Scientists at the California Institute of Technology (Caltech) have developed the first mass spectrometer using nanoelectromechanical systems (NEMS) to detect single individual molecular species in real time. This revolutionary prototype results from 10 years of research on NEMS sensors and nanoscale devices by Michael Roukes and his group. Michael Roukes is a professor of physics, applied physics and bioengineering, and the co-director of Caltech’s Kavli Nanoscience Institute.

The new technique integrates a NEMS sensor (used both as mass analyzer and detector) with an electro-spray ionization injection system. Unlike traditional mass spectrometry systems that measure the charge-to-mass ratio, the new nanoscale spectrometer measures shifts in frequencies that are directly proportional to the mass of the species that are analyzed. According to Akshay Naik, the first author of the study published in Nature Nanotechnology [Naik et al., Nature Nanotechnology (2009) 4, 445-450, DOI:10.10.38/nnano.2009.152], “when a protein lands on the resonator, it causes a decrease in the frequency at which the resonator vibrates, and the frequency shift is proportional to the mass of the protein”.

Naik and his colleagues tested their technology on bovine serum albumin protein (BSA, 66kDa) ions produced in vapor form, and sprayed onto the NEMS resonator at a rate of only one to two proteins per minute landing on the resonator. The decrease in vibration frequency observed by the authors was as much as 1.2 kHz, a small but detectable shift. Additionally, when testing their new system on β-amylase (200kDa), the researchers observed a frequency shift of approximately 3.6 kHz.

One of the current limitations of the prototype developed by the Caltech team is the inability to determine the mass of a protein with a single measurement. This is because the shift in frequency measured by the scientists can be affected by the position where the protein lands on the resonator. In their study with BSA, Naik and his colleagues needed to perform over 500 separate measurements in order to accurately determine the mass of the protein. However, the researchers are working on a new system that will enable them to decouple measurements of the mass and the position of the protein on the resonator. They are also working on additional injection and delivery systems that will eliminate the ionization process and make it possible to work with neutral species.

Ultimately, Roukes and his team hope to create a compact high-throughput biological mass spectrometry system in which densely-packed arrays of thousands of nanomechanical devices will work in parallel to determine the masses of hundreds of thousands of molecules, in real time. According to Roukes, “the ultimate system will be able to analyze all the contents of a mammalian cell in 20 minutes”. NEMS-based mass spectrometry could dramatically impact the fields of proteomics and systems biology, and open new windows of opportunities to elucidate the deterministic circuit diagrams of living systems.