The question "what is man?" is very general, and generally speaking, very hard to define. Conflicting answers to this question among people are likely to emerge, as answers given to any question are often experience dependent and manifest themselves within the context of a given individuals system of values.Defining the nature of human beings as it pertains to existence on both a metaphysical and epistemological level is challenging. From an ontological angle, subjectivity is an inexorably contaminent of perception that makes the clear elucidation of the essence of human existence impossible thus far. Epistimologically, characterizing man is challenging because the paucity of our knowledge concerning human nature creates an obstacle for scientists and philosophers who have consecrated a life in approaching this question in novel ways.
One such example of a scientist interested in the cognitive attributes unique to man at such a high degree of complexity, is research scientist Fred Gage at La Jolla's Salk institute. Gage has been working on trying to pinpoint the molecular events that cause individuals to have a large spectrum of neural diversity based on the difference in protein expression profile's across neuronal cell subtypes. Understanding the differences in protein expression and they ways that these differences arise, Gage believes, will offer insight into the relationship between the generation of neuronal diversity and complex cognitive functions like conscioussness and synaptic plasticity. In Gage's work, to be published in Nature, he and his team of scientists have found reasons to believe that mobile genetic elements coupled with different mechanisms that post-transcriptionally control how genes are regulated are responsible for the rich variety of neuronal cell types found in the human brain that is unlike any other organism. The mobile elements that Gage holds responsible for this diversity are LINE (L1) Retrotranspositions or long interspersed nuclear elements.
LINE retrotransposons are mobile pieces of DNA that generate random and reversible insertions through a copy and paste mechanism. The L1 gene has an internal promoter in its 5' UTR to drive expression of its two gene products from its two open reading frames. ORF 1 encodes and RNA chaperone protein and ORF 2 encodes the dual action endonuclease/reverse transcriptase enzyme. By making a nick in DNA via the endonuclease the L1 element is able to make an insertional copy of itself via the RT enzyme anywhere in the genome with the consensus sequence 5'TTTA3'. These L1 insertions are non bias, thus, they can be used to generate a large number of mutations within any single cell population. The mutations caused by L1 mediated insertions and how they might lead to brain specific phenotypes affecting cognition seems to be only speculative rather than conclusive at the moment. However, L1 retrotransposition mediated mutagenesis combined with several different systems of gene regulation can offer insight into how neurons are so diverse even within a single subpopulation of differentiated cells. One example of a post-transcriptional gene regulation system that might be working in conjunction with L1 elements to produce the incredibly high level of complexity seen in human brain cells are small non-coding regulatory RNAs called (of course) microRNAs. MicroRNAs reveal ways in which post-transcriptional gene expression can be modified and controlled in an epigenetic fashion or without changing any underlying DNA sequence. A possible example that conveys how mobile genetic elements, neuronal diversity and microRNA regulation are related is the gene SOX-2. According to Gage, L1 retrotransposable elements are silenced in neural stem cells due to SOX-2 mediated transcriptional repression. Downregulation of SOX-2 can lead to epigenetic changes that trigger neuronal differentiation. Besides Gage's observation about SOX-2, scientists in the Pasquinelli lab have found SOX-2 to be a direct target or suppressor of micro RNA let-7 in C. elegans. According to scientific literature, let-7 expression is strongly downregulated during neural differentiation of EC cells. If SOX-2 is really a direct target of let-7 then this might mean there is a regulatory feedback loop at work governing the timed expression of let-7 and differing modifications responsible for nueronal diversity such that differentiation and genetic diversification is coupled. For example, if let-7 negatively regulates SOX-2 and SOX-2 silences L1 retrotransposistion via transcriptional repression then there might be communication between mobile genetic elements and let-7 mediated by SOX-2. This hypothetical mechanism would reveal the sort of control at work when a neuron differentiates with regaurd to when genetic modifications are occuring during development of the cell.
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