It’s a vision prompted by an emerging science called metabolomics, which is the study of the small molecules, or metabolites, found in cells, tissues and organs. And it’s a vision that could well rely on a tool that Hill – widely acknowledged as the foremost expert in the field of ion mobility spectrometry – may be uniquely qualified to provide.
As scientists have completed the draft sequencing of the human genome and embarked on the study of the human proteome, there has been growing recognition that yet another major effort is needed to understand the function of expressed genes – those whose coded information is converted into the structures operating within the cell. By developing a better understanding of how such genes and their encoded proteins interact within cells and organisms, scientists expect to gain powerful new insights into functional biology.
“The idea of looking at metabolites has been around for some time,” said Hill. “They were doing that back in the ‘70s — looking at metabolites and determining disease through metabolite analysis — looking at targeted bio-markers for stress or disease and looking at individual metabolites within the system. The idea of looking at the entire metabolome, however, is relatively new.”
But creating a profile of the human metabolome will require the systematic analysis of the full range of metabolic compounds in the human body. It’s a scientific challenge that will rely on the development of novel new methodologies for the detection, identification and characterization of numerous components in complex mixtures.
And it’s a challenge Hill and his fellow researchers are seeking to meet through the use of a highly sensitive and sophisticated new technology known as high-resolution ion mobility spectrometry.
“What we are trying to do is develop a way we can look at as many metabolites as possible at one time, so that we can see the interrelationships between them. Our technology has the potential for doing just that.”
In fact, Hill’s previous work in ion mobility spectrometry has already paved the way for the commercial development of a number of highly sophisticated molecular-detection instruments. They include devices for the rapid detection and identification of explosives that are now common in major airports, as well as similar instruments capable of detecting trace amounts of drugs in human hair, chemical warfare agents in the air, hydrocarbon pollutants in groundwater, and nitrites in agricultural runoff.
In developing the IMS technology for application in profiling the metabalome, Hill is leading a consortium of colleagues from WSU and elsewhere under a $2 million grant received last October from the National Institutes of Health. The grant was provided through one of a series of far-reaching NIH initiatives designed to transform the nation’s medical research capabilities and speed the development of scientific discoveries.
The group conducting the research effort includes James Bruce, director of WSU’s Core Proteomics Laboratory, Luying Xun, professor of molecular biosciences at WSU, J. Albert Schultz, president of a Houston-based IonWerks, a manufacturer of mass spectrometry instrumentation and equipment, and Prabha Dwivedi, a WSU doctoral candidate and lead graduate student researcher on the project.
Their effort to apply IMS technology to metabalomic research and diagnosis is made feasible by the research team’s earlier advances in developing a technology capable of analyzing small molecules in a liquid state.
“All of the IMS systems out in the world today use a vapor-phase technique, where you get the molecule into the gas phase first and then you ionize it and you analyze it,” said Hill. “What we have been developing here at WSU – and we’re the only people doing this for atmospheric pressure systems – is putting liquid samples into a gas phase using a technique called ‘electrospray.’”
He said the electrospray process pioneered for ion mobility spectrometry by WSU involves introducing a positive or negative charge to the solution, which then is drawn into a fine mist from which all of the water is evaporated, reducing the sample to individual ions in a gaseous state.
“What happens is we create a single pulse of ions moving through an electric field at atmospheric pressure – the smaller ones moving faster, the larger ones moving slower,” Hill said. “They arrive in milliseconds, sorted into a spectrum that is based on their mobility and mass.”
While other processes are capable of achieving similar results, Hill said one of the primary advantages of the technique developed by WSU researchers is the speed with which a complex molecular profile can be obtained.
The goal of their research is to develop a technology capable of detecting and analyzing a wide range of small molecules obtained from a complex mixture of metabolites within a cell or a biofluid.
“The ability to obtain an immediate and comprehensive metabolite analysis would allow a physician to identify specific patterns that are indicative of stress or wellness in medical diagnosis, and to rapidly monitor changes in a patient’s metabolome as they occur,” Hill said. “It would give researchers the ability to identify and further characterize metabolic pathways, and to relate the metabolome back to both the proteome and genome.”
In order for the instrument to provide the wealth of structural information needed for it to serve as an effective bioanalytical research tool, the team will need to demonstrate that the device is capable of achieving unparalleled levels of analytical sensitivity.
So, while Hill and his colleagues have already established the basic technology needed for such an instrument, they must now focus on improving its capabilities and developing the data needed to demonstrate the reliability of their technique.
“What we are attempting to establish through our research is that we have an instrument that can separate complex metabolite mixtures from a single sample and identify all of those compounds in a reproducible manner,” he said. “It’s a matter of demonstrating that we have a reliable instrument that consistently provides you with data you can believe in.”
Hill has been at WSU since 1976. He earned a doctoral degree in chemistry in 1975 from Dalhousie University of Halifax and is a founder of the International Ion Mobility Spectrometry Society. From 1985 to 1987, he served as the director of the WSU Office of Research and Development and in 1989 he received the Keene P. Dimick Award in Chromatography for his work in chromatographic detection methods.
Graduate student Prabha Dwivedi works on a project that may one day allow complex medical diagnostics will be performed within milliseconds. Led by Herbert Hill, a WSU chemistry professor and an acknowledged leader in the field of ion mobility spectrometry, the project is focused on creating an instrument that produces a comprehensive profile of the human metabalome — metabolites, found in cells, tissues and organs — from a single sample of blood or other bodily fluids.