Aptamers and the RNA World, Past and Present

Abstract

SUMMARYAptamers and the SELEX process were discovered over two decades ago. These discoveries have spawned a productive academic and commercial industry. The collective results provide insights into biology, past and present, through an in vitro evolutionary exploration of the nature of nucleic acids and their potential roles in ancient life. Aptamers have helped usher in an RNA renaissance. Here we explore some of the evolution of the aptamer field and the insights it has provided for conceptualizing an RNAworld, from its nascence to our current endeavor employing aptamers in human proteomics to discover biomarkers of health and disease.

The Persistent Contributions of RNA to Eukaryotic Gen(om)e Architecture and Cellular Function

“…After a long lag phase on the sidelines, functional RNA currently is in the spotlight of biology, even medicine, as RNomics shows promise to detect additional disease genes, greatly develop the diagnostic toolbox, and revolutionize therapeutic possibilities (Esteller 2011;Cech 2012;Erdmann and Barciszewski 2012;Gold et al 2012). However, the development from only two decades ago when the mere mention of RNA generally exposed grant proposals to monkey hammering resulting in poorer scores and the current situation in which a feeding frenzy of RNA discovery fueled by ultradeep RNA-sequencing technologies endorses almost any detected transcript or degradation product as functional RNA borders on the grotesque.…”

“…In any event, by applying in vitro synthesis and selection procedures (Ellington and Szostak 1990;Tuerk and Gold 1990;Gold et al 2012), several laboratories are making great strides toward generating RNA molecules with the ability to self-replicate (Doudna and Szostak 1989;Johnston et al 2001;Zaher and Unrau 2007;Lincoln and Joyce 2009;Shechner et al 2009;Wochner et al 2011;Attwater et al 2013;Mast et al 2013), although these RNA polymerase ribozymes still fail to completely self-replicate (Deamer 2005). Cooperation of two or more RNA enzymes in hypercycles (Eigen and Schuster 1977) may be a solution to this problem (Vaidya et al 2012) (see also below).…”

High-content affinity-based proteomics: unlocking protein biomarker discovery

“…Other versions could include printed aptamers. Solution binding obviates issues of avidity and rebinding, which are certain to enhance non-specific binding of aptamers to proteins that contain patches of positive amino acids (the 'growth factor problem' mentioned in [74]). …”

“…Approximately 10 years ago, the entire literature for aptamers may have included the identification of (classic) aptamers for 100 proteins. A goal was set at SomaLogic (CO, USA): aptamers (good enough to measure proteins in complex matrices) would be generated against a large number of human proteins, and an assay platform would be developed that would allow ELISA-like performance without sandwiches [12,66,74]. The goal at SomaLogic, while correct with regards to the problem of deep multiplexing, was difficult to reach.…”

“…We have determined the structure of a SOMAmer with its protein target at approximately 2.5 Å resolution [Janjic et al,Unpublished Data;74] and more structures are in progress. As expected, the contact between the protein and SOMAmer is extensive and contains elements never seen before in either classic aptamer-protein structures [80,81] or structures between natural RNAs and their binding partners [82].…”