It was 1979. Robin Warren, a pathologist at the Royal Perth Hospital in Western Australia, was examining tissue samples from stomach biopsies under a microscope, and he noticed several areas of inflammation. In every case, he saw spiral-shaped bacteria close to the irritated areas, nestled just inside the stomach's thick mucus layer. Warren wondered how any bacteria could have survived their acidic voyage into the stomach, let alone slip into the mucus that coats the inner surface of the stomach.     Barry Marshall (left) and Martin Blaser (right) at the 1995 Lasker Awards ceremony. With the aid of a young doctor named Barry Marshall, Warren tried to grow the bacteria on nutrient-coated culture dishes in the laboratory. They failed. Time after time, the researchers painted culture plates with a solution that contained the mystery bacteria, then left the dishes to incubate for two days. The result was always the same: no growth. Then, in April 1982, Warren and Marshall left for the Easter holiday. When they returned to the lab after their five-day break, they were amazed to find thriving bacterial growth on the culture plates! Their problem had not been the culture process, but the length of time the bacteria needed to grow. With this stroke of good luck, Warren and Marshall continued to investigate the bacteria, which belong to an entirely new genus, ultimately named Helicobacter (after its helical, or spiral, shape). They used the species name, pylori, because it refers to the region of the stomach near the pyloric valve, a common site for the development of ulcers. The pyloric valve opens from the stomach into the upper end of the intestine, known as the duodenum. At this point in the research, Marshall had become convinced that H. pylori –as opposed to stress, acid, or aspirin overuse–was the cause of gastritis and probably of ulcers in most people. In 1983, Marshall presented his hypothesis to an international meeting of distinguished specialists in infectious disease. Many of the scientists and physicians attending the meeting were shocked by the notion that bacteria cause gastritis and stomach ulcers. Marshall's ideas seemed to be the reckless notions of a scientific upstart. Attributing gastritis or ulcers to a bacterial infection seemed outlandish. Martin Blaser of Vanderbilt University School of Medicine in Nashville, Tennessee–a leading American researcher in infectious disease–called Marshall's ideas "preposterous." Marshall, however, was certain he was on the right track. The results of his work with Warren were published in the respected British medical journal Lancet and research by other scientists supported the association between H. pylori and inflammation of the stomach lining. Most physicians, however, remained unconvinced. Most stomach ulcers are caused by the bacterium H. pylori (purple), which burrows into the mucous lining of the stomach. The bacterium secretes an enzyme that produces ammonia, a strong base that damages stomach tissue, especially epithelial cells of the stomach lining. Immune system cells infiltrate the area of the ulcer to attack the bacteria, but this often leads only to further inflammation and damage. The reluctance of his colleagues to accept the idea that H. pylori causes ulcers provoked Marshall to act. Intent on proving his point, he made himself the guinea pig. Marshall prepared a broth of active H. pylori and drank it. "Those were frustrating times for me," Marshall recalled in a recent interview. "Most of the experts believed that the presence of H.pylori in those who turned up with ulcer problems was just a coincidence. I planned to give myself an ulcer, then treat myself, to prove that H. pylori can be a pathogen in normal people. I thought about it for a few weeks, then decided to just do it. Luckily, I only developed a temporary infection." That "temporary infection" gave Marshall stomach pain, nausea, and vomiting–classic symptoms of gastritis or the early signs of an ulcer. While he was ill, he underwent an endoscopy, a procedure in which a doctor uses a flexible fiber-optic tube with a tiny video camera on the end to examine the inside of the digestive tract. Within a week after ingesting the H. pylori, Marshall's stomach showed marked inflammation, with crowds of the distinctive spiral bacteria hovering around the areas of inflammation. Marshall became famous for this self-experimentation, and today researchers and doctors recognize H. pylori as the cause of more than 90 percent of ulcers worldwide. The U.S. Food and Drug Administration has approved several combinations of antibiotic drugs as therapy for active H. pylori infection. Marshall, once scorned for what seemed to be a ridiculous idea, is now celebrated as a pioneer and a scientific visionary. Martin Blaser, who was initially skeptical about Marshall's hypothesis, has said that "science needs people with great vision, and Barry has vision." In 1995, Marshall received the Lasker Award, one of the highest honors in medical research. "Rarely do the discoveries of a single individual change the lives of countless millions in the span of a decade," the Lasker Award committee wrote, "but the revolutionary research of Barry Marshall has accomplished just that. In so doing he has dispelled the darkness surrounding a chronic disease and lighted a pathway to a cure." Barry Marshall's story tells much about the way innovative scientific work is often accomplished. Beginning with the difficulty of culturing H. pylori and the lucky accident of a five-day holiday break that allowed the bacteria to grow, the discovery and study of H. pylori has been pushed forward by intuition, intellectual courage, and serendipity. Moreover, Marshall demonstrated to his peers and to the world at large a powerful motivation to know the truth. He was willing to stand up to ridicule from other scientists and to infect himself with H. pylori in his quest to learn whether the bacterium causes infection and illness in human beings. The biotechnology age has opened hundreds of new doors for young scientists," Marshall says. "If a testable hypothesis can be developed, then it's usually only a matter of the right steps to prove or disprove the hypothesis. The reward lies in major advances in how we diagnose and treat disease." Marshall is particularly excited about genetics research, a field of inquiry that he believes holds the promise of "understanding the true mechanisms of what are now mysterious disease processes. This is a very exciting time to be involved in medical science," he says.