Scholarship / Battling against cancer - Research interest for a PhD application [2]

research interest for a PhD application

Hi everyone,

I hope you don't mind reviewing my research interest for a PhD application in TU Dresden.
Here's the instruction.

============================
Please write an essay (max 3,500 characters) describing your research interests. Specifically, describe which research area you find most interesting and why. Explain your research objectives and how they relate to our program.

============================

Battling against cancer has been embodied as my interest, stemming from my experience working in a national cancer centre. Specifically, I have been fascinated in two aspects: the genomic consequences of DNA repair damage and the integration of multi-omics to elucidate the potentially targeted aberrations.

Firstly, I have been fascinated by DNA repair damage especially in terms of how it leads to the accumulation of mutation and structural rearrangements. Through my dissertation, I discovered that even before precancer lesions (histologically normal lung epithelium) occur, mutational burden differed among the neighbouring basal cells whose low mutational burden showing overexpression of DNA repair pathways. This suggests that high risk of mutagenesis may link to DNA repair damage. What intrigued me more is that whether it can be measured and extrapolated to the application of drug-patient matching of currently available targeted drugs. In my opinion, it will be revolutionary to find and refine the cancer subtype based on omics properties: genomics, transcriptomics, and epigenomics.

Secondly, I am interested in the comprehensively and holistically molecular view of cancer, provided by omics (epigenomic, genomic, transcriptomic, and proteomic) as the system biology. The relationship between these omics layers and how to bridge the gap between genotype and phenotype were then becoming my curiosity which translated into a multi-omic project during my master's degree. I was perplexed by the result revealing the functional heterogeneity linking to mutational heterogeneity of lungs' basal cells related to the smoking effect, which became the first to interrogate lung basal cells at a wider resolution.

What intrigued me after my thesis project is applying omics analysis for pharmacological purpose. Recent studies only addressed pharmacogenomics, yet I am interested in expanding the investigation of pharmacogenomics and pharmacotranscriptomics to determine biomarkers predicting the drug response. This will prevent cancer patients from unwanted complications from mismatched treatment and enhance drug effectiveness for specific subpopulation, revolutionizing the current treatment selection.

What is more rewarding from further implementation is the use of machine learning prediction based on the omics key features to determine the prognosis and treatment outcome of the patients. In this case, the interplay between lifestyle, environment, and heritability might be of interests to define high-risk individuals of acquiring mutations. Assessing and elucidating the biological information combined with clinical data are essentials for guiding therapeutic decisions as they provide a comprehensive view.

This PhD program offers computational biology as one of the multidisciplinary scientific fields which I am interested to join. Specifically, I found that Dr Anna Poetsch's projects align with my research curiosities. In line with her previous work entitled "Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis" and "AP-Seq: a method to measure apurinic sites and small base adducts genome-wide, it will be of the utmost importance to map the genomic aberrations and link them to the treatment selection. Additionally, what is equally exciting is to quantify the DNA damage pattern by other mechanisms (nucleotide excision repair, mismatch repair and double-strand breaks) and incorporate them into a single pipeline, similar to what Dr Poetsch developed in AP-Seq.

Letters / Physician-scientist - Letter of Motivation for Medical University of Graz, Austria [2]

Hi everyone,

I'm currently preparing my motivational letter for PhD program in Austria.
Any review and feedback will be much appreciated.

Thanks,
Ayu

=======================================================

Here's the instruction for the motivational letter.
Please provide an original statement why you are interested particularly in the three chosen projects (letter of motivation).

Letter of Motivation

My motivation for applying for this PhD program is to be a skilled and knowledgeable physician-scientist. These combinatory roles as a medical doctor have a synergy in clinical observation and laboratory experiment to solve problems in cancer. The thirst for knowledge and curiosity built from clinical experience encouraged me to seek a scientific explanation for better decision making. For me, a top doctor not only practices a well-established guideline but also thrives for an improvement through a consistent questioning of the status quo of medical care. This also means that a doctor should continuously and actively work through research to answer the question.

Building on two years of research experience and clinical work in Indonesia National Cancer Centre and studying MSc Precision Medicine at University College London (UCL) make me believe that being a doctor and a scientist at the same time would bring benefit not only for me but also for cancer patients around the world. Working under supervisor Dr Karl Kashofer in a research project entitled "cause and consequence of structural DNA damage in cancer" is a way of implementing precision medicine concept and research skills I have learned throughout my master study and contributing to elevate the quality of cancer treatment and to strengthen personalized and tailored decision makings for cancer patients.

My research skills were sharpened when I had an opportunity to work intensely on a multi-omic project as my dissertation. Over the course of 6 months, I strived to excel in the bioinformatic algorithm of RNA sequencing analysis and whole-genome sequencing of the lungs' basal cells and to perform statistical analysis for gene expression-mutational burden correlation. This preliminary project was later successfully announced to be the most impressive project in my program. My wet lab skills were also strengthened during a three-month period in my postgraduate study when I took a hands-on practice in both biomedical and hospital research centre. Needless to say, most of my time during the clinical work and the master study was spent on engaging in scientific writing, to train myself to be a world-class author. Throughout 2 years of my scientific career, I have secured six co-authorships, in both national and international peer-review journals.

My master study equipped me with comprehensive evaluation through genomic, transcriptomic, and epigenetic approach. One finding I discovered in my dissertation is that even before precancer lesion occurs, mutational burden existed and differed among neighbouring basal cells. Two aspects that fascinated me was the low mutational burden happens in the presence of overexpression DNA repair pathways and cells with high mutational burden showed activation of the immune system. What intrigued me after this study is the mechanism of histologically normal tissue expressing more immune-related genes. I speculate that mutational burden contributes to neoantigen expression, therefore allowing for immune response. It is critical considering that DNA damage, dysfunctional DNA repair, and mutational burden trigger and drive carcinogenesis. Pursuing this question may lead to the promotion of immune checkpoint inhibitor and DNA repair restoration. A study by Dr Kashofer entitled "Time series analysis of TP53 gene mutations in recurrent HPV-negative vulvar squamous cell carcinoma" interests me in a way that genetic instability is a dynamic phenomenon thus requiring multiple time investigations. Perhaps, the use of dynamic biomarker is also critical to determine the success of immune checkpoint inhibitor and to measure the extent of the damage of DNA repair. This is potentially implemented in Homologous Recombinant Deficiency (HRD) measurement using either surrogate markers (RAD51, ATM, MRE11 genes) instead of merely HRD score or BRCA positivity or the extent of genomic scars and mutational burden as time series. This is where I believe that the multi-omics analysis that I performed during my master study will be of great advantage to prove that mutational burden, HRD gene markers' expressions, and TCR expression profiling have a correlation. Furthermore, another potential implementation is to measure and calculate the genomic scars and mutational burden at the same time to precisely determine the dose of the immune checkpoint or PARP inhibitor and using this dual therapy for HRD+ cancer. One particularly intriguing for me is that whether the identification of tumour subsets from spatial profiling T cell receptor in tumour tissue among different tumour regions may determine to the extent an individual will benefit from immune therapy.

My second interest is airway remodelling in COPD. Identifying a subset of COPD comprehensively based on microenvironment (immune profiling), clinical data, and histopathology will enable a precise therapeutic approach, an extension of the precision medicine concept. What I found interesting in my dissertation is that inflammatory response and epithelial-mesenchymal transition marked the subset basal cells in the lungs. A susceptibility of some cells to undergo airway remodelling may bring evidence that certain phenotypes benefit from preventive measures, similar to gender as a potential predisposing factor for vascular hypertension in COPD. However, identification of other microenvironment elements, such as fibroblast and extracellular matrix, are important. Also, validation using immunoreactivity test, a co-culture between epithelial cells and immune cells to check cellular interaction, is an approach that worth trying.

Being a PhD student and working in a world-renowned institution such as Medical University Graz would be a dream come true. As one of the universities of excellence in Austria, Medical University Graz would be an encouraging research environment for me. It would provide me with an interdisciplinary and international research collaboration within the translational framework. Furthermore, the integration of laboratory-based research and clinical data analysis in the project would be a suitable platform to apply and upgrade my research skills, enabling one step toward my dream as a physician-scientist. Overall, I believe that my relevant expertise in clinical work and dissertation project combined with a strong motivation and determination would be valuable resources for this PhD program.