On a cool evening last April, at exactly 8:01 p.m., the International Space Station traced a bright silver arc over Pullman. Inside, astronauts went about their routine while a small sensor scanned the air for hazardous vapors and relayed the data to flight controllers in Houston.
Meanwhile, 200 miles below in the rocky Syrian desert, soldiers searched through rubble carrying a handheld device that sounds an alarm in the presence of chemical warfare agents. At airport security gates and customs stations all over the world, similar devices sniff out explosives and narcotics.
The technology behind those detectors is finding its way into the medical field as a rapid, ultrasensitive method to diagnose disease. It is also helping scientists probe the obscure workings of metabolism and complex conditions involving cancer and the immune system.
That technology is called ion mobility spectrometry or IMS. While it may be unfamiliar, IMS is emerging as one of society’s most powerful workhorses, able to detect and identify an extensive range of potentially harmful materials.
For Herbert Hill, the Washington State University chemistry professor who led the development of ion mobility over the last 40 years, the journey has been nothing short of a grand adventure.
I navigate a labyrinth of hallways, elevators, and staircases one afternoon to meet with Hill. His laboratories take up most of the fifth floor of Fulmer Hall, the WSU chemistry building. The genial professor waves me in.
Seated behind a large computer monitor and dressed in jeans, boots, and a puffy brown vest, Hill takes a sip from a can of Pepsi and points to a chair. Papers and books are stacked everywhere. The wall behind me holds a dusty green chalkboard covered with equations. On the opposite wall, a long row of red-framed, faded photographs displays the smiling graduate students who have worked their way through Hill’s classrooms.
Hill is an analytical chemist and Regents Professor, a modest man with a soft Southern drawl, who tends to downplay his role in the success and commercialization of ion mobility spectrometry.
Simply put, IMS is a fast, highly sensitive method to identify the chemical makeup of virtually any substance based on the speed of its molecules as they shoot through a cylinder. Tiny samples are first vaporized, and then turned into charged ions. Some ions zip through the cylinder quickly while others move more slowly, providing each a signature mobility rate.
On its own, IMS can be made into a small, simple, and reliable handheld device. When coupled with other analytical tools, IMS reveals the details of a chemical compound in three-dimensional ways never before possible.
The door opens behind me and Bill Siems ’74 PhD comes in with a cup of coffee. Research professor and master of the mandolin, Siems has played a pivotal role in many of the Hill lab breakthroughs.
Doctoral students Brian Hauck and Jessica Tufariello follow behind. I listen as they chat with Hill about the progress of their dissertation projects. Hauck is refining IMS for national security measures and Tufariello is building what could be the first marijuana breathalyzer. Within a year or so, their faces will be featured in the row of red frames—the last graduate students to join the Hill legacy at WSU.
Herbert Hill grew up in Helena, Arkansas, a town on the Mississippi and birthplace of the Delta blues. “It was the 1950s and KFFA was the first radio station to play blues in the rural south,” he says. “I remember racing home at noon to catch a 15-minute segment of the King Biscuit Boys on the radio while having dinner.”
It was also the Jim Crow era and the radio frequently carried news of emotional confrontations taking place in Little Rock, as the town struggled to integrate Central High School in 1957. Hill was sympathetic. “My heroes are the people who stayed in Arkansas and tried to build civil rights,” he says, likely following in the footsteps of his great-great-grandfather, a Quaker pacifist who refused to fight in the Civil War and was later elected to Congress.
Hill says he always liked science and, as a boy, set up a small laboratory complete with test tubes and Bunsen burners in the family garage. “We took gunpowder out of shotgun shells and blew stuff up,” he says. “I also had chemistry kits and did experiments where things foamed and changed color.”
His undergraduate years were spent at Rhodes College in Memphis, where he met an English major named Jannette, whom he later married. It was there, too, that he dedicated his life to the study of chemistry.
In 1970, Hill entered graduate school at the University of Missouri and was taken under the wing of a dynamic young professor named Walter Aue. There, collaborating faculty members studied moon rocks retrieved from the first lunar landing and Hill’s best friend was conducting the organic analyses.
“They were looking for traces of life on the moon—searching for amino acids,” says Hill who was thrilled by the research. In the end, the scientists found no evidence of lunar life forms but the experience sparked Hill’s interest in the field of trace organic analysis. He soon found himself immersed in the lab for hours on end, teasing out tiny concentrations of pesticides and heavy metals contaminating the environment.
As often happens when living through historic times, Hill and his fellow graduate students were only vaguely aware of the revolution unfolding around them. The early 1970s had just ushered in the first Earth Day along with acclaim for Rachel Carson’s clarion call, Silent Spring. It was the awakening of the modern environmental movement.
The times certainly affected Hill’s chemistry department. “Silent Spring was required reading for two or three of my classes,” he says. The book documented the harmful effects of DDT in the environment and prompted a surge of funding for trace organic analysis.
“It was a happening time for science,” says Hill. “The idea that I could build instruments and develop methods to enable people to ‘see’ chemicals they couldn’t see before was very exciting for me. I’ve always felt that new discoveries aren’t made until the new measurement methods are first developed.”
Indeed, it was the invention of two innovative detectors in 1957 that made it possible to identify environmental contaminants such as DDT, and provided the provocative data for Carson’s book.
The air of excitement continued as Hill followed Aue to Nova Scotia in 1973 when the professor was hired to run a trace analysis center at Dalhausie University.
“There were new labs, new faculty, and I went with them to finish my PhD,” says Hill. During the dissertation process, Hill also met Frank Karasek, a scientist who offered him a postdoctoral position at the University of Waterloo. “I went because Karasek had an exciting new tool called ion mobility and had just started using it for analytical work,” he says.
In Karasek’s lab, Hill and the other students were free to test a wide range of compounds including narcotics and explosives. They learned the basic mechanics of IM but had yet to discover its full potential.
“We thought it was just a rapid method of separating and analyzing volatile organic compounds, or VOCs, at atmospheric pressure,” says Hill. This alone was impressive as it gave the chemist a new tool capable of identifying substance in milliseconds.
In 1976, Hill joined Washington State University as an assistant professor. Though eager to continue his work with ion mobility, he had to put it on the back burner. “There were problems with the technique and people had decided it wasn’t going to be a useful analytical tool after all,” he says.
Hill bided his time with other projects until 1982 when he received tenure and felt free to gamble a little. “I understood why ion mobility didn’t work well,” he says, “and I wanted to try building an instrument the way I knew it should have been done.”
He recruited graduate student Mike Baim ’84 PhD and the two of them built the first computer-controlled ion mobility spectrometer. The design was Hill’s first big breakthrough and it enabled IM technology to go mainstream where it was widely copied and commercialized.
“The key to making ion mobility work was to sweep ‘all the neutrals’ out of the system,” says Hill. Using a countercurrent gas flow, they were able to push the non-ionized molecules away from the detector while the charged ions continued forward.
They initially tested the system with gasoline from a friend’s motorcycle. “We injected a tiny sample into the IMS and were amazed to see peak after peak of compounds being identified. It was so impressive that the first book written about IMS used the image on its cover,” he says.
Buoyed by their success, Hill took Baim to his backyard to test soil near dandelions that had been sprayed with the herbicide 2,4-D. “The sample about blew the instrument apart,” Hill says. They followed with dirt from Hill’s garden that had not been sprayed, but still detected a strong signal for 2,4-D. Intrigued, they collected samples from all over Pullman and found traces of the herbicide in each one. “We never could find any clean dirt. They all had 2,4-D in them,” he says.
Hill was about to accuse poor Baim of being a sloppy chemist but instead took a horseback trip into Idaho’s pristine Gospel Hump Wilderness to search for uncontaminated soil samples. “When I came back and tested them, every one of the samples still had traces of 2,4-D,” he says. Baim was vindicated but Hill was mystified.
One day, Hill heard about the campus soil bank where samples from the Palouse have been warehoused over the decades. He gave it a try.
“We had to go back to 1940—before the advent of 2,4-D—until we could find clean soil,” he says. “This is an example of how widespread environmental contamination is at the trace level, and how well ion mobility can detect it.”
Hill left for sabbatical in 1983, and fellow Southerner Siems was hired to oversee the IM research group during his absence. Siems liked the laboratory’s pioneering atmosphere and ended up joining the team. “Herb has always been a fountain of knowledge and invention,” he says. “He had a million ideas. As a physical chemist, my role has always been to bat the ideas back to him or whack them down as the case may be.”
During this interval, Siems helped incorporate the idea of multiplexing which gave IMS the capability to run multiple experiments simultaneously. Their work quickly drew the interest of the Federal Aviation Administration. “There had been a number of bombings around that time and they were interested in detecting explosives on planes,” he says.
“It was the beginning of our involvement with explosives, drugs, and chemical warfare agents, which continues on today through Homeland Security and our development of the marijuana breathalyzer,” says Siems.
He explains that most people have had an experience with ion mobility at the airport when a TSA agent swabs their laptop or carry-on luggage during security screenings. “The swab goes into an IM device set to look at a specific window of compounds and an alarm sounds if they detect molecules that fall within that range.”
When Hill returned to WSU in 1984, he was ready for a new challenge. At that time, IM could only identify volatile organic compounds, yet a world of non-VOC molecules remained. “How can we get compunds like large proteins into IMS detectors to measure them?” asked Hill. They tried a number of new laboratory techniques, but it wasn’t coming together.
The answer arrived through another of Hill’s grad students, Chris Shumate ’89 PhD, who heard about electrospray technology at a conference in 1985. Electrospray uses high voltage electricity to turn liquids into an aerosol of ions. It is especially useful for ionizing proteins and other large molecules. Setting another milestone for the lab, Hill and Shumate built their first electrospray ion mobility spectrometry unit in 1986.
The discovery broadened the use of ion mobility spectrometry and set the stage for future work in the field of medicine. In 1995, Hill, Siems, and graduate student Ching Wu ’97 PhD, advanced it yet further when they successfully coupled an IMS to a mass spectrometer, which can be likened to a tiny scale for weighing molecules. “The combination gave us a complex array of mass and mobility information never before possible,” Hill says. “It allowed us to identify molecules in a much more comprehensive way.”
With ion mobility-mass spectrometry, or IMMS, Hill finally had the vehicle to study the chemical processes involved in health and aging. In 2005, he introduced the idea of using IMMS as a tool for mapping the human metabolome—or the entire set of physiological byproducts called metabolites. IMMS can measure hundreds of metabolites simultaneously. Within 30 minutes, it can detect thousands of compounds in a single drop of blood.
Each metabolite produces a specific IMMS pattern, or signature, that can be altered by disease. IMMS can monitor these patterns to diagnose or track conditions such as cancer, heart disease, diabetes, depression, Parkinson’s disease, and others. Hill has also shown that IMMS can detect colorectal cancer in the feces of mice, and most likely in humans as well.
Similar technology is being adapted for use on the International Space Station. NASA engineer Tom Limero has known Hill for 20 years and invited him to Houston in 2011 to help the agency develop electrospray ion mobility for space. “NASA is just moving forward on this,” says Limero. “We want to monitor physiological changes using saliva or breath instead of drawing blood, which is problematic in space,” he says. Several versions of IM have also been used for monitoring air quality on the space station since 2001.
Hill’s cell phone rings playing Muddy Waters’ “Bad to the Bone.” While he tends to the call, Hauck and Tufariello invite me to the lab to see the ion mobility instruments.
Hauck is polite and articulate. “This instrument is currently the most accurate IMS in the world,” he says, introducing me to a large machine bristling with wiry projections. Hauck explains that his doctoral project involves fine-tuning the accuracy of IM instruments for national security purposes. His goal is to eliminate the number of false positives that occur while searching for drugs, explosives, or chemical weapons agents, yet not err on the side of false negatives, which could result in disaster. “The government wants to set a standard for 0 percent false negatives,” he says.
Tufariello is a freckled former art student from New Jersey who came to WSU on a whim. I watch as she tinkers with several small instruments, one of which will become a marijuana breathalyzer for detecting THC in human breath.
The idea for a marijuana breathalyzer grew out of a longtime friendship between Hill and Nick Lovrich, WSU Regents Professor Emeritus in political science. The two have neighboring cabins in North Idaho’s Selkirk Mountains where they’ve spent vacations since 1977. One night in 2009, the two were seated at the same table at a WSU fundraiser. Their usual conversation revolved around fishing, barbeques, and the like, but that night Lovrich finally asked Hill, “Just what kind of work do you do?”
Hill replied that he was an analytical chemist and explained the concept of ion mobility. “What do you do?” Hill asked in return. Lovrich said he worked with law enforcement and was trying to help control impaired driving due to illegal or prescription drugs. “Why don’t you use a breathalyzer to detect drugs in the breath?” asked Hill. “No such thing exists,” said Lovrich. “Interesting,” said Hill, “I think it’s possible.”
The two obtained funding and Tufariello volunteered to tackle the project with the intention of studying an array of drugs. Soon after in 2012, Washington state voters approved Initiative 502, which allowed the legal use of recreational marijuana. Hill and Tufariello changed their focus to the detection of the cannabinoid THC in human breath.
“I believe it will work,” says Hill, “but we have only just begun the study in breath and how it correlates to blood levels of THC.”
Though the marijuana breathalyzer is still under development, the initial prototype is so encouraging that the National Highway Traffic Safety Administration and the United Nations Office on Drugs and Crime are interested in the technology.
When Tufariello’s project is completed, Hill and Siems will slowly begin to close up shop. Brian Clowers ’05 PhD, who not long ago took notes in Hill’s classes, will carry on the ion mobility work in his own laboratory across the hall.
“There is still a lot of research to be done in the realm of IM,” says Clowers, particularly in glycomics, the study of the body’s sugar molecules. The work promises to shed new light on immune system function as well as how cells recognize bacteria and viruses and whether or not a cancer develops.
In mid-April, Hill took a preliminary step away from the chemistry lab and planted 600 young fir trees near his daughter’s house outside of Pullman. “I’m going to have a U-Cut Christmas tree farm,” he says—one, no doubt, where wandering customers will hear holiday blues drifting through the grove.
Hill will eventually transition to the role of consultant for academic and industrial research. He’s happy with the way things have turned out. “I feel great,” he says. “To be one of the earliest people in ion mobility… and to have said that it could be used for everything, and seeing it turn out to be true. It’s been a lot of fun.”
Chemical Warfare Agents
The military uses ion mobility spectrometry (IMS) for detecting chemical warfare agents like mustard gas or the nerve agents VX and sarin. More than 150,000 handheld units are currently deployed worldwide to help soldiers monitor the disposal of chemical weapons as well as warn of their accidental release. IMS is also used in a forensic manner to determine if chemical agents—banned for warfare by the Chemical Weapons Convention of 1993—have been used for combat or to attack civilians, such as those documented in the ongoing Syrian civil war.
The safety of our national food supply relies on the use of accurate screening methods to detect chemicals, bacteria, or other contaminants as food travels from farm and processing plant to local markets. Ideally, detection methods should be fast, sensitive, and portable—all characteristics of IMS, which is gaining ground as an analytical tool of choice for the food industry. IMS can detect traces of pesticide residue on food as well as identify mold and bacteria. IMS is also used to monitor quality during the production of cheese, beer, wine, and pharmaceuticals.
Glycomics is the study of the body’s sugar molecules, or carbohydrates. Assistant Professor Brian Clowers is developing innovative IMS techniques to identify the various forms of carbohydrates, which can be turned into novel therapeutic drugs like Herceptin®, an FDA-approved treatment for breast cancer. “There are a range of carbohydrates in a biological system which appear in different states for healthy and diseased tissue,” says Clowers. “We don’t have fast, sensitive tools to differentiate them right now, but we are developing them.” Clowers expects many more drugs like Herceptin® to be developed in the future.
CWA Graphics Courtesy Andy Brunning/Compound Interest