Modern ionisation methods make it possible to make large molecules, such as proteins or DNA, "fly". In order to measure the largest ever singly-charged ion a molecular weight of more than a million Dalton (MDa) - a new world record - ETH Professor Renato Zenobi and his team of researchers at the Laboratory of Organic Chemistry (1) had to overcome two hurdles. First, samples had to be desorbed and ionised in a nondestructive way. Then the big ions had to be recorded and measured. Their work was published two weeks ago in the online edition of "Analytical Chemistry" (2).

In order to record the biggest mass-to-charge ratio (m/z) ever registered, the team made use of a so-called time-of-flight mass spectrometre. For this, charged molecules are accelerated and the drift time through a vacuum tube is measured. "An analogy of the method is an athletic race," explains Zenobi. In a race the lightest and spryest athlete usually reaches the finishing line first. "It is the same with ions. So we measure their weight by recording their arrival time," he says.

Mass spectrum of two big proteins: Immunoglobulin M (above, 1MDa), and the "von Willebrand" factor (Signals at 0.5, 1, 1.5 and 2 MDa, below). (All pictures: Analytical Chemistry) large

Illustration of the adjustable ion source. The accelerated ions, which leave the source in the direction of the dotted line, have to be focused on to the surface of the cryo-detector by a precise tipping of the entire source twice around its axis (measurements: only 1mm x 1mm). large

Detection at cryogenic temperatures

A challenge in time-of-flight mass spectrometry is the difficulty of recording especially heavy ions. They fly slowest and traditional detectors barely register when they impinge, if at all. One way to solve the problem would be to create multiply charged ions in order to bring them into an m/z range that is more accessible.

The ETH scientists chose a more elegant and more direct way: they used a so-called cryo-detector for their measurements. This detector system to observe single ions is combined with cryo cooling stage and greatly improves the sensitivity of the measuring. The cryo-detector (3) was developed by the Swiss company Comet AG (4) in collaboration with Dr. Damian Twerenbold then at the University of Neuchâtel. "The Laboratory of Organic Chemistry at ETH Zurich is a test lab for the machine," explains Zenobi.

Diagnosis in seconds

The innovative use of this technology could be extended to medical diagnostics in future, according to Zenobi. For example, it would enable the measurement of one of the proteins important in blood coagulation, known as the "von Willebrand factor" and its oligomers. Professor Zenobi explains: "Wounds of people with small protein-oligomers heal badly." Diagnosing this condition, which is related to haemophilia, was quite time-consuming until now. "If our method can be introduced for a routine analysis a diagnosis could be delivered within seconds," predicts the scientist.