After 10 years of trial and error, Brown University researchers have discovered a method to dramatically improve mass spectrometry technology, a development that could have far-reaching effects in numerous areas of health care.
Mass spectrometry is a tool that allows scientists to analyze and identify the components of a sample by finding the mass of tiny charged particles called ions inside the material – knowledge that can be used for a range of medical applications, from identifying cancer biomarkers to developing pharmaceuticals. The problem with current mass spectrometry methods: about 99% of the sample being measured is lost even before it can be analyzed.
“We’re hemorrhaging information,” said Derek Stein, a professor of physics at Brown.
Researchers typically use a technique called electrospray ionization to convert molecules into ions for analysis. This involves passing molecules through a tiny needle in front of a mass spectrometer. Using an electric field, charged droplets are formed and evaporate, leaving behind ions. Some of those ions make it into the mass spectrometer and can be measured. Most ions are lost in the process. But the Brown research team’s new method preserves more than 90% of a sample, Stein says.
That means more accurate and efficient analysis.
The team developed what’s called a nanopore ion source to transfer samples directly into a vacuum from a water solution. At the core of the technique is a tube called a quartz nanopipette with a microscopic opening of about 30 nanometers, or 100 atoms – about 1,000 times smaller than the width of a human hair. That’s about 600 times smaller than the needle used in electrospray ionization.
The nanotube delivers ions dissolved in water directly into the mass spectrometer, losing few particles in the open air. The team’s work also has practical applications in health care.
“The grand mission for all this, beyond just improving sample loss and mass spectrometry, is understanding proteins and the proteome,” said Nicholas Drachman, a physics Ph.D. student at Brown who led the work.
One of the biggest applications of mass spectrometry is proteomics, which is the study of proteins and how they interact within cells. Proteomics helps scientists find new biomarkers for cancers, COVID-19, cardiovascular disease, renal diseases and diabetes.
Mass spectrometry is also used in toxicology, pharmacology and drug development because of its high precision and sensitivity to changes.
But the team had to overcome several roadblocks.
Because mass spectrometry is performed on such a small scale, scientists can’t see exactly what is happening in the lab. So they had to use the limited information they could get and their knowledge to decipher whether their method worked. Or if it didn’t, what should be done next.
“This was something uncharted. So there were lots of possible approaches and it was not at all clear which one – if any – would work,” Drachman said. “I was very drawn to it as sort of a way to use basic physics to understand some really important problems in biology.”
The team began by creating its own mass spectrometer that held the ion source inside a vacuum – instead of conventional methods where the ion source is separate. Then they created a tiny opening, which is key to the ion source’s success, by heating a glass tube and pulling it apart.
Because they were working with such small scales, the researchers went through many rounds of trial and error before they reached a breakthrough.
“There’s just a lot of things that you have to get right to even understand what you’re working with before you can even start to improve upon it,” Drachman said.
It wasn’t until three years ago that the researchers realized that they were able to weigh individual amino acids. This was a crucial revelation because scientists use amino acids’ weights to determine the weight of a protein, Stein says. Also, the researchers found that their method conserved more than 90% of the sample – a dramatic improvement from conventional mass spectrometry where all but a tiny fraction of samples were lost.
“That’s when we knew when we were on to something big,” Stein said.
The work was peer-reviewed and published in Nature Communications this year.
Now the researchers have patent applications pending for their ion source. But it’s only been used by the researchers, and they hope to commercialize the technology so it can be used with mass spectrometry equipment already used by scientists, Drachman says.
“The most important thing is figuring out how to integrate our ion source with some existing mass spectrometers and seeing if we can integrate it into more widely used workflows,” Drachman said.
Stein says that once the team has developed a more accessible version of the ion source, they will use feedback from other scientists to improve the design.
“This will be valuable to anyone using mass spectrometry,” Stein said.
