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The doctors’ view in Peru In Lima, a graduate student finds answers to the question, “What do doctors want in a diagnostic device?”
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he first thing Alfredo Ibañez did when he joined Sabeth Verpoorte’s research group at the University of Groningen (The Netherlands) in 2003 was to see a doctor. Actually, five doctors, half a world away in Lima, the sprawling coastal capital of Peru. Ibañez had just completed a master’s degree in Joseph Wang’s lab at the University of New Mexico and was about to begin his Ph.D. studies in The Netherlands. But first, he had to return to his native Peru for several weeks while his visa paperwork was being processed. “I needed something to do [while I was waiting],” he says. So, before he returned home, he talked to Verpoorte about the microfabricated devices that the lab was working on and which specifics he might research. Foremost in his mind, he says, were the comments that reviewers would make when they eventually submitted the work for publication. “One of the first questions that they ask is, ‘Why?’” he explains. If there is already a method available, “why . . . do you want to publish one that actually measures the same [thing] but with only a few differences?” He and Verpoorte wanted to be able to say that their method would be truly useful in a clinical setting. Members of the lab had learned the hard way that users don’t always embrace devices just because the ideas are clever. The question, then, was what doctors would want.
Hooked on sensors It was winter back in Lima, but the seaside fog had withdrawn, giving the city © 2004 AMERICAN CHEMICAL SOCIETY
a respite. In the bright sunshine—it was sunnier than The Netherlands in summertime, quips Ibañez—he set out for the library at his undergraduate university, Pontificia Universidad Católica del Perú. He had been feeling misplaced because his hometown seemed unfamiliar after years in the United States, but
To Ibañez’s surprise, the consensus among the doctors was that most of the time, they don’t need a diagnostic device. he began to settle in after looking up Eric Cosio, his undergraduate research advisor. The professor had caught “the Indiana Jones virus” about a year before that, says Ibañez, and was preparing for another venture into the jungle to look for plant specimens. Ibañez did not sign up for the trip. He had previously accompanied his advisor on two recreational trips into the mountains, “and both of us agreed that I will never go again,” he says cheerfully. Cosio is the one who had gotten the undergraduate Ibañez hooked on biosensors by telling him about the arraybased detectors known as electronic noses. Ibañez then gathered more information during a brief visit to some U.S. universities, and when he returned, he
asked Cosio whether he could build an immunosensor as his undergraduate research project. Although Cosio taught an instrumentation course at the time, the project was a departure from his studies of plant biochemistry. Nevertheless, he was enthusiastic about the biosensor, and they mapped out a plan. Their first successful experiment was a quartz crystal microbalance immunosensor for 3,3´,5triiodo-L-thyronine, a growth hormone. As Ibañez approached graduation, he knew that he wanted to study biosensors in more depth. Some contacts he had made via the Internet pointed him to Wang’s lab in New Mexico, and with his parents’ encouragement, he went. Wang introduced him to labon-a-chip devices, which piqued his interest because they were small, fast, and flexible enough to accommodate either heterogeneous or homogeneous immunoassays. While working on his master’s degree, he happened to meet Verpoorte at a conference. “She was working in the same area,” he says. “I thought, ‘I am still young. I can learn new things here,’ so I [made] the jump over the ocean,” even though it meant starting over. He admits that learning Dutch makes him feel like a five-year-old again. “[I’m] reading small books, talking in simple sentences,” he says lightheartedly. A person can get by quite well in The Netherlands speaking English, which he had learned in grade school, but he wanted to try Dutch because “it’s part of the experience.” Besides,
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he jokes, “Nobody told me that Dutch was complicated.”
Having grown up in Lima, Ibañez was familiar with the 43-year-old Universidad Peruana Cayetano Heredia, which has established a reputation in medicine and public health despite being a relative newcomer in this city more than four and a half centuries old. Two of Ibañez’s friends obtained medical degrees there, and Giovanni Poletti, one of the coadvisors on his undergraduate thesis, works in the school and its hospital. Ibañez doesn’t like hospitals, saying that he prefers to be in neutral territory, but he went to the campus of boxy, modern buildings because he hadn’t found the kind of information he needed just by reading. Poletti, a doctor who practices and teaches clinical analysis, told Ibañez to start by reading the book Clinical Chemistry: Theory, Analysis, and Correlation. “He made me sit in his office and go through the book,” Ibañez recalls, laughing. Two medical students stopped by while Ibañez carried out his instructions, so he began to ask them questions. Later, he interviewed four general-practice physicians. One was a European doctor and AIDS researcher who showed Ibañez how doctors use the ubiquitous reference book Harrison’s Principles of Internal Medicine, which catalogs the classic symptoms of known illnesses. (Her husband subsequently tutored Ibañez in Dutch.) To Ibañez’s surprise, the consensus among the doctors was that most of the time, they don’t need a diagnostic device. “They were very honest,” he says. The doctors explained that, when they see ill patients, they “follow the symptoms of the sickness,” Ibañez says. And perhaps 90% of the time, the symptoms are similar from patient to patient, “so there is no need for an analytical system.” However, the doctor may run a simple test, perhaps a blood count, “to be sure he has the right thing in his mind.” In the remaining ~10% of the cases, the doctors said they are more likely to run clinical tests, perhaps checking lev350 A
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City by the sea. Ibañez’s hometown, Lima, fades into the Pacific Ocean in this view from La Costa Verde.
els of insulin, urea, or immunoglobulins to look for telltale signs of disease. Even then, Poletti told him, physicians are typically dealing with a small variation of a condition that they’ve seen before. It’s only in a stubborn minority of cases, perhaps 2%, that the doctors don’t know what they’re dealing with; then, their first instinct is probably to confer with specialists.
Accuracy over speed On the laundry list of desirable characteristics for a clinical diagnostic device, an analytical chemist might begin with good S/N, resolution, and sensitivity. “But when you talk with a doctor, they care about . . . how simple it is or how autonomous it is,” says Ibañez. Of course, doctors are concerned with accuracy; to them, “accurate” means that a test reveals when a patient is sick and that it doesn’t erroneously diagnose a healthy person as sick or clear a sick person as healthy. And unlike analytical chemists, who often emphasize real-time measurements, doctors don’t necessarily place as much importance on an instant result, he adds. A short response time seems to be a good thing, he notes, but if you get better results by waiting a little longer, the doctors might very well prefer to wait.
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This is not to imply that the concerns of chemists and doctors are mutually exclusive, but one’s training and experience define one’s approach to a problem, and sometimes the gap can be hard to bridge. Ibañez jokes about a chemist and an electrical engineer working on a project. The chemist says, “I want to measure picograms,” and the engineer replies, “Okay, how much current is that?” Even between a chemist and a doctor, who have some common background, there can be disconnects. Ibañez recalls the first time he presented his immunoassay to Poletti. “[I was] very happy with my experiment, showing him I [had] good results, good sensitivity,” he says. “And he began to point [out] these things that I never thought about, like, ‘What’s the throughput of your system compared to an ELISA plate?’” Poletti also explained how biological samples are collected and handled in a hospital. Back then, “things like that never came into my mind in the design of these biosensors,” Ibañez confesses. Later, a biologist who was reviewing the immunoassay that Ibañez was developing for his master’s thesis asked him, “Have you considered that maybe you will have cross-reactions?” He hadn’t. But he was beginning to understand how complicated it is to conduct diagnostic assays on real clinical samples. By the time he arrived in Verpoorte’s lab, such considerations “were at the front of my thinking,” he says. “When we began to discuss the new project, I always [was] thinking, ‘Okay, which is the sample that I want to analyze?’ For example, blood is different from saliva [which] is different from urine.” As Ibañez puts together his dissertation project, he reflects on what he really learned from his interviews with physicians. It wasn’t that diagnostic devices need to be autonomous or have a low false-positive rate; it was how to broaden his point of view. “The good thing,” he concludes, “is that the more time you spend [at] this, the more you begin to understand the other people.” a —Elizabeth Zubritsky
