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Little Green Ions, or Honey, I Shrunk the Mass Spectrometer

February 2007--Micro-organisms killed off the Martian invaders in H.G. Wells’ War of the Worlds. Physical chemist Bob Cotter hopes for a more pragmatic outcome when he and colleagues attempt to study Mars in a search for clues of simple life forms. Namely, they’d like chemical precursors to register on the portable mass spectrometer they’re readying for a joint NASA/ European Space Agency mission to the Red Planet in 2013.

Cotter, with Hopkins Pharmacology, and Will Brinkerhoff of the Applied Physics Lab have joined researchers at UC Santa Barbara to create a miniature instrument capable of picking up traces of amino acids,  peptides or DNA on Mars.

“We aren’t necessarily looking for signs of life now, but things that show either that there was life at one time, or some effort to start it,” says Cotter. “It’s not inconceivable that if there’s any organic material at all on Mars, some attempt would have occurred to form molecules according to the usual chemical rules.”

If this seems an unlikely project to garner a School of Medicine professor $750,000 in grant money (with a potential $26 million down the road as the project ramps up), Cotter provides a simple explanation of the path that led him to Mars.

 “I’m an instrument builder,” he says. “The reason I originally came to the School of Medicine is because they needed someone with technical expertise in mass spec instrumentation.”

The same principles would apply, he says, to using the devices for more earthly purposes, such as more accessible medical diagnostics or bio-agent detection.

Back in 1978, mass spec technology presented challenges to biologists. One was size. At the time, mass spectrometers took up whole rooms, and were operated exclusively by experts trained in their use.

The other problem was technical. Mass spectrometers measure the mass-to-charge ratio of ions; the resulting mass spectrum is then used to identify chemical components of samples. Positively charged ions are created by blasting samples with a laser.

“But you can’t ionize a protein using a laser,” Cotter says. “The molecule just breaks.”

 The solution is to immerse the protein in a matrix, an organic compound that will crystallize and absorb the wavelength of the laser. This process is called matrix-assisted laser desorption ionization (MALDI), and its discovery greatly enhanced the utility of mass spec for biomedical researchers.

“Now we have instruments that let us take a spectrum, send it to a database and have the database tell us what the protein is,” he says.

These new developments have made mass spec a common and increasingly critical tool in biomedical research, and kept mass spec experts like Cotter busy as collaborators.

 “Today, my lab is half instrumentation and half biological work,” says Cotter, director of the Middle Atlantic Mass Spectrometry Center, which began at the School of Medicine in 1980. “The biology covers everything—Alzheimer’s, cancer, cardiology, resistance to bacteria, anemia, HIV. They are collaborative studies, all of which come down to the ability to identify proteins involved in the biological processes going on in a particular disease.”

It’s his work on the instrumentation side, however, that led to the Mars collaboration. Cotter has long worked on “time-of-flight” instruments in which newly created ions race down a long tube, with the lighter ones arriving first and the heavier ones afterwards. Time-of-flight doesn’t require a magnetic field, so such instruments theoretically have an unlimited mass range and can test a greater variety of compounds—large proteins, for example. Working with collaborators , Cotter developed a number of different designs for portable time-of-flight instruments that could be used for bio-agent detection based on the proteins in bacteria or spores.

The experience gained in those projects helped when it came time to put together a proposal for an instrument for the Mars project—an ion trap mass spectrometer in which charged ions oscillate in mid-air, held in place by a radiofrequency electrode.

Though it’s not a time-of-flight instrument and won’t have the power to address large proteins, Cotter’s new toy will be able to break down molecules one jump smaller, like peptides. And, measuring just three inches long, it’s small enough to fit snugly inside a rover that’s sniffing out organics in core samples below the surface of Mars. 

Like other technologies developed for use in space, Cotter’s portable mass spectrometer could be adapted to improve medicine. Mass specs are one of the few instruments able to measure an intrinsic property, Cotter explains, permitting greater sensitivity in identifying proteins in concert with protein chips. One day, he believes, a portable mass spec device could be in every doctor’s office, ready to detect protein markers of disease.

--Deborah Rudacille

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