Missing Nucleus in RBC

My latest love with evolution is an exciting and adrenaline-rich experience. We are trying to develop neutrophil based drug delivery at the inflammation sites. Neutrophils are white blood cells with dumbbell shaped nucleus and are the first ones to reach the site of inflammation to seek and destroy foreign bodies. It turns out that neutrophils are good at reaching for not only invading virus or bacteria but also cancer cells. The first striking property of neutrophils is their multi-lobled nucleus though continuous. What are the evolutionary benefits of such nucleus in constructing the first line of defense? Is it possible that chromosomes are separated from each other so that they can function independently without genetic interference? Can one set of genes switch on/off another set of genes? Or, are we evolving towards neutrophils without nucleus like red blood cells (RBCs) as both of them get differentiated from hematopoietic stem cells (HSCs)?

The missing nucleus of RBC has baffled the scientific community for ages. Several possible explanations are given, maximizing oxygen carrying capacity through disc shaped structure is the most notable explanation. We, now, know that HSC differentiates into two daughter RBCs, one with nucleus and the other without nucleus. The daughter cell with nucleus is phagocytized by macrophages leaving behind the RBC without nucleus. Mature RBCs cannot divide due to lack of nuclei and hence, no chance of cancer of RBCs. Hemoglobin is the oxygen carrying protein interacting with four porphyrin-Fe molecules present in the RBC membrane. If RBC doesn't have any genetic material, how does globin protein bind to the cell membrane of RBC? It is the HSC from which RBC differentiates, supplies the membrane bound protein. We have evolved with RBCs which circulate for about 120 days and then perish. HSCs generate RBCs continuously in the bone marrow. Removing nucleus from RBC kills the prospect of making mistake in genetic level and therefore, in the protein synthesis level extending mammalian life. You can counter-argue the survival of other vertebrates with nucleated RBCs! More questions need to be answered for complete understanding of this "weird" phenomenon.

References:

1. Ji, Peng; Jayapal, Senthil Raja; Lordish, Harvey, F. Enucleation of cultured mouse fetal erythroblasts requires Rac GTPases and mDia2. Nature Cell Biology, 2008, 10, 314-321

The Smart DNA

Ion channels are transmembrane proteins that play pivotal role in functioning of human biochemistry. From smell to touch, from stupidity to intelligence, from love to love making depend on firing of action potential in the neuron, the smallest unit of brain. It is very interesting to note that there is only a few ions responsible for initiation of action potential resulting myriad of biochemical functions. Only known ion channels are of Na+, Cl-, K+, Ca2+, Mg2+ ions. Most of these channels are ligand gated i.e. open or close only after binding of small organic molecules followed by transportation of these ions. For examples, we feel happy when serotonin ligand binds K+ ion channel and open it for K+ to rush out of the cell prompting depolarization of inner cell membrane (potential of the inner membrane changes from -60mV to +55mV). This process leads to cascade of protein synthesis switching on or off effector gene. The structural change of the neuron reflects in our everyday mood.

Dumb and Smart Gene

Repeated boost of serotonin is also responsible for converting short term memory into long term memory through extra axonal growth. The more we repeat, the more serotonin gets released to bind with ion channel, firing action potential frequently. A small molecule cAMP builds up inside the cell which in turn activates protein kinase A (PKA, all kinase enzymes phosphorylate another molecule). PKA phophorylates MAP kinase in order to act on a protein CREB-2 and deactivates it. CREB-2 is a regulatory protein which attaches on a gene to switch it off inhibiting protein synthesis for long term memory. On the contrary, PKA activates CREB-1, a regulatory protein binds with a gene to switch it on for protein production. This strengthens the neural connectivity consolidating memory. In a simplistic version, a dumb person is one who has high CREB-2/CREB-1 ratio.

The most interesting part is that one ligand is responsible for two completely different functions (mood change and memory formation) through two separate pathways. Is it possible that there is connection between these two pathways? I believe that we can learn better when we are in good mood (in both cases, serotonin is released). Evolution is minimalist! It uses one molecule available to optimize different functions.

Science Fiction 

The ions transport through protein channels on cell membrane are extremely abundant in nature. Na+ and Cl- are probably the most abundant ions found in ocean, evolutionary origin of us. Mg2+ and Ca2+ are also abundant in the rocks. Is there any ion channel for U238 in us? Probably not! U238 is a radioactive element which has disastrous health effect on human. I argue that a world full of U238 would have an evolutionary route to species with U238 channels and radioactive humans! Imagine a world of radioactive isotopic humans. Anything is possible in the universe of infinite worlds.

References:

1. Kandel, Eric. In Search of Memory, W. W, Norton & Company Inc, 2006
2. Jacob, Francois. Evolution and Tinkering, Science, 1977, 196 (4295), 1161-1166