Almost all methods used to analyse cells and their metabolites rely on measurements that are averaged over a large population. But even genetically identical cells can vary greatly in molecular content, so techniques that can analyse single cells could provide crucial information on many cell- and disease-related processes. Now, Renato Zenobi and colleagues1 from the Swiss Federal Institute of Technology in Zurich have used a mass spectrometric method to measure the metabolites of single yeast cells.

The technique is so sensitive that it can detect species such as adenosine triphosphate at levels of only tens of attomoles (10−18 moles) — three orders of magnitude more sensitive than previous methods. This was achieved by first spotting picolitre amounts of a cell suspension onto a thin layer of an optimized matrix made of 9-aminoacridine. These spots were ionized by a laser and the resulting ions examined by MALDI–TOF mass spectrometry. The sequential deposition of matrix and analyte not only improves the sensitivity of the technique, but also enables the liquid to be handled with a piezoelectric dispensing system, creating a sample spot that is similar in size to the laser.

This confinement of the sample means that every laser shot gives detectable peaks, which in turn enables the metabolites to be detected in amounts of sample that contain a single cell or less. A further advantage of this technique is that the cell extract can be analysed directly, without any labelling or chromatographic separation. The system could be combined with a microfluidic cell to provide insights into metabolic variations between single cells.