In the recent past, we have heard a lot of research in the field of molecular mechanisms of diseases. Let us look at what it means to study molecular mechanisms of a disease.
It is essentially the process of creating models of human diseases in order to study them in-vivo. Additionally, the molecular mechanisms of several cellular processes including replication, metabolism, migration etc. have been firmly studied for the last 60 years.
Advancements in studying the molecular mechanisms of diseases
Several instances has resulted in significant progress in understanding the diseases at a clinical scale due to molecular studies.
A brief description of each of those examples is as follows:
Photocarcinogenesis
2002: Investigating the molecular mechanisms of Photocarcinogenesis.
The advances in Molecular and Cell Biology back then clarified the mechanisms of carcinogenesis. This included formation of DNA photo- products, DNA repair, mutation of Protooncogenes and Tumour Suppressor Gene in addition to UV induced Immunosuppression. This was crucial for the development of effective prevention and interventions for skin cancer. Studying the molecular mechanisms of skin cancer helped us understand the precise effect of UV radiation on the skin and DNA repair mechanism. Also, the in-depth knowledge of several genes and pathways involved showed immense potential in identifying crucial aspects of skin cancer.
Indeed, this work represents a breakthrough in cancer research.
Autoimmune diseases
2002: Molecular mechanisms involved in autoimmune diseases using mice as a model.
Researchers wanted to identify the molecular mechanisms of autoimmune diseases associated with defects in peripheral T cells . They did so by generating mouse models with different genetic manipulations. Later, they studied the signalling pathways involved in the autoimmunity. This was a breakthrough in getting a better understanding of autoimmune diseases. Also, emphasis is given on the importance of extrapolating the experimental results to pre-clinical and clinical stage.
Amino acid substitutions
2009: Molecular mechanisms of amino acid substitutions relevant to several diseases.
Single nucleotide substitutions in a protein coding region are very crucial. They could potentially give rise to amino acid substitutions and largely affect protein structure. The structure of a protein could mean the difference between a healthy and a diseased state. Over the last few decades, the development of computational methods has helped us identify these single nucleotide mutations. However, they were not accurate in determining the molecular mechanisms of the disease. The team led by Bioa Li, developed a new computational technique called MutPred. This accurately predicts a mutation in a given protein at a molecular and structural level. Knowledge on computational techniques like Sorting Intolerant From Tolerant (SIFT) and PolyPhen is necessary. This breakthrough has significantly impacted the prediction of crucial disease causing mutations.
Mis-sense mutations
2013: Molecular mechanisms of mis-sense mutations involved in certain diseases
Mis-sense mutations is when a single base pair change can substitute a different amino acid resulting in the translation of a completely different protein. This is very crucial in many cases as it could give rise to several diseases. They could result in complications ranging from mild to severe, depending on its effect on the protein stability, structure and function. Identifying mis-sense mutations could potentially tell us the origin of the disease. The work emphasised that the molecular mechanisms of effects of these mis- sense mutations would help us study more about specific genetic diseases.
Breast cancer
2015: A team led by Atefeh Tehrian- Fard outlined the characteristics of biologically and clinically relevant subtypes of breast cancer. Breast cancer was initially thought of as a a single disease. However, after effective studies on its gene expression and genomic profiling in 2015, the identification of a collection of diseases led to a range of outcomes and thereby treatments. This was primarily due to the study of the pathways and subtypes at a molecular level. This study correlated the molecular and clinical outcomes. It thereby tells the importance of studying the molecular mechanisms of a disease in order to come up with effective diagnostic and treatment methods at a clinical scale.
Genomic Profiling
The Precision Medicine department at the University College of London (UCL) specialises in giving personalised treatments to patients through genomic profiling. Genomic profiling is the basis for precision medicine. It is useful to understand the relationship between a person’s genetic makeup, cell type and its epigenetics. Understanding this has led to personalised treatments for each patient based on their genetic profile. This is a significant milestone in the field of Molecular and Cell Biology. In general, Genetic screening can help identify the different genes involved in a disease. The detailed analysis of those genes can give insights into the metabolic pathways and the pathophysiology of the disease.
Why study a disease at a molecular level?
Better understanding of the disease
Understanding the molecular mechanisms of diseases is one of the key goals of modern medical research. Studies on molecular mechanisms can help in the development of new therapeutic strategies for metabolic, infectious and other diseases including cancer. Studying the mechanisms of the disease at a molecular or genetic level can also help us understand more about the disease and thereby provide insights into its diagnosis, treatment and prognosis. Molecular mechanisms of certain mutations can help understand the origin of certain diseases. Understanding the mechanism or pathways of a disease at a molecular level can help identify the pathological conditions. This can thereby influence the susceptibility to the disease and can thereby influence its treatment. Without effective understanding of the molecular mechanisms of a disease, the treatments are purely based on the disease symptoms, which makes it ineffective in most cases.
Work at UCL
A deeper understanding of the molecular mechanisms can help us link the clinical data, MRI findings and the actual process of the disease. This could also be relevant in a related group of diseases. For instance, in a research work at the University College of London (UCL) in 2015, the investigated genes involved in Neurodegeneration with Brain Iron Accumulation (NBIA), a numerological condition. The obtained results could also apply to other groups of related diseases, such as Frontotemporal dementia (FTD), Parkinson’s disease (PD), and Alzheimer’s disease. In their review, they discussed the potential cellular pathways that link the entire spectrum of the disease .
Potentially offer new drug targets
Molecular mechanism of a disease also includes information about the metabolic pathways, signalling pathways, growth factors, and many other proteins and enzymes that may be be a part of the pathogenesis of the disease. Finding more about the pathophysiology of the disease could help offer new drug targets. One such instance where the entire paradigm of a disease has changed due to information on its molecular mechanism is Pulmonary Arterial Hypertension. It was initially thought that vasoconstriction and thrombosis was dominating the disease. However, studies on the molecular mechanisms of this disease gave an in-depth understanding of the structural changes and the role of different types of cells involved in the vasoconstriction. Studies on Molecular mechanisms can largely influence clinical outcomes. This is because they enable a deeper understanding of the mechanisms of disease. They can therefore allow better decision making at the clinic.
My contributions to studying molecular mechanisms of diseases
Investigating the molecular mechanisms of a disease can help us gain insights into the fundamental processes of a range of diseases. This includes diseases of the nervous system, digestive system and respiratory systems in addition to cancer. Molecular genetics can help us find therapeutic targets that can increase the efficiency of the treatments by several fold.
As a researcher, I had an opportunity to investigate the molecular mechanisms of oral squamous cell carcinoma (OSCC) in 2017. In my research findings, I came across 2 specific epigenetically silenced micro RNA’s (miRNA) involved in OSCC. Previous studies have shown that several miRNA’s have been de- regulated and have contributed to the complex tumorigenic process. I investigated the promoter hyper-methylation patterns of the above miRNA’s using Bisulphite Sequencing. The above research findings have implications at a clinical scale. sIt could potentially be used as a diagnostic tool and a therapeutic marker.
The first genetic disease to be identified by studying it at a molecular level
It is sickle cell anaemia. It was first published by James Herrick, a physician in 1910 describing a 20 year old student who was severely anaemic. The irregular shape of blood cells, especially a large number of elongated sickle shaped RBC’s in the patient’s blood intrigued him. It was Linus Pauling who later identified that sickle cell anaemia was a molecular disease (1940) and that it was caused by a single nucleotide mutation of valine replacing glutamic acid.
Diseases for which molecular mechanisms remain unknown
Despite commendable advancements in the field of molecular mechanisms of diseases, there are many conditions whose exact mechanism has not been known at a molecular level. Studying the molecular mechanisms of such diseases can help in efficient diagnosis, treatment and prognosis of the same and could end up saving lives. Among the diseases are those which are considered irreversible by the WHO and they are- certain age related Macular Degeneration (AMD), diabetic retinopathy, glaucoma and other related eye diseases as irreversible. Furthermore, Irreversible diseases like neurodegenerative diseases like Alzheimer’s, Parkinson’s and Huntington diseases are on the rise. Although previous research has attributed its reason to oxidative stress caused by Reactive Oxygen Species (ROS), the exact molecular mechanism of the disease remains unknown.
Among the diseases with unknown molecular function, my specific interests lie on the molecular mechanism of sudden cardiac death (SCD) / cardiac arrest. This is due to a personal affliction. Another blog post is coming up shortly where I discuss the current understanding of molecular mechanisms of cardiac arrest.