PhD students who complete their studies are encouraged to share their experiences with us.
Name: Chaitanya Erady
Research group: Brain mapping Unit
Supervisor: Prof Ed Bullmore and Dr Mary-Ellen Lynall
Title of your PhD: Transcriptomic and proteomic dysregulation in neuropsychiatric disorders
Can you give us a short background into what your PhD was about?
The role of the human genome in neuropsychiatric disorders is not fully understood. This thesis conducted a comprehensive meta-analysis on three major neuropsychiatric disorders: schizophrenia, bipolar disorder, and major depressive disorder, comparing gene, transcript, and protein levels between individuals with these disorders and non-neuropsychiatric controls. Additionally, the study explored novel genomic regions known as “novel open reading frames” (nORFs) that have recently been found to code for small proteins. By providing a broader clinical perspective on the genetic architecture of neuropsychiatric disorders, including nORFs, this thesis aims to contribute to the development of improved diagnostic and therapeutic approaches for these debilitating conditions in the future.
How would you sum up your main findings?
The key findings of this thesis are as follows:
• Multiple dysregulations at the transcriptomic and proteomic levels affecting various biological processes were observed in neuropsychiatric disorders. This suggests that disorders such as major depressive disorder (MDD) should be considered complex, whole-body problems rather than being attributable to a single causative gene or biological pathway.
• The observed dysregulations varied across different patient subgroups, individuals, and biological sexes. To a degree, this helps explain the lack of consistency in the existing literature on the aetiology of neuropsychiatric disorders and highlights the importance of considering these factors when interpreting expression data from different patient cohorts.
• A novel catabolic process consistently exhibited decreased activity in MDD samples compared to non-neuropsychiatric controls across five independent datasets. This finding suggests the potential involvement of this process in the pathophysiology of MDD.
• The role of novel open reading frames (nORFs) and their associated transcripts and proteins was investigated in neuropsychiatric disorders. A novel transcriptomic and proteogenomic methodology was developed to systematically study the functions of nORFs in the human genome. This exploration provided new insights into how these genomic regions may contribute to the pathophysiology of neuropsychiatric disorders, presenting promising avenues for further research.
Overall, these findings advance our understanding of the genetic architecture of neuropsychiatric disorders, emphasising the importance of comprehensive analyses of transcriptomic and proteomic dysregulations. The discovery of the consistently decreased catabolic process and the exploration of novel genomic elements offer potential directions for future diagnostic and therapeutic strategies aimed at addressing these debilitating conditions.
What made you want to do a PhD?
During my undergraduate studies, I had uncertainties about pursuing a PhD. While I had a strong interest in biology, my true interest lay in understanding the human brain and its disorders. However, opportunities to explore neuropsychiatry were limited during my undergraduate years, so I focused on delving into other sub-disciplines of biology. It was during my Master’s thesis in computational biology that I learned about transcriptomics and proteomics. The fast-paced nature of computational research resonated with me more than traditional wet-lab work, and I was keen on learning more about this field. I decided to pursue a PhD when I found a project that matched my interests, combining the study of neuropsychiatric disorders with multiomic analyses.
What was your best day during your PhD?
Pinpointing a single best day is challenging. During a PhD, you go through waves of emotions, experiencing both highs and lows. The days that stood out were the ones where I felt a sense of belonging with my research group. The unwavering support from my labmates and supervisors played a crucial role in my personal and academic growth. Another memorable highlight was the thrill of discovering a research paper directly relevant to my work and the subsequent excitement of applying those newfound concepts. Engaging in discussions with fellow academics and learning from their perspectives was also a valuable and enjoyable experience. Also, I really enjoyed the writing phase of my thesis. Seeing all the work I had put in over the past few years come together into a coherent thesis was truly enjoyable.
What was your worst day during your PhD?
There were definitely moments during my PhD that were very challenging. In the beginning, I felt overwhelmed by the uncertainty of how my research would progress and the daunting task of creating a clear and feasible research outline. To cope with this, I found it helpful to approach the vast literature systematically to identify knowledge gaps within the field.
Staying motivated proved to be a challenge at times, especially when I encountered roadblocks in my project. Unexpected obstacles like delays in accessing data consortiums or experiencing network issues with my lab computer while working from home added to the difficulties. On some days, multiple setbacks occurred, but I learned the importance of taking things one task and one day at a time to maintain a positive mindset.
The pandemic presented its own set of challenges. Although I was fortunate to continue working from home, the absence of face-to-face communication with my labmates was tough. However, we made it a priority to connect through virtual platforms like Zoom, which helped bridge the gap and provided much-needed support during these challenging times.
Do you have any words of advice to future PhD/MPhil students in Psychiatry?
Embarking on a PhD journey can be overwhelming at first. I found it helpful to establish a clear research outline and further break it down into smaller, manageable tasks. As my research questions evolved, I consistently updated this outline and my work plan. It is also natural to feel disheartened when your research progress or the results of your research deviate from your expectations. However, I have learned to embrace these moments as valuable opportunities for growth and use these setbacks to re-evaluate my research methods or refine my research questions. It is also crucial to separate your personal worth from the outcomes of your research. Instead of internalising these setbacks, learning from these experiences, and persisting is key.
Maintaining self-motivation throughout the PhD process can be tough. Reflecting on the initial enthusiasm that drove you towards carrying out a PhD can sometimes provide the necessary drive. However, you may also encounter tasks that feel boring or tiresome but are important for answering your research questions. In these cases, rewarding yourself when you finish those tasks can sometimes help sustain motivation.
Having a support system is crucial. Interacting with fellow students, even if their research differs from yours, can provide comfort in the knowledge that you are not alone in your struggles. I also recommend taking advantage of relevant university courses to broaden your skill set. Lastly, don’t forget to take breaks and enjoy the whole process!
What do you hope to do next?
I am keen on exploring the practical applications of my scientific background. Presently, I work as a policy analyst at the Public Health Genomics Foundation, where I assess emerging scientific methodologies (predominantly related to genomics) and their potential utility within healthcare settings.