Know your model.

In biomedical research, we are often trying to answer questions at different levels. By “level,” I mean from molecules, cells, tissue, organ, organ system, organism, community, and ecosystem. It is rare that biomedical research gets to the community and ecosystem level. There’s also a cost / benefit consideration to what “level” your particular research question is answering. Studying a problem at the level of the organism is much more expensive than studying a problem at the level of molecule — however one might argue that studying at the level of the organism is more biologically / clinically relevant.

The cell model used in my lab, SH-SY5Y cells. Left: Non-differentiated cells, neuroblastoma, continue division. Right: Differentiated cells, stopped dividing, extended axons & dendrites, secrete neurotransmitter.

At each level, you have the thing in your lab that you are actually manipulating and observing and this thing is used to represent something greater, hopefully a more general concept. That’s known as a “model.”

It really comes down to what question you want to answer … and then you have to justify the importance of that question relative to all the other possible questions that other scientists want to answer. Here are some examples.

Molecule Level — Studying an enzyme and how it functions; does it metabolize a drug? Does it perform a function that can be enhanced or diminished to improve health? Does it pump ions or chemicals in one direction to maintain homeostasis?  etc. These studies can range from very cheap (say — thin layer chromatography and test tubes) to very expensive (say — nuclear magnetic resonance). I think perhaps studying genetics (like DNA methylation) falls in this category too. A very small bit of my research has been in this category, say with co-precipitation experiments to demonstrate that two or more proteins form complexes. Here, the “model” seems most closely tied to the thing that you are studying — I’m interested in Protein 1 to Protein 2 interactions and that’s what I’m observing.

Cellular Level — Studying how a cell behaves or reacts to things; does it get infected? What damages it? How is its function diminished or enhanced? Much of my research is at the cellular level. For this, the model gets a little fuzzier. I’m interested in neuronal cell biology, so I have a clonal cell line that perform experiments on. They are much different than a neuron residing in a brain, but they get the job done as far as understanding cell biology of neurons; but not necessarily neuronal function inside an organism.

The reason I’m thinking of this is because I was discussing the cells with someone who was interested in adapting this model in their lab. They wanted to know “what is the purpose of the retinoic acid and BDNF steps? Why don’t you just use the cells for an experiment?” We go through a “differentiation step,” before performing experiments. That is — we add factors that stop the cells from dividing and get them to express more neuronal markers, a neurotransmitter, and the molecules that are associated with synapses. I feel this is a better model for studying neuronal biology. I have reviewed manuscripts that were published that lacked the differentiation step and I tend to ding them for it. One particularly bad example was a study used a method which they explained displayed cell toxicity & cell death. They used a technique that essentially gives a snapshot of how many living cells were present. This method couldn’t distinguish between their treatment/toxin causing cell death or just slowing cell division. That’s why it’s important to assess the validity of your model, as it pertains to your research question, before doing the experiment. These cells also look way cooler under a microscope after they’ve been differentiated too.

It is important to understand your model system and measurements used. In this example, if the cells are actively dividing, the experimenter’s methods cannot distinguish between slowed cell division or cell death.

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