aromatic amino acid at a specific position enhances the thermostability of the modified insulin by maintaining its structural integrity over extended periods, even under extreme unfavourable conditions.

Experimentally, synthesizing the modified insulin required precise chemical conjugation and concerns about compromising its biological efficacy. To address these, we optimized extensive reaction conditions and employed advanced techniques to predict and confirm the enhanced stability and preserved bioactivity of the modified insulin. These efforts were made possible through close collaboration among synthetic chemists, biologists, and computational experts, ensuring that the modified insulin remained effective under rigorous testing conditions.

MFCEM: Since the initial breakthrough by Authur Riggs that led to the creation of the first artificially synthesized insulin in the late 1970s, dedicated efforts continue to improve the overall efficacy of synthetic insulin as a therapeutic, such as, its sensitivity, selectivity, duration of action among others. What was the motivation to work on the stability of the protein? Where you mindful of not compromising the other properties of the insulin peptide? How did you strike a balance?

Shantanu Sen: The motivation arose from the critical need to address insulin's thermal instability, which is a major obstacle to its global accessibility. While improving insulin stability, we ensured that the modification did not interfere with its biological activities, such as glucose-lowering efficacy. To achieve this balance, we conducted extensive studies in cellular and animal models simulating diabetic conditions, confirming that the modified insulin retained its biological activity. Additionally, other experiments helped to ensure that the structural modifications did not disrupt the insulin’s interaction with cellular receptors, preserving its therapeutic potential.

I believe the key to our innovation lies in the minimal modification approach—we found the ideal spot with the right amount of chemical modification.

MFCEM: Shantanu, the immense relevance of your study is further cemented by the many recognitions that the invention attracted. You were among the top 3 winners of the Falling Walls Lab Event India, for "Breaking the Wall of Insulin Dosage Wastage"; besides, you were selected for the Gandhian Young Technological Innovation Award for the year 2023, for patented technology concerning detecting spurious aggregated insulin hormone in commercial injectable formulations. How important are these validations? Is the team, planning to take this invention to the market? could you elaborate.

Shantanu Sen: These recognitions stand as a testament to our research, emphasizing its practical impact and reinforcing confidence in its potential to tackle real-world challenges. Under the mentorship and guidance of Prof. Sandeep Verma, we are actively working to translate this innovation into a practical solution through our start-up, STABLIN BIOSCIENCES PRIVATE LIMITED. Our ultimate goal is to make these innovations widely accessible, especially in regions where cold-chain logistics are impractical, ensuring that no diabetic patient is deprived of life-saving medication.

One of the critical issues we also aim to address is the uncertainty surrounding insulin dosage quality—early-degraded insulin solution can appear as clear as fresh insulin, making it difficult for patients to visually identify without advanced testing. To tackle this, we are developing next-generation insulin variants and user-friendly methods for instant insulin quality detection before injecting.

Additionally, we are exploring applications of this research for other heat-sensitive therapeutics, such as vaccines, to overcome similar storage and distribution challenges.

Shantanu, thank you much for speaking to us, and wish you success for all future endeavours.