First thoughts on the molecular basis of disease
An Immunologists Approach
A stipulation of any aspiring research immunologist is perhaps a somewhat unnatural and overly effervescent fascination for therapeutic target discovery. The most common drug targets. comprising nearly 33% of all drug binding partners are G protein-coupled receptors (GPCRs) 1, a family of proteins that mediate signal transduction upon molecular binding events at the outside of the cellular membrane. Biological systems are perhaps the most complex systems humans have ever attempted to understand. Therefore, when designing a drug target there is a question that every sensible researcher must ask themself. Where is the best place to modulate a biological system in a manner that is both safe and efficacious for the treatment of disease?
GPCRs are such common targets because they are relatively straight forward. Returning to my previous discussion of the top-down versus bottom-up duality championed by biology and biochemistry respectively, the same analogy can be assigned to therapeutic drug targeting. The targeting of surface-exposed proteins can be thought of as a top-down approach as they are the cell’s first exposure to a chemical signal, whereas a bottom-up approach considers the molecular signals that occur at down-stream enzymatic mediators.
In BCM:441 Advanced Biochemistry, we have been encouraged to think of the nature of the disease from a chemist’s perspective. While some might consider this approach to be rather reductionist, in the past it has proven to be extremely useful in dissecting complex biologic systems to uncover their basic mechanism(s) of action.
To satisfy my obligations to this course, I have been tasked with exploring the biology of a disease of one’s choosing, with the precept that whatever ailment explored must be done so at the mechanistic level. Sticking to my roots in immunology, I have identified three pathologies of interest.
Diseases of Interest
1. Systemic Lupus Erythematosis: SLE is a multifactorial autoimmune disease in which the immune system activates in misdirection against self-tissues. The disease can present with what is commonly referred to as the “butterfly rash”, however, this phenomenon is actually quite rare and only occurs in a small number of cases.2 While the root cause of lupus is unknown, the onset of the disease has been associated with a rare loss of function mutation in the FcgammaR2B inhibitory receptor3, exposure to Epstein-Barr virus4 and dysregulation of type 1 interferon producing pathways.
Photo obtained from https://www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789
2. Mycobacterium tuberculosis infection: According to the CDC, up to 13 million people living in the United States are living with latent TB infections.5 My curiosity for TB lies in the fact that these individuals carry TB and yet seem to suffer no ill effects from the infection.
I am interested in the genetic factors that control the maintenance of TB in the lungs and the mechanism through which the infection is kept at bay. Previous studies have identified iNOS (inducible nitric oxide synthase) as a key mediator in the control of tubercle formation.6
3. Coronavirus: The recent outbreak of Wuhan virus has sparked interest in a family of +ssRNA viruses known as coronavirus. The coronavirus’ genome is translationally active, in that once it enters the cell it is immediately ready to replicate due to its genome being comprised of mRNA. Since the virus neither requires integration into the host genome, reverse-translation into DNA, or transcription into mRNA, there are far and few mechanisms through which the virus can be inhibited once it becomes intracellular, therefore, I am particularly interested in the mechanism through which the coronavirus enters and infects the cell.7
1. Santos R, Ursu O, Gaulton A, Bento AP, Donadi RS, Bologa CG, Karlsson A, Al-Lazikani B, Hersey A, Oprea TI, et al. A comprehensive map of molecular drug targets. Nature Reviews. Drug Discovery. 2017;16(1):19–34. doi:10.1038/nrd.2016.230
2. Mayo Clinic staff. Lupus. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789
3. Smith KGC, Clatworthy MR. FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nature Reviews Immunology. 2010;10(5):328–343. doi:10.1038/nri2762
4. Draborg AH, Duus K, Houen G. Epstein-Barr Virus in Systemic Autoimmune Diseases. Clinical and Developmental Immunology. 2013;2013:1–9. doi:10.1155/2013/535738
5. CDC. TB. CDC. https://www.cdc.gov/tb/statistics/default.htm
6. Dutta NK, Karakousis PC. Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms. Microbiology and Molecular Biology Reviews. 2014;78(3):343–371. doi:10.1128/MMBR.00010-14
7. de Wilde AH, Snijder EJ, Kikkert M, van Hemert MJ. Host Factors in Coronavirus Replication. In: Tripp RA, Tompkins SM, editors. Roles of Host Gene and Non-coding RNA Expression in Virus Infection. Vol. 419. Cham: Springer International Publishing; 2017 [accessed 2020 Jan 30]. p. 1–42. http://link.springer.com/10.1007/82_2017_25. doi:10.1007/82_2017_25