Chemical biology-what was old is new again

After reading this article¹ last week, I decided to finally write a post about a subject I'm actually quite familiar with and even wrote a review article² for. Johnson K et al.¹ found a novel chemical they are calling kartogenin that can simulate cartilage repair in mice via native stem cells, and protect it from further damage by dialing down cartilage-degrading enzymes. This compound may have a huge impact on arthritis patients because this drug doesn't simply reduce pain or slow cartilage erosion; it can promote repair without a complicated regiment of hormones and growth factors, which can have unintended side effects and be very expensive. Their report is a powerful example for the practical uses of chemical biology in regenerative medicine and proof that a single molecule can initial complex biological outcomes.

The term "chemical biology" has been introduced to describe the use of chemicals as tools for manipulating and studying biological systems. It may be considered an offshoot of pharmacology, but they differ significantly in one key aspect—chemical biology seeks chemicals that have a specific phenotype in a whole organism (chemical > phenotype > molecular target), rather than chemicals that bind a single, specific molecular target (i.e. receptors) that correlates with a specific disease/phenotype (chemical > molecular target > phenotype). You may think of it as a twist on the traditional forward genetics practiced by Thomas Morgan with the aid of his fruit flies. Today's chemical biologists are using their favorite disease/cell phenotype/organism models to screen for chemicals that yield the desired response.

The evolution of this system-wide approach to drug development is due to the recognition that biology is complicated (Insert smart aleck comment here). The more recent drug development approaches that relied on intimate knowledge of specific molecular targets have been unfruitful—hitting single drug targets cannot treat even the most minor ailments. Even the most effective drugs found during the early heydays of pharmaceuticals (e.g. Aspirin), were later confirmed to be relatively non-specific and possessed a myriad of biological targets. So, what was once old is new again and now terms like "system-wide" and "organism-based" pharmacological developments are passed off as innovative development pipelines. But the same problem that bedeviled Morgan and his disciples is the same one that slows organism-based drug development, which is target identification. It's very hard to identify which specific targets a new chemical may hit. I'm actually quite impressed that Johnson K et al. were able to find them and present a fairly complete story. Most papers I read in this field only describe the phenotypes in detail and guess at possible targets, or don't say anything about targets at all. I think this paper also makes clear that a few chemicals (if we can find them) may do just what we need.

Photo source: http://www.chem.sunysb.edu/chembio/

References:

1. Johnson K et al. A Stem Cell-Based Approach to Cartilage Repair. Science 5 April 2012. DOI: 10.1126/science.1215157
2. Ao A et al. Regenerative Chemical Biology: Current Challenges and Future Potential. Chem Biol 18, 413-424 (2011).