By John G. Szeto, Matthew D. Godin, and Angela B. Schmider
The following opinions and perspectives are our own and do not reflect the views of any institution.
Amino acids are the building blocks of proteins, and proteins are responsible for nearly all reactions that keep our bodies alive. There are 20 amino acids commonly found in proteins that, when ordered in sequences, manage to combine in an almost infinite number of ways. From these sequences, we get four basic levels of protein folding; from primary to quaternary, characteristic alpha helices to beta sheets, these polymers form unique and dynamic structures (see, e.g., the figure) that have various functions. The way proteins organize creates enzymes, structural units, ligands and receptors (keys and locks). These types of proteins are common targets of medicinal drugs. But because of subtleties in protein structure and interactions, there are medicine limitations, such as side effects, that originate from limitations in knowledge, including basic mechanism and biology.
In the March 30 blog post “Making Dollars, But Does It Make Sense?” the authors write that we need reform in the drug approval process for cost efficiency. This is problematic in pharma, but we’d like to go further and state that changes are needed in the basic scientific process of research and development. Currently high-throughput screening is prevalent, which is a way of forcibly finding “keys”, aka ligands, to drug targets of interest. There’s also a growth of “me-too” drugs. Searching for patentable new molecular entities this way doesn’t constitute a way that allows intuition to escape from a local maxima, a mathematical concept that’s similar to plucking “low hanging fruit”, of patient treatment. Such techniques can yield results but may not result in innovative progress. We define innovation in this space as working toward understanding the science of the disease. This takes time, expertise, and resources to reach new peaks of innovation.
An example of a local maxima that is not the global maxima are the various drug therapies for diabetes. A recent WebMD article refers to a study that found that patients treated with three diabetes drugs had significantly lower blood sugar levels, yet when adding a glitazone drug along with the standard treatment metformin, there’s a higher risk for kidney failure than with metformin alone. In addition, patients were less likely to have diabetes-related blindness compared to metformin treated patients. These findings, though (un)pleasantly surprising, proves that we need to better understand the targeted effects of drugs as a mono or combination therapy on proteins (e.g., insulin receptor) in a system as complex as the human body.
We need the proper tools to better understand the science of the disease, in order to overcome the stymied nature of advancements in medicine. Small changes in the blueprints behind protein creation can cause significant functional changes. Utilizing advanced scientific techniques that increase resolution to better understand proteins and their interactions is important. For instance, single molecule imaging and diagnostics is an exciting nascent field. We think in addition to drug approval reform, we need research and development reform that propels basic science, characterizing the mechanism, which cost efficiently benefits the patient without sacrificing understanding/innovation.