Oligonucleotides: The Next Big Challenge for Analytical Science

It is now over forty years since I started my career in analytical chemistry and during that time I have been privileged to witness many significant advances in the science and technology that underpin this important branch of chemistry. Most of these advances have arisen as a result of challenges from trace level analyte determinations, complex matrices, subtle structural idiosyncrasies and the omnipotent demand to make everything run faster and more reliably. One of the most challenging analyses I have encountered personally was almost 20 years ago whilst developing chromatographic and electrophoretic methods for the separation and quantitative measurement of unnatural synthetic oligonucleotides, as part of developing antisense drugs.

Resolution of diastereomeric phosphoramidate bridged unnatural oligonucleotides by micellar electrokinetic chromatography. Journal of Chromatography A Volume 636, Issue 1, 23 April 1993, Pages 113-123 Micellar electrokinetic chromatography was used to resolve diastereomers of oligonucleotides possessing several chiral phosphoramidate bridges. These materials were not resolved by conventional liquid chromatographic techniques.

Technological advancements employing novel nano switching and flow management means have been applied to solve capillary switching in instrumentation to decode the human genome; arguably the biggest challenge ever to analytical chemistry! A multiplexed freeze/thaw switching principle and a distribution network were utilized to manage flow and sample transportation.