Larry Gold has a solution for the problems faced by users of antibody arrays — stop using antibodies. Gold, founder and chief executive of SomaLogic in Boulder, Colorado, is outspoken in his belief that aptamers — small nucleic-acid molecules with specialized functional properties — should replace antibodies in capture arrays.

Years ago, Gold and his team tried to calculate how much multiplexing could be done with an antibody array before background noise became a significant issue. “We guessed that sandwiched antibody arrays were going to start running into serious noise problems when there were 20 analytes per array,” Gold says. He thinks that aptamers could provide a level of specificity that surpasses what most antibodies achieve.

More than 15 years ago, Gold was one of the inventors of a now widely used procedure called SELEX — systematic evolution of ligands by exponential enrichment. In this system, multiple rounds of selection and amplification can be used to select for DNA or RNA molecules with high specificity for a target of choice.

Gold and his colleagues have since enhanced the procedure, and SomaLogic uses a high-throughput version of SELEX to generate 'photoaptamers', which can be covalently crosslinked to bound targets following irradiation. As a result, aptamers with high affinity and specific crosslinking can be used to measure proteins in complex samples without needing the extra specificity provided by secondary antibodies.

Another advantage of the aptamer platform is simplicity of detection — once protein targets are bound, they can be labelled with a generic protein-binding fluorescent dye, eliminating the need for analyte-specific sandwich detection reagents.

Larry Gold believes his aptamer arrays will succeed in applications where antibody arrays fall short.

Early platform tests have been promising — SomaLogic is achieving success rates of about 80%, Gold says, and he believes a product launch is imminent. “With the right partner, we could launch a product for the research market within some months,” he says, “but we think diagnostics is key, and we're even more interested in transforming evidence-based healthcare.”

Some antibody experts are impressed by aptamers, but doubt whether they will unseat the current king. “What Larry Gold and others have shown is that when it works, it works very, very well,” says Mathias Uhlén of the Royal Institute of Technology in Stockholm, Sweden, “although I would be surprised if aptamers are the dominant scaffold in the future, due to limitations in the chemical space.”

But SomaLogic is banking on the use of novel nucleotides to increase this chemical space, and believes that a full proteome complement of aptamers is unnecessary — so that high specificity against a few thousand well-chosen targets could be more than sufficient. “We think that, for diagnostics, there's so much redundancy in biology that you'll be able to do useful biomarker discovery with an incomplete proteome that's still quite large,” says Gold.

Michael Eisentein