Ask a Scientician

Janelle has posed a couple of questions, so I’ll deal with her initial one first:

What would you say is the most promising research going on in your field today, both with respect to technological advancements (which will eventually affect the general public) and with respect to broadening our general knowledge of science (which the general public probably doesn’t care about)?

This was a little difficult to answer at first because my field of expertise (if you can call me that) is in pharmacology and toxicology. I deal with the way drugs and toxicants interact with biological systems. From this field I reach into metabolism, physiology, neurology, and most other biologic sciences. It leaves me in a position where I know a little about a lot of fields and a lot about a few smaller fields.

To me the most exciting prospects are in the “-omics” areas: genomics, transcriptomics, and proteomics. Genomics is a term that most people know, dealing with the study of the genome. Projects to decode the human genome have been completed and many other animals and microbes are underway. This is not news though. The biggest difficulty in genomics is the vast amount of data. It only gets more complicated. Even when we reach the point where we can look at the entire genome of an individual it does not tell us the whole story: just because the “code” is built into the DNA does not mean that we know anything about the use of it. The central dogma of molecular biology is:

DNA –> RNA –> Protein

While there are exceptions to this rule, the central dogma leads us from genomics to transcriptomics looking at the expression of mRNA from the coding regions of DNA. Understanding the expression of mRNA adds a level of context to the DNA code. No longer is it simply potential, but the DNA has actually “produced” a product that is measurable. The production levels of mRNA are highly variable and depend upon the presence of outside drugs, the diet and health of the individual, the environment surrounding that individual, and the base code in the DNA.  What transcriptomics can tell us is the rate and extent of activation of a specific region of coding DNA. There is still a further complication.

Proteomics is the study of the proteins expressed in a cell, tissue, or organism. While the presence of mRNA can tell us the extent to which a region of DNA was transcribed it does not provide correlative data with protein expression. Said another way: DNA tells you what the cell is capable of, RNA tells you what’s being activated, but protein tells you what the call can actually do. Proteins are the major players in the cell. They catalyze reactions, provide structure, and can act as signaling molecules.

What does all this mean? I don’t want to go into more details about protein structure and function but I want to pull back from the details and try to hit the big picture. Drug development focuses on finding compounds that can affect biological systems. The drugs themselves are often either small molecules or protein derivatives. The better we understand the genomics, transcriptomics, and proteomics of humans the better the drugs can be.

Here’s a hypothetical situation or two:

Person A needs a drug for high blood pressure. Company X makes a small molecule antagonist (SMA) for receptor Q. The SMA will interact with Receptor Q and prevent it’s function, affecting production of the renin-angiotensin system and lowering blood pressure.

Situation 1: Person A has a mutant form of Receptor Q with an altered active site that responds appropriately to the endogenous (normal) compounds in the body but has only a 10% binding of the SMA compared to the wildtype receptor. In this case a genomic analysis would provide information about the mutation and alert the doctor. The solution would be to use a different SMA that was designed specifically for the mutant receptor. Why would we not simply increase the dose of the original SMA? You run the risk of providing a toxic dose, increase the chances of drug-drug interactions if the patient is on other medications, and it gets expensive.

Situation 2: Person A has a normal form of Receptor Q but is unresponsive to the SMA drug or any mutant-designed forms. Genomic analysis shows that the DNA sequence is normal, and mRNA analysis shows that production is at expected levels. However, there’s no protein reaching the cell surface (where many receptors are located). Proteomic analysis of the cell would reveal that a shuttling protein in the endoplasmic reticulum (for this example assume the shuttling protein is specific for this receptor, otherwise the person would be dead) is mutated and instead of sending Receptor Q to the cell surface, it sends it to the proteasome for degradation.  The solution here is less clear, but would likely mean trying a different approach to controlling hypertension through another mechanism.

The reason I brought all this up is because science is discovering more levels of complexity in the interactions of cellular machinery. A better understanding of all levels of this machinery will lead to better and safer medicine and improve the overall human condition.