You recently received the prestigious Human Frontier Science Program (HFSP) grant of 1 million dollars to pursue your work on epidermis development. Can you describe the research that helped you win this grant?

I work in the field of mechanobiology, where I combine the tools of physics and biology to answer the questions about how the mammalian epidermis develops. I completed my Ph.D. at the Indian Institute of Technology Kharagpur (IIT-KGP), combining microfluidics and cancer biology. There, I was first introduced to the world of epidermis development. Later, I did my post-doctoral research in the lab of Prof. Joachim Spatz, Max Planck Institute for Medical Research, Dept. Cellular Biophysics University of Heidelberg. In his lab, I focused on understanding the biophysics of epithelial cell migration. When I joined TIFR, Hyderabad, I committed myself to discover the mechanisms of cell migrations and cell division in a multilayer setup. Here, I decided to answer the question of multilayer epidermis formation in the mammalian system. My previous experience had helped me understand the biomechanics of the unilayer of epidermis development, but now I wanted to know the dynamics behind multilayer epidermis formation. You might ask, what’s the difference between monolayer and multilayer development of mammalian epidermis? Well, till now, we know that multilayers of cells display a different molecular identity than cells that are unilayer, and that there is a mechanical drive behind how this multilayer of cells progresses to form the epidermis. This novel quest of deciphering epidermis development through an understanding of the dynamics of multilayer cell development fetched us the HFSP grant this year. 

How crucial was the research topic in getting the funding?

When it comes to research ideas for HFSP, the keywords are risk and fundamental questions. In our case, our research idea and the hypothesis involved answering questions with considerable risk. Although we stand on the shoulders of giants, our topics are still relatively untested in the scientific community. For a long time, epidermis development has been seen through the eyes of fixed tissue, but rarely are the dynamics behind this phenomenon noticed. My team aims to clear the murky waters of multilayer epidermis dynamics with a completely new approach of using mouse embryonic stem cells and skin embryoids. Our topic is both fundamental in nature as well as untested for any other funding agency to grant us money. The HFSP recognizes such topics and invests readily to help scientists like us take them further.

How did your team and research come together? Which came first – the team or the question?

My team comprises two long-known companions, Friedhelm Serwane from Ludwig-Maximilians-University, Munich, and Dapeng ​“Max” Bi from Northeastern University, Boston. It was almost simultaneously that the research idea and the team came together. The idea of working with the epidermis was always there. Then came Max. Being a theoretical physicist, he added the concepts of cell competition and cell mechanics to my question and offered to further dissect the mechanism through his computational models. On the other hand, Friedhelm offered his ferrofluid droplet technology for understanding the viscoelastic properties of cells during division and migration. The addition of my team members improved the perspective of my question, which I think helped us in getting the grant. 

In what ways did you ensure that each team member brought a novel approach while building a proposal? 

In my lab, we work with elastic properties of the epidermis, where we follow cell dynamics in monolayer conditions. When I collaborated with Friedhelm, he suggested that we understand the fluidic properties of the epidermal cells too, as they behave more like sheets when in multilayer. His approach of using ferrofluids in the magnetic field would give us an upper hand in studying the fluidic properties of the cell. On the other hand, Max utilized his expertise in the physics behind cell shape and size to fine-tune the problem. He brought computational power to the table. His idea was to build a robust model, using the biological data that Friedhelm and I were going to give, that would predict essential factors responsible for proper multilayer of epidermis development. All three of us had defined roles. However, the success of the grant was because although we all brought together different approaches, we kept the project’s objective unified. Each member of our team is a vital cog in solving this puzzle. Hence, we decided not to segregate our objectives but rather keep them together and answer collectively in a thematic fashion.

How did you ensure that your team was well balanced?

I realized earlier that my team would consist of individuals who use an interdisciplinary approach to solving problems of cell dynamics. The HFSP also insisted that the team should be intercontinental in nature. These criteria helped me narrow down to Max and Friedhelm, who work in North America and Europe, respectively. I now understand that the principal investigator must address the scientific problem upfront and identify the best people who may answer the problem in their own manner. Both of my team members brought in expertise which was essential for the success of the grant. 

How and when did you start thinking about applying for HFSP?

I started working on the grant in January 2021. I focussed on including innovative and collaborative elements in the grant. With collaborators on board, we started working towards the letter of intent due to be submitted in early April. When it comes to HFSP, a letter of intent is considered for the initial screening of applicants. We kept the brief description of our project concise with elements of risk and solid rationale supporting our hypothesis. After we were selected in July, we began the tenacious process of writing the main grant proposal. The three time zones we all were in also helped in our cause, as we all spent substantial amounts of time scrutinizing each other’s work. This improved the writing quality of the proposal and the question we asked in the process. For example, we started initially by working on the monolayers of the epidermis. As discussions and inputs from my team went on, we proposed using the epidermis multilayer to answer the questions. As we approached the deadline, we started putting in more inputs and the proposal was constantly under watch, improving its quality significantly. Writing a risky proposal for HFSP meant relying less on proof-of-concept and more on innovation and a will to go beyond what we currently do to answer a fundamental question in biology. 

Any advice for prospective HFSP applicants from India? 

They must actively work on the concept and consider their area of expertise for their input to be essential. In most collaborations, there is usually one major contributor and several supporting members. In the case of HFSP, that will not function. Every team member should play a critical role in the project; otherwise, it would be incomplete. Another aspect to consider is that, while the HFSP requires that what you propose to accomplish be distinct from what your lab is currently doing, reviewers must also be convinced that you can carry out your proposal. It’s critical to strike a balance between these two seemingly opposing features.