The two theoretical underpinnings of chemical genetics are: first, that pure biologically active substances can be obtained; and second, that such substances act by binding to specific molecular targets within an organism. The origin of these pivotal ideas can be traced back to the eighteenth century, when many researchers began to suggest that plant extracts that affect animals each contain a single active ingredient that acts on a discrete part of the animal14
. Subsequently, Frederick Serturner succeeded in isolating the first active compound (morphine) () from a medicinal plant (opium)15
. The first conceptual pillar of chemical genetics was therefore solidified — that biological activity resides within pure substances.
Small molecules have a large range of structural complexity
The second premise of chemical genetics — that low-molecular-weight compounds act by binding to specific protein receptors — took another hundred years to develop. In the early nineteenth century, François Magendie and Claude Bernard proposed that small molecules act within a specific body structure, and Rudolf Buchheim formulated the idea that drug action could be explained on the basis of a physicochemical reaction between cell constituents and a particular drug16
. However, the crucial breakthrough came at the beginning of the twentieth century, when Paul Ehrlich developed both the term for, and the concept of, a ‘receptor’ — the single, specific protein target of a small molecule17,18
. (Note that a small-molecule receptor may or may not function as a cell-surface receptor in the traditional biological sense.) Today, Ehrlich’s breakthrough has been extended with the vision that we will eventually identify a small-molecule partner for every protein10
Finally, the usefulness of SMALL ORGANIC MOLECULEs for studying biological systems was discovered at the same time that the theoretical bases of chemical genetics were developed. Before the nineteenth century, uncharacterized, naturally occurring plant extracts were used to perturb biological systems. Then Paul Ehrlich showed, somewhat surprisingly, that small organic molecules derived from an industrial waste product, coal tar, could selectively interact with cells and tissues19
. Ehrlich discovered that methylene blue () could stain nerve cells selectively, and he promoted the idea that low-molecular-weight organic compounds could be of value for studying their receptors in biological systems14,18
. Furthermore, in 1884, Hans Christian Gram found that a particular dye, crystal violet (), could selectively stain certain types of microorganism in a process now referred to as ‘the Gram stain’20
. Several useful small molecules, such as aspirin () and saccharin (), were also discovered by studying coal-tar extracts, showing that even very simple organic molecules could have a range of interesting and useful biological effects21,22
. Before long it was accepted that simple organic molecules could profoundly affect cellular and organismal systems, paving the way for a comprehensive chemical-genetic approach to understanding biological systems.
So, by the early twentieth century it was substantiated, first, that pure substances have biological activity, and second, that these substances interact with specific proteins within an organism. Furthermore, small molecules were discovered to be generally useful tools for probing biological systems because of their ability to interact selectively with different cells, tissues and organisms. Nonetheless, the development of these principles into chemical genetics, a general method for determining protein function, took almost another century. It is only now that we are beginning to witness the full power and extent of these simple ideas.