Measuring Proteins with DNA. Twisting the Central Dogma for Better Understanding of Biology.

Information in biology, according to the central dogma, flows in a defined order: DNA, the master copy that contains all genes, is transcribed to RNA, which is then translated to proteins. It is proteins, the final product of this process, that execute most of the instructions encoded in the genes. Unlike DNA, which is relatively static through life, protein composition changes dynamically as the organism goes through various stages of development, responds to a variety of stimuli, and cycles through health and illness.

Much of biology is driven by interactions among three-dimensional objects. Through shape recognition, enzymes transform their substrates, cell-surface receptors transmit signals after binding to their ligands, ions travel through pores of precise dimensions, and genes are activated by transcription factors. To better understand biology, we need a large collection of shapes with which to measure other complementary shapes. In humans, there are 20,000 genes that encode proteins. If we want to fully understand dynamic changes in the body, measuring many proteins at the same time is crucial since proteins do not work in isolation but rather operate in networks. For this task, we have employed aptamers, affinity reagents made of single-stranded DNA.

The realization that a large collection of sequences of single-stranded nucleic acids can be thought of as a large collection of shapes, from which rare molecules capable of binding to other molecules with high affinity and specificity can be selected, arose independently in two labs. This notion, initially considered to be of questionable utility, proved to be both robust and applicable to a wide range of molecular targets. Over time, aptamers have been improved through chemistry to incorporate molecular features typically found in proteins, which further expanded the range of molecular targets for which a useful aptamer can be identified. Three decades on, aptamers have found many uses in research and medicine. They have also turned out to have several unique advantages for simultaneous measurement of many proteins, which has led to a better understanding of health and wellness, as well as progression to disease. The common denominator in this adventure has been the commitment to ask open-ended questions, to make and test all possible solutions, and to view biology as being more complex and surprising than we often appreciate.