Demet Sag, Ph.D, CRA, GCP
We learn how to count when we start to speak one, two three…. Counting to balance check book. Counting on people vs. counting people. Counting from fly to human and life. It is a process we rely on counting things and counting on people. Both of them are necessary.
It is a common practice to count number of blood cells, hematocrit, and assume physiological responses for simple screening of a disease.
Counting X:A ratio is not just for flies what that means is that variations in human diseases also doing share similar signaling processing and create variations. Counting GC%, comparing populations and developing biomarkers are all in the name of finding the cure.
Counting helps to program the cell to respond and produce proteins that is needed. Counting polymorphisms, variations, mutations and alleles are important to measure disposition of the disease. Make educational guess based on statistical analysis and bioinformatics.
The living systems regardless of their shape or size have their own counter / scale that includes gene control mechanism that may contain RNA binding proteins, DNA binding proteins, dimers, protein complexes or sensors to measure concentrations of molecules, hormones, elements, gases.
There can be one key gene but many others contribute for its function that is called transregulators either turn it on or turn it off that depends on the cues received from surrounding cells. Thus, extending this simple rule we can explain why predisposition of human diseases controlled or occurred differently in each person even though we all do carry the same blue print we do have variations on different locations of the genome. There are projects going around the world to count variations, analyze population genetics, determine pre-natal vs. natal outcomes. Thus, we have tons of data to analyze and to make sense.
As a result, these variations reflects on types of diagnostics tools and therapies. Therefore, each individual may respond to the treatment differently. However, it is also possible inherited characteristics may shifted, lost or acquired due to environmental factors, infectious diseases, stress, trauma, surgery and many more.
There is a counting mechanism in genome. This mechanism is actually “shared”. When counting mechanism is mentioned people who took biology 101 immediately may say Drosophila melanogaster (fruit fly) determines its sex determination based on counting numbers of X:Y. Yet, the signaling process in the embryonic stem cell or sex determination is a common mechanism that we observe in cell differentiation and system biology.
The idea of using “a universal standard ruler” for measuring these shifts with three dimensional presentation DNA (x), RNA (y) and protein (z) responds to mainly time (age), gender, origin/race/country can be possible. Data sharing and medical records are necessary but with respect to privacy and safety of people.
RNA binding proteins are important part of genome and central to many biological processes.
For example,neurodegenerative diseases are already complex to study but there are many efforts. The Japanese study provided a study on CNS cell differentiation and counting mechanism. Their intention was to understand the basic mechanisms of the generation of cellular diversity in the CNS, upon which therapeutic treatments for CNS injuries, degenerative diseases, and brain tumors. In rat animal studies they showed that generated rat monoclonal antibodies (Mab 14H1 and 14B8) that recognized an RNA-binding protein Musashi1. The amino acid sequences at the epitope sites of these anti-Musashi1 Mabs were remarkably conserved among the human, mouse, and Xenopus proteins. Since cells committed to the oligodendroglial lineage were Musashi(-), it is advantageous to identify each cell and count cells in situ.
There are many examples of counting and role of RNA binding proteins through alternative splicing in immune response mechanisms, muscle cell differentiation, measuring an enzyme activity or analyzing evolution of plant development. This decides type of cell proliferation, creates number of receptors, proteins and actions.
During development alternative splicing occurs. This also requires counting and balancing the act. RNA binding proteins has a big role in this. There are other factors of course. Thus, establishment of early differentiation under the inherited blue print displayed through counting. On the other hand, there can be a switch for a specific cellular response possibly for an immune response to fight against a disease or infection or against self due to acquired modifications on genome.
RNA binding proteins help to create diversity through gene expression control from transcription to post-translation that we count on throughout the life cycle at various developmental stages. Furthermore we should keep close attention to the viruses especially to RNA viruses and their metabolisms. Microorganisms, fungi, yeast, bacteria and viruses, do interact with their host to create living. Some of the diseases basically start from failure to defend host towards pathogen that leads into a disease such as a cancerous tumor, an autoimmune disease, a neurodegenerative disorder or a metabolic malfunction.
Furthermore, one can wonder about circulating RNAs with various shapes and sizes and their impact on gene expression control. Their role is making customized responses but still they can be counted as well.
There are 79 clinical trials on RNA binding proteins. One o these studies were on whole genome sequence analysis for schizophrenia. Furthermore determining the type of RNA-protein with high throughput sequencing is available, but determining the precise interaction sites would help to identify underlying function in the genome and biological processes.
Kramer et al, (Nature Methods, 2014, doi:10.1038/nmeth.3092) provided an open-source software pipeline developed for this purpose, RNPxl, is available as part of the OpenMS (project.http://www.nature.com/nmeth/journal/vaop/ncurrent/carousel/nmeth.3092-F3.jpg)
How do we use the data to modulate cellular responses, count variations properly with genomic sequencing and make a clear understanding of physiological outcome for human health are the questions that we are after. As we all know that RNA-protein complexes show crucial importance in many central biological processes. Therefore, we can modulate cells by synthesizing these data towards personalized medicine. Chemical and physical properties of these structures may identify these cells to target for selective elimination. Next Gene Sequencing based on two main molecular technologies hybridization and polymerase chain reaction. It is possible to make a sandwich of DNA, RNA and protein concurrently.
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