Mr. Atchuta Srinivas Duddu is currently a PhD student in the Cancer Systems Biology Laboratory of Dr. Mohit Kumar Jolly at the Centre for BioSystems Science and Engineering, Indian Institute of Science (IISc) Bangalore. He holds an M.S. in Electrical and Computer Engineering from the University of California San Diego and a B.Tech. in Instrumentation from IIT Kharagpur. He is the first author of the paper titled “Multi-stability in cellular differentiation enabled by a network of three mutually repressing master regulators”, published in Journal of the Royal Society Interface (2020).
Author Interview
How would you explain your paper’s key results to the non-scientific community?
Phenotypes are the observable characteristics of an organism, such as eye color, structure, biochemical properties, and behaviors. These are governed by genes in our DNA and can change due to environmental factors—a process called phenotypic switching. One example is the epithelial-to-mesenchymal transition seen in cancer and development.
Gene regulation—via transcription factors (TFs) and proteins—plays a critical role in such switching and in development. For instance, a single zygote turns into many cell types during embryogenesis, thanks to gene regulatory networks.
A classic model is the “Toggle Switch,” where two TFs (say A and B) mutually repress each other, leading to a bistable system. The cell commits to either A-high/B-low or A-low/B-high, determining its fate.
We extended this idea to a “Toggle Triad,” where three TFs (A, B, C) mutually repress each other. This system shows tristability: the cell can settle into states like A-high/B-low/C-low or B-high/A-low/C-low, etc.—called “single positive” states. Interestingly, it can also stabilize in “double positive” hybrid states with moderate levels of two TFs.
Our findings help explain the behavior of CD4+ helper T-cells, which can differentiate into Th1, Th2, or Th17 subtypes. Experimental evidence already shows hybrid states like Th1/Th2 and Th1/Th17. Our model offers a theoretical framework to explain how such mixed states arise and persist.
What are the possible consequences of these findings for your research area?
Our study suggests that hybrid cellular states—previously thought to be unstable or temporary—can in fact be stable identities with distinct functional traits. This has broad implications for understanding development, cancer, and immune responses. The findings also lay groundwork for synthetic biology, where we aim to design artificial gene networks for applications like cellular reprogramming or bioengineered systems.
What was the exciting moment (eureka moment) during your research?
The first exciting moment came when I started reading the initial set of papers my advisor suggested. Coming from an engineering background, these papers opened my eyes to the incredible world of genetic regulation and cellular decision-making. Another moment was realizing how powerful mathematical modeling could be in decoding these biological systems. Every time I learned a new method or optimized my code, I felt like I was uncovering a new layer of understanding.
What do you hope to do next?
We aim to study the reversibility of phenotypic switching. If switching were entirely reversible, cells could lose their identity—something that doesn’t happen in reality. We are working to develop a mathematical framework that captures irreversibility and stability in cell fate decisions. We also plan to expand the model to larger networks to understand how their structure influences dynamics and function.
Where do you seek scientific inspiration?
I find inspiration in reading papers, brainstorming with labmates, and engaging in lively scientific debates. These interactions make research exciting and fuel my curiosity. I enjoy the rhythm of daily scientific life and learning something new every day.
How do you intend to help Indian science improve?
While I may not have a direct strategy right now, I believe that focusing on my research and completing my PhD is a step toward contributing meaningfully. I actively participate in science communication and awareness within my community. As an artist exploring scientific illustration, I also believe that art can be a powerful tool to engage people with science.
Reference
Duddu AS, Sahoo S, Hati S, Jhunjhunwala S, Jolly MK. Multi-stability in cellular differentiation enabled by a network of three mutually repressing master regulators. J. R. Soc. Interface (2020), 17: 20200631.
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