Mitosis - Asking the Question of "Why?"

When things get complicated (read: when thesis papers just become one huge, overwhelmingly disastrous mess), I often find that it helps to return to the basics and find stable foundation in the givens we base our deliberations upon. Although this may almost always result in far more questions than answers, it definitely proves to be helpful throughout the revision process in terms of analyzing the information from different points of view. You know; end to beginning, beginning to end, with one eye closed, while pulling your hair, with a cup of tea - as they say, it's all about perspective... All joking aside though, it has definitely been telling to go back and read the narrative I had begun constructing at the beginning of the year and observe the ways in which my project and paper have evolved over the past 9 months.

One of the biggest things I think we, collectively as humans, often wonder about whenever something out of the ordinary happens is "why?" Whether that thing or event is easily explained or even if it's Alzheimer's Disease, the desire to understand what causes could have, and did in fact lead to such an effect is common across all areas of human life. The other day, I was looking through my introduction where I lay out some ground rules established in previous research on Alzheimer's Disease and the Nervous System in general. I started to think about how understanding the "why," much like getting lost in the detail-rich rabbit holes of research/questioning, requires of us to retrace our steps and think about the sequences of events that have led up to this moment and our current dilemma of thought.

Asking why Alzheimer's Disease afflicts people's brains is a mammoth-sized question, probably even larger than a mammoth, but maybe if we start from the beginning and take it step by step, we can get somewhere. So, here is the beginning - what part of the body does Alzheimer's Disease affect? The brain. Okay, well what is the brain made of? A combination of neurons (cells carrying out electrical and chemical conductivity to send messages) and neuroglia (cells that act as immune support for neurons). Now, we go back to the disease - how does Alzheimer's Disease affect neurons and neuroglia respectively... And that's one of our largest obstacles. Surely, I needn't remind you of the several journals I have spent reporting and questioning the never ending (and never definitively proven) theories of Alzheimer's pathogenesis. Every experiment, every scientist, and every type of cell has their own story when it comes to how things happened. Unfortunately, we're always going to have to concede that many events which occur out of the ordinary, whether they're in science or elsewhere in our lives - won't always have a clear "why." The fortunate thing about science though is that questions are more readily valued than answers. Perhaps, this is because the reality is often more complex than our imagined answers may let on. But nevertheless, trial and error is a thing. This doesn't mean that we get to the answer any quicker, or even that we get an answer at all, but essentially, I take it to mean that not all hope is lost. That's probably why in almost any research paper you'll read, there is a section called "delimiters" which is really just a set of parameters that the scientist purposely sets for their experiment - almost like a "this is what I'm testing, based upon these assumptions, and taking these factors into account." Considering the nature of controlled experiments, it's important to understand that every single experiment ever done could have taken on a multitude of different appearances that tested different variables or even different variations of the same variable. But I digress.

Let us return to our obstacle question from not too long ago - "how does Alzheimer's Disease affect neurons and neuroglia respectively." The first thing I always consider when thinking about this particular question is almost like a mental t-chart comparing the characteristics of neurons and neuroglia. Obviously, these are very different types of cells - one conducts electricity and one does not. And furthermore, maybe asking how Alzheimer's begins in the brain isn't the most advantageous route to take in this research - indirect questions and ponderings can certainly be just as valuable. If we can figure out how Alzheimer's affects each of these individual types of cells, trace those effects back to causal differences in cell structure and function, maybe pathogenesis will be clearer when viewed in the light of glial cell morphology. But anyway, let's stick to the basics - cell cycle. Neurons don't divide by mitosis because they last a lifetime. Once you lose a neuron, there won't be another growing in it's place. We have to be careful though not to confuse this longevity of individual neurons with rewiring between neurons that is possible in the brain - that's called neuroplasticity which is probably one of the most astounding processes I've ever learned about but we should probably save that for a different post so as not to confuse you, dear reader. Now, glial cells on the other hand are constantly dividing by mitosis. We're talking interphase, prophase, metaphase, anaphase, and telophase/cytokinesis, just like any other cell in the body. One of the key things to remember about mitosis though is also that you get identical copies of replicated DNA in the daughter cells produced.

This gives me pause. I pause here when I think about this characteristic of neuroglia because my next question immediately becomes, if glial cells divide by mitosis, how come they can't keep up with plaque buildup? Many of the cycles throughout our bodies operate on a need for function basis. So if there's a ton of plaque buildup in the brain, then theoretically, shouldn't that send a message to the glial cells - start dividing! We need more of you! - unless of course, Alzheimer's disease affects the differentiated nature of glial cells. If the genetic code telling these cells to clear away plaque and regulate substances is being manipulated in any way, could that paralyze glial cells' role as helper cells? I'm going to guess "probably" on that one.

This then brings up the consideration of our epigenome. According to a very official Genome.gov, the epigenome is defined as " a multitude of chemical compounds that can tell the genome what to do. ... When epigenomic compounds attach to DNA and modify its function, they are said to have "marked" the genome. These marks do not change the sequence of the DNA. Rather, they change the way cells use the DNA's instructions." Personally, I just like to think of it as an interpreter for our genetic code. Every single one of our cells possesses the same exact genetic information, the same exact chromosomal data, down to every single base nucleotide. But the epigenome then steps in to tell our cardiac cells how to act in the setting of our hearts, and that goes for every organ or type of tissue throughout our bodies. The interesting thing though about the epigenome is that it can be affected by one's external environment. Abrupt changes or adverse exposures will force our bodies to adapt. In some cases, negative stimuli can cause a gene that prevents cancer to be turned off. So all of a sudden the risk for tumor growth skyrockets. And this could be localized to a certain type of cell or eventually spread in tumor metastasis (although that's more of an internal result of a chain of epigenetic and cellular changes). The point is, when we think about what causes a disease such as Alzheimer's - something that usually shows up extremely late in life, we have to take into account these environmental changes. Our bodies go through quite a bit in a single lifetime and to say that the resulting circumstances are sole effects of genetics or predetermined biological conditions may just be an oversimplification.

As you can see, there's never a straightforward answer to really just about anything. We start out with a single question of "why" and in the following process end up producing quite a bit more queries about the things we are exploring. In this short time, we've worked through some questions. Although I don't think we've arrived at any real, concrete answers, the new questions aren't a poor reflection on our intellect or effectiveness. On the contrary, just like in a lab when we figure out how something doesn't work before understanding the way it does work, this process of questioning may actually help us to find the correct question that needs to be asked. No question is bad, but sometimes the questions we are asking may not be most effective to reach the goal we are trying to achieve or the information we need to discover.

In all honesty, I can't say that questioning is always comfortable. Starting from a place of confusion and using questions to find my way has it's frustrating moments and of course, it leads to further confusion no matter how far down the information Mary Poppins-like bag you get. I know this journal was probably more difficult to follow than others and I really do apologize but if I have at all reached the scientist within you (no matter how deep down you keep your science geek, we all have one), this is a journal article on the mitotic division of glial cells that I found rather intriguing. Questions are exhausting, revising papers is exhausting, but once this is all over I really do hope I can tell you that the value of this process far outweighs the cost.