Each Easter at Bardstown Road Presbyterian Church the congregation finishes off the service with rousing, if somewhat chaotic, rendition of Handel's Hallelujah Chorus.  For historical reasons unbeknownst to me, the sheet music we are provided for this chorus is not only antiquated but also written in four-part harmony for professionals.  I've never seen so many notes on a single page.

 Undaunted, and wishing to participate because I am caught up in the moment, I decide on the bass voice since it seems to have fewer notes and words.  As we are a small church and we don't have strong singers in each voice category, those of us choosing more under-represented voices are left on our own with no one's coattails to cling to.  I start off reasonably well but things rapidly turn south when each category goes its own way and I am left to my own devises.  Fortunately, every now and again, we are all brought back in register, "e.g., the kingdom of this world" and for the time being anyway, I am back on track.

 I'm not entirely sure why, but my muddling through the Hallelujah chorus was the analogy that sprang to mind when I began considering a Journal Club having to do with human development.  When sperm joins with egg, the process of human development begins; a process infinitely more complex than the Hallelujah chorus, but one that is played out at different levels simultaneously, with a myriad of individual notes, all of which have to come together in sync to produce a new human being.

 So let's consider human development starting at the beginning, with the fertilized egg.  The instructions for what will become a human being are embodied within the 3.5 billion bases pairs of DNA packaged on 46 chromosomes, half coming from mom and half coming from dad.  The fertilized egg, a single cell, will ultimately give rise to the 50 or so trillion cells of the human body.  Some of these cells become the rods and cones of the eye and give us vision, whereas others become precursors to red blood cells; the latter we all know, being charged with transporting oxygen through the blood.  And these are just a small sampling of the potential fates of the trillions of cells arising from the original fertilized egg.

 So what differentiates one cell's fate from another during human development?  Does each cell type receive a different set of instructions?  The answer to this, at least from my perspective, is yes and no.  The written instructions laid down in the sequence of bases for in those 3.5 billion bases of DNA, with certain rare exceptions, are the same in all cells of the body regardless of whether they are a cell of the eye or the bone marrow.  What differs from one cell to another are how these instructions are interpreted.

 Major players tasked with interpreting the instructions laid down in the sequence of DNA are a tremendously important family of proteins referred to as transcription factors.  Transcription is the process by which DNA is converted into RNA.  RNA, in turn, is used to program ribosomes for the synthesis of proteins.  It is the constellation of proteins synthesized within a cell that by in large give it its defining characteristics.  So cells differentiate into a particular cell type by turning on genes to make one set of proteins while turning off genes coding for other sets of proteins. The decisions as to which set of genes to turn on and those to turn off are controlled in large part by transcription factors expressed in different cell types.  As to what determines which transcription factors are expressed in a particular cell type, well, other transcription factors, a point I will return to later.

 This discussion brings us to a very interesting review recently published in Blood by John Crispino and Mitch Weiss1, two physician scientists that attended this year's DBA ICC Meeting.  The title of their review was "Erythro/Megakaryocytic Transcription Factors Associated with Hereditary Anemia."  This review, as the name implies, summarizes transcription factors that to date have been linked to hereditary anemia and suggests that additional transcription factors necessary for erythropoiesis may be encoded by some of the still unidentified genes responsible for congenital anemia, including DBA.

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