Future directions for electrospray ionization for biological analysis using mass spectrometry.

When John Fenn and coworkers first realized Malcolm Dole's dream of electrospray ionization (ESI) (1), the broad impact it would ultimately have was not obvious to most researchers working in the (admittedly much smaller) field at the time (2). Indeed, between his first publication in 1984 and ground breaking report in 1988 that described ESI-mass spectrometry (ESI-MS) as a tool for analyzing large proteins (3), my laboratory was one of the very few (and perhaps the only?) working with ESI-MS (4). After Fenn's 1988 seminal publication, the MS community broadly recognized the potential of ESI-MS for providing the long sought effective interface between liquid chromatography (LC) separations and MS that would allow a large range of previously intractable biomolecules to be studied. Over the last 20+ years, the range and types of ESI-MS applications has expanded in a breathtaking fashion to include essentially every class of biomolecules and, for example, the characterization of extremely large noncovalently associated protein complexes. As a result of its sensitivity, now broad availability, and applicability, ESI-MS has become a dominant analytical tool for areas of biological research such as proteomics, which is the study of the array of proteins in an organism, tissue, or cell at a given time. Its ability to broadly measure biological macromolecules, especially proteins, can play an important role in delineating complex cellular networks and pathways, as well as in a range of other applications, such as candidate biomarker discovery efforts. In this context it is fair to ask, what's next? Will ESI be displaced by some other method of ionization or LC-MS interfacing? Are there important new developments still to come? Of course, the possibility of completely new approaches— " disruptive " new technologies that revolutionize how we work—should never be excluded. By their nature, one cannot predict such developments , but we can more reasonably speculate on, and more reliably predict, the impact of more evolutionary developments that arise from the naturally selective process of ongoing focused efforts. I believe that such forces, involving ESI driven by the need for more sensitive and better quantitative measurements, are now at play in ways that will greatly expand its utility for biological applications. The need for greater sensitivity to better detect, identify, and quantify biomolecules in proteomics is essentially open-ended; every improvement enables new applications. For example, the ability to make comprehensive proteomic measurements generally depends on the sample size, as …