Building in silico blocks of gene networks involved in cancer

Lakshya Chauhan, Uday Ram and Kishore Hari’s joint interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Lakshay and Uday are joint-first authors on the recent research paper “Topological signatures in regulatory network enable phenotypic heterogeneity in small cell lung cancer”, published in Elife (2021). In this undergraduate special interview, authors talk about this work, its relevance in the context of the cancer and their motivation for research.

Lakshya is a third-year undergraduate student majoring in Biology at the Indian Institute of Science, Bangalore. His interest lies in classical molecular biology and developmental biology. Lately, he got piqued by interdisciplinary fields like systems biology, biophysics, and biomechanics. Besides work, he can be found playing tennis and multiplayer games.

Uday Ram is a third-year undergraduate student majoring in Physics at the Indian Institute of Science, Bangalore. He is interested in exploring the physics of exotic systems, particularly looking at how collective phenomenon leads to the strange properties of these systems. When not doing physics, his entire focus is on coding in python and playing video games.

Kishore is a third-year PhD student at the Center for Biosystems Science and Engineering, Indian Institute of Science, Bangalore. His interests are using systems biology to understand the diversity in biological systems. Specifically, he is trying to decipher the design principles of regulatory networks that allow cancer cells to bypass various barriers in the body. In his free time, he likes to sing and watch anime.

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How would you explain your paper’s key results to the non-scientific community?           

Every single living being is governed by their genetic make-up. This genetic material, DNA or RNA, is further divided into smaller units called genes which encode proteins and other machinery important for functioning. These genes often interact amongst themselves, in large networks. These networks result in all the different cell types in an organism, ranging from neurons (brain cells) to nephrons (kidney cells), from muscles to bones. Going on a tangent, let’s talk about cancer. Cancer cells have been shown to be of multiple types, such as metastatic (the dreaded type that roams around one’s body to find new areas to latch on to), epithelial (the type that latches on and grows) and hybrid types (still under research, but shown to exhibit greater drug resistance and recurrent rates). We focused on subtypes of Small Cell Lung Cancer (SCLC), a deadly cancer with no known cure and abysmal survival rates. In silico methods (simulations done in a mathematical framework) were utilised, and results were compared to the actual patient and experimental data to find anticipated similarities. We also performed a successful reduction in the network size from 33 genes to essentially 4 partners, suggesting that such a large network can be reduced to more intuitive components that still gives one the same subtypes in silico. This is indicative of an idea that a large majority of genes resort to “groups”, where individual groups support/activate amongst themselves but inhibit other groups. Hopefully, this knowledge of such a reduction in large networks is universal in nature and can be applied to other networks/diseases as well. Further, the two major groups acted against each other, and such a “tug of war” could potentially be present throughout biological networks!

Schematic

The metric suggested by us provides a quantifiable measure of the same and could be implemented to find such core principles in a multitude of networks.

What are the possible consequences of these findings for your research area?

If explored further, a universal presence of “groups” could highly impact the time taken for in silico methods for large networks, thus speeding up research. Another possible impact would be an increase in the understanding of roles played by different genes and proteins in various disease stages and types and could further drug/cure development. Such information could potentially also help in finding effective drug targets to subdue various disease subtypes and support faster recovery.

One of the methods used during grouping was the concept of an “Influence matrix”, which suggests that over the course of evolution, gene interactions grow to support the core “principle”, and the entire network evolves around the same, enforcing the principle over aeons. The metric suggested by us provides a quantifiable measure of the same and could be implemented to find such core principles in a multitude of networks.

What was the exciting moment (eureka moment) during your research?

Uday: The most exciting moment I had while doing this project is finding out the fact that this huge network (SCLC network) can be successfully reduced to a 4 node network which preserves all the properties of the bigger network. This implies that big and dense biological networks can in fact be reduced into smaller networks that are both analytically and computationally easy to work with.

Lakshya: For me, it was when I observed that the concept of “Influence matrix” gives the same results as experimental and simulation data. This might not seem huge, but it’s amazing to think that just the network without any simulation and experimental data could give us a clear insight into the properties arising from later. This was quite fascinating for me!!

Kishore: For me, it was when we identified that such a large network has only four states and we figured out that this is due to the nodes of the network forming groups that act together. This implies that the complex interactions are not increasing the complexity of the system, but are working together to preserve the simplicity.

What do you hope to do next?

Uday: At the moment I am exploring different fields of Physics to figure out which one suits me the best. I am certain that I will continue to work on the physics of collective phenomenon.

Lakshya: Currently, I am still exploring various fields of biology. While sure of my resolution to pursue science, I am unsure about which field could be my niche. I hope to stay in more quantitative fields of biology, and over my master’s figure my interests to the best of my capabilities.

As undergraduate students, what motivated you to pursue research?

Uday: Ever since my childhood, I have a desire to face the challenge of solving complex problems. The fact that there are many unsolved questions to be solved made me pursue science. After coming to IISc, I came to know about the existence of exotic systems both in Physics and Biology. These systems are often so complex and diverse yet they follow the same laws of physics. The desire to study them is what motivates me to pursue research.

Lakshya: This would be quite a difficult question to answer. However, if probed, I would say it’s simply curiosity and amazement that drives me. The very nature of science and how evolution drove, from very basic physics-based principles to the rise of sentient creatures and such complex biological systems is something that constantly overwhelms me. I would say it’s this boundless nature of research that keeps my interest piqued.

6.    What was your biggest lesson about interdisciplinary research setup?

Uday: My biggest lesson from this interdisciplinary project is that “to never restrict your thinking to a specific domain of Science while solving a problem”. The questions of “how” and “why” related to a domain-specific question often has a very interdisciplinary answer to it. So as a researcher, it’s always good to go through the work done in other disciplines which will help in the long run.

Lakshya: it is very important to not constraint one’s thought process when it comes to interdisciplinary work, and that’s my biggest takeaway. Constantly reading up other fields, searching for multifaceted components to your research has been an interesting, sometimes exhaustive but definitely fruitful process!

Kishore: Interdisciplinary research thrives on putting various science and engineering disciplines together. It always helps if one has thorough training in one of the disciplines before entering this setup, but communicating with experts of various fields about the problem one is working on becomes a crucial part of interdisciplinary research. Not only is this a quick way to expand the horizons of one’s thought process, but it also makes for a lot of interesting interactions.

7.    Where do you seek scientific inspiration?

Lakshya: YouTube at large is my perfect place for inspiration. Random videos and talks from scientists and educators, and the amazing pace of research and the sheer magnitude of information not known to me is overwhelming, and a constant reminder to keep learning. Documentaries, talks and research showcases help in this!

Uday: Science related articles. Whether in the form of social media posts or news articles, the articles on current research topics is what inspires me to explore more, read more about current research and constantly think about the problems that interest me. Also talking to researchers and attending their talks also inspires me a lot to learn about new things in science.

8.    How do you intend to help Indian science improve?

Lakshya: I think the best way I can help Indian Science improve right now would be to keep honing my skill set and continue on my currently decided path. I do wish to take part in community outreach a bit more, where I would love to teach high school and secondary students about research and science in a more friendly manner than our conventional schools. The way most people are introduced to Biology and science at large is not optimal, often driving students away from even considering research as a career option. This and the opinion that only “smart” people can do science are, in my personal opinion, the two biggest bane to Indian science. Doing my part in changing these would be my way of contributing.

Uday: Coming from a Physics background, I feel that oftentimes students feel that physics is very hard to grasp and is not worth giving a shot. And also because of the huge popularity of JEE and IITs among Senior High School students, a lot of them really don’t get to see the active research happening in the field of Science and how amazing it is. Many coaching institutes just focus on training the students to get marks in exams and won’t make attempts at demonstrating the beauty of Science. So taking part in community outreach programmes and making an effort in bringing awareness about science among parents and students will hopefully make some of the students interested in the field of Science.

Kishore: In my opinion, the best way to improve science in India is by giving undergraduate students a good environment to nurture their research aptitude. The excellent undergraduate programme at IISc is proof of that. Moving forward, I would like to enter academia and prepare teaching modules for undergraduates across the country to expose them to the exciting area of research and improve awareness of various opportunities available in the field.

Reference

Chauhan L, Ram U, Hari K, Jolly MK. Topological signatures in regulatory network enable phenotypic heterogeneity in small cell lung cancer. Elife. 2021 Mar 17;10:e64522. doi: 10.7554/eLife.64522.

Lab website: https://mkjolly15.wixsite.com/cancersystemsbiology

Edited by: Pragya Gupta

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