Nobel Centennial Symposia
"Frontiers of Molecular Science"

December 4-7, 2001
Friiberghs Manor, Örsundsbro and Stockholm University

Prospects for Advances in Micro- and Nano-scale Chemical Analysis

by Richard N. Zare
Department of Chemistry Stanford University Stanford, CA 94305-5080, USA

The ability to separate the individual components of a mixture is a critical requirement in the chemical sciences. Often a substance must be available in pure form before an understanding of its structure and function can be obtained.

Dynamical processes can only be followed through knowledge of the concentrations of individual species as a function of time. As far back as medieval times and even into the 20th century the main separation methods available were:

filtration

precipitation

distillation

crystallization

This work led to many triumphs including the accurate determination of atomic weights through careful precipitation measurements by Richards for which work he received the Nobel Prize in Chemistry in 1914. The evolving complexity of the systems studied, especially in the biochemical sciences, led to the development of new analytical separation technologies:

mass spectrometry

centrifugation

electrophoresis

chromatography

In each case, a Nobel Prize in Chemistry recognized these achievements - being awarded in 1922 to Aston, in 1926 to Svedberg, in 1948 to Tiselius, and in 1952 jointly to Martin and Synge. As the 20th Century came to a close, we witnessed the cracking of the genetic code, the recording of the human genome, and the rise of combinatorial synthesis. All these efforts point to the need for automated, high-throughput analyses, involving complex samples present in tiny amounts. Chemical analysis can be the gating step in screening candidate molecules for various properties and in advancing our understanding of life processes. These factors drive miniaturization of analytical devices as seen in the ongoing development of capillary-format separations and laboratory-on-a-chip devices. This presentation addresses what necessary milestones must be achieved to carry out chemical analyses on small volumes containing complex mixtures of analytes.

Special attention is given to individual cells and cellular compartments. It is important to recognize cells as chemical factories. It is possible to use libraries of cells to express large numbers of different proteins. It is also of vital interest to be able to understand the workings of individual cells and how they communicate with other cells, nearby and distant. To appreciate the challenge, it is necessary to recognize that a typical cellular dimension of 1 micron in diameter implies a volume of 0.5 femtoliters, that is, 5 x 10^-16 liters. Moreover, chemical species in the cell typically range from millimolar to micromolar in concentration, which implies that the amount of species present range from 0.5 attomoles to 0.5 zeptomoles. These facts put a premium on the invention and development of new analytical tools having the ability to separate tiny volumes and to detect ultra trace amounts of species present in such mixtures. Progress to achieve these goals will be described in terms of electrophoretic and electrochromatographic separations combined with detection schemes using laser induced fluorescence or using mass spectrometry or both. The possibility will be presented that cells not only serve as passive analytes but also as active detectors/sensors. We conclude that cells are mesoscopic objects whose analytical challenge lies between single-molecule spectroscopy and microscale analyses. Moreover, new techniques will open single cells and its individual parts to investigations at exquisite levels of detail.