Overview

The famous "central dogma" of life has information flowing through macromolecules, from DNA to RNA to proteins. But life would not exist with macromolecules alone. For the central dogma to be fully descriptive, it should include small molecules, which are key to a range of topics at the heart of the life sciences, including the origins of life, memory and cognition, sensing and signaling, understanding cell circuitry, and treating disease. Chemical biology provides this missing small-molecule piece of the central dogma (click on the "Introduction to the Chemical Biology Program" animation above for more information).

What are small molecules? We best know what they are not - Nature's DNA, RNA and protein macromolecules residing within their cellular contexts. Cells make small molecules - naturally occurring small molecules - but chemical biologists in the laboratory using, for example, DNA template-mediated, and target- and diversity-oriented organic synthesis, peptide and carbohydrate synthesis, and enzyme-mediated synthesis, also make them. Chemical biologists make both small and large "small molecules". They make them in tubes and cells, on glass surfaces, in monolayers, and even on phage viruses, and they use them to illuminate the principles that underlie life.

Connections exist between the three families of macromolecules and small molecules in both directions (see Image). Small molecules have been synthesized that bind and modulate DNA, and DNA has been used as a template to synthesize small molecules. Small-molecule riboswitches regulate RNA function, and certain small-molecule antibiotics bind and inhibit RNA macromolecules. Small molecules are synthesized in cells by protein-based catalytic machines, and both natural and non-natural small molecules have served as powerful probes in biology and as drugs in medicine.

Grand Challenges for Chemical Biology. This emerging field has several audacious goals, including ones relevant to the Chemical Biology Program at the Broad Institute:

1. Complete the inventory of all naturally occurring small molecules.
2. Identify a small-molecule modulator for each individual function of all macromolecules.
3. Create an effective bridge between basic and clinical research through the use of small molecules.

It's difficult to predict when the field might achieve these lofty goals, but it's clear that achieving them will have a transforming effect on science and society.