Meet Ranya Virk, a graduate student in the Backman Lab and Szleifer Research Group

Ranya Virk is a graduate student in the Backman Laboratory, which focuses on elucidating the function of the human genome and its dysregulation in disease, enabled by the development of new nanoscale imaging, predictive computational genomics, and computational electrodynamics technologies that lead to new methods for regulation of global patterns of gene expression and their clinical translation for disease diagnostics and therapeutics; and the Szleifer Research Group, which focuses on the molecular modeling of biointerphases, aiming toward a fundamental understanding of the properties of complex molecular systems that encompass problems at the interface between biology, chemistry, physics, and materials science.

Where are you originally from?

I grew up in Lexington, Massachusetts.

Where did you complete your undergraduate degree?

I completed my undergraduate studies at McGill University, which is in Montreal, Quebec in Canada. At McGill I majored in quantitative biology with a minor in computer science.

When did you first become interested in biomedical engineering?

Surprisingly, I wasn’t even aware of the field of biomedical engineering until I began searching for potential PhD programs. I was originally thinking of doing my graduate studies in biophysics, since I had a background in both molecular biology and physics from my undergraduate degree and my thesis was in a biophysics research group.

However, when I happened upon a biomedical engineering program at one of the research institutions I was looking into, I immediately became intrigued. The research that was going on in these biomedical engineering departments was not only incorporating physics and computational methods to study biological problems, something that I was invested in from my undergraduate experiences, but also had direct applications for healthcare. Importantly, biomedical engineers framed their research to be able to meaningfully contribute to the medical field by incorporating basic physiological and biological principles with an engineering problem-solving approach.

My father is a healthcare professional and has been working in emergency medicine since I was a child so you could say that I grew up surrounded by exemplars of the critical value of medicine and medical advancements in our society. Biomedical engineering drew me in because of both my research interests as well as — however clichéd it may sound — the potential the field has to change the world through medical research.

How do you explain what you study to non-scientists?

The “Central Dogma of Biology” is that DNA, which contains our genetic information, is transcribed into mRNA, which is then translated into proteins. Patterns of gene and protein expression collectively constitute a cell’s phenotype, which defines cellular processes and functionality ranging from responsiveness to low nutrient conditions to cell morphology and motility.

Chromatin, including DNA, RNA, and proteins, is the substance which controls accessibility of genes to transcription processes and, therefore, can be considered as a gateway to regulating cellular phenotype. Additionally, large-scale alterations in chromatin structure are associated with cancer, numerous neurological and autoimmune disorders, and other complex diseases, underlying the importance of chromatin structure in maintaining normal cell functions.

In general, my research focuses on developing physics-based computational methods to predict the effects of specific biophysical mechanisms on chromatin structure and function. To ensure these molecular models translate to biological reality, we validate our results through a combination of nanoimaging and biochemical experimental techniques.

My past work demonstrated the existence of a genome-wide regulator of transcriptional activity: chromatin packing, the statistical conformation of chromatin in three-dimensional space, which may modulate gene expression by orders of magnitude. Additionally, chromatin packing controls phenotypic plasticity, the adaptability of a cell to an external stressor, such as the responsiveness of cancer cells to chemotherapy. Thus, characterizing mechanisms which alter chromatin packing could provide insight into how to biochemically modulate chemoresistance, the ability of cancer cells to evade cell death by chemotherapeutic drugs.

As chromatin is a highly electrostatically charged system, the intranuclear ionic environment directly influences chromatin structure at small, molecular-level scales. However, there is currently no definitive mechanistic basis for how the molecular effects of the intranuclear environment propagate to influence large-scale chromatin structure and transcription processes.

My current work focuses on developing and applying a multi-scale computational approach to determine the effects of the major intracellular ions (K⁺, Na⁺, Mg²⁺, Ca²⁺) and pH on chromatin structure with molecular-level detail. Using our computational models of transcription we can then predict how these chromatin packing changes would alter gene expression and, consequently, cell phenotype. A potential future application of this work is the identification of adjuvant compounds that alter the intranuclear physicochemical environment, which could be administered together with chemotherapies to improve the efficacy of therapeutic treatments.

More generally, this work could discern principal mechanisms which control large-scale genome organization and phenotype, with wide-ranging applications from increasing cellular plasticity to combat the effects of neurodegenerative diseases and retinopathies to decreasing the adaptive potential of stem cells to improve the efficiency of cell-type-specific differentiation for regenerative engineering purposes.

Recently, you’ve been focused on the structure, density, and other characteristics of chromatin. What inspired you to study that? What are you excited about in your current research?

I have been interested in using theoretical physical principles to describe the behavior of polymers since my undergraduate research thesis, where I characterized statistical changes in DNA conformation under varying external forces. Chromatin is an especially powerful polymer that is directly relevant to our understanding of human health.

Our liver cells have the exact same genetic information as our cardiac cells. However, the chromatin structure is different between these cell types, which modulates the accessibility of DNA to transcription for cell-type-specific processes and thus directly influences cell fate. Cancer is a classic example of how a cell’s phenotype can be dysregulated, altering cell fate. There are distinct differences between the chromatin in the nuclei of normal cells versus cancer cells, which become more glaring for more malignant cancers.

However, chromatin structure and how it influences cellular function are inherently tortuous. Recent chromatin work does not always incorporate the complexity of the intranuclear environment on transcription processes. In dilute test tube conditions, molecular factors such as concentrations of transcriptional reactants influence the rate of transcription reactions.

However, the nucleus is a highly crowded and heterogeneous environment. Within these conditions, macromolecular crowders greatly influence the kinetics and efficiency of chemical reactions by occupying physical space in close proximity to the reaction taking place. Transcription reactions are essentially a network of chemical reactions with nuclear DNA as input and cytoplasmic RNA as output. In the nucleus, chromatin density is the major crowder and, thus, the statistical distribution of chromatin density should greatly influence transcription reactions.

I have recently been focused on characterizing principal statistical descriptors of chromatin structure which most influence large-scale transcription patterns and cellular adaptability. What excites me the most about my research is that, although a plethora of intricate biophysical processes influence the chromatin system and transcription to varying degrees, we are able to use physics-based models to deconvolve these complex relationships and distill the essential elements that are important for cellular function, including interactions such as macromolecular crowding.

Altogether, discerning important physical mechanisms which regulate cellular phenotype could allow us to modulate these processes for increased biomedical therapeutic efficacy as well as to identify critical processes that, when altered in the disease state, could contribute to faster disease progression.

What has been a highlight of your time at Northwestern?

One of my major highlights at Northwestern has been the inherent collaboration that has been built-in to my PhD. The researchers that I work with, both within my two research groups as well as other groups at Northwestern and beyond, are highly passionate about their work and have diverse research backgrounds and interests. Altogether, my extensive collaborations have been educational — providing me with a wealth of knowledge from each individuals’ expertise — as well as engaging and inspiring.

What has been the most challenging aspect of your work or your time at Northwestern?

COVID has been a challenging time for me. Although I have been fortunate to have made progress with my research, as my work is computational, I have really missed the supportive work environment that I experienced in-person during my first several years at Northwestern. Working from home and interacting with my colleagues solely over Zoom has been an entirely different research experience.

Can you tell me about your experiences either being mentored or mentoring others?

I have been fortunate to have received extensive, meaningful mentorship during my PhD from both of my advisors as well as from my labmates. I am co-advised by Prof. Vadim Backman, an expert in developing nanoimaging approaches to investigate chromatin and its relationship to cancer, and Prof. Igal Szleifer, an expert in molecular modeling of complex biological systems.

Both of my advisors have a “hands off” approach, which has allowed me to independently explore research directions that I am interested in. However, they are both always there to guide me when I am stuck. We have regular meetings, sometimes even daily depending on how my projects are going, where they provide valuable feedback and suggestions.

Additionally, they focus on developing my scientific thinking process, which goes hand-in-hand with the development of my independent research abilities. When I am planning computational experiments or analyses, I must always be able to thoroughly rationalize what I am doing: clearly identify my research question and relate it to current open questions in the field, what my approach is, and why I chose this approach, and what my hypotheses are based on prior literature and experience.

Both of my advisors have also provided me with ample opportunity to improve my scientific communication skills, whether this involves contributing to grant writing or presenting my research at a seminar or conference.

During my PhD, I have had experiences mentoring high school students, undergraduates, and graduate students. I have learned that explicitly telling my mentees exactly what to do and why is not an effective mentoring technique. I aim to embody a mentorship style that my advisors have with me, where I treat them like colleagues and train them to be able explain their scientific process to me in a clear, cogent manner. Rather than solely focusing on external achievements, I aim to help my mentees develop critical thinking and independent problem-solving skills.

What are your hobbies outside of the lab?

Outside of lab I love biking, hiking (and being outdoors in general), pilates, cooking, watching movies, and reading. Fortunately, I’ve been able to do all of these things during the pandemic, which has allowed me to read much more than before. My book preferences range from memoirs like “Heavy: An American Memoir” by Kiese Laymon to historical fiction such as the Neopolitan Novels by Elena Ferrante to nonfiction discussing science and society like “Medical Apartheid: The Dark History of Medical Experimentation on Black Americans from Colonial Times to the Present” by Harriet Washington.