3 mindsets that led to scientific breakthroughs

Caption: After the Golden Goose Award ceremony at the Library of Congress, David Sachar, MD, talks with Rhema Bjorkland, PhD, a former AAAS fellow who is now Staff Scientist and Technical Advisor for Environmental, Health & Safety at the National Nanotechnology Coordination Office. (Photo by Alison Bert)

Their seminal research was done decades ago, but its impact prevails and their approach to science is as timely and relevant as ever.

This month, three distinguished scientists traveled to Washington, DC, to accept an unusual and prestigious honor. The Golden Goose Award S’ouvre dans une nouvelle fenêtre recognizes "silly sounding" federally-funded research that has led to major breakthroughs in science and medicine. At the ceremony, the scientists — and family members of their deceased research partners — talked about their research for a standing-room-only audience at the Library of Congress.

Earlier that day, we interviewed each of the living awardees in the Kennedy Caucus Room of the Russell Senate Office Building, where they were honored at a private luncheon. Here's a sample of the wisdom they shared and their advice to young researchers.

1. Question the "obvious."

It can be daunting to challenge your teacher, especially when questioning a scientific "truth" that has endured for decades.

But that didn't stop Noel Rose S’ouvre dans une nouvelle fenêtre, Professor Emeritus in the departments of Pathology and of Molecular Microbiology and Immunology at Johns Hopkins University. He is now Senior Lecturer in Pathology at Brigham and Women’s Hospital/Harvard Medical School.

As a junior faculty member and medical student in 1951, Rose joined the lab of Ernest Witebsky — an immunologist he came to "revere" as his mentor. Their aim was to learn more about antigens specific to various organs. Rose conducted a series of experiments with thyroglobulin, hoping to figure out the biological mechanisms behind organ-specific antigens and possibly use them to screen for certain cancers. To induce an immune response, he injected thyroglobulins from various species into rabbits. As expected, the rabbits produced thyroglobulin-specific antibodies.

Caption: On the Golden Goose panel, Noel Rose, MD, speaks with moderator Frank Sesno, Director of the School of Media and Public Affairs at George Washington University, as David Sachar, MD, and Frank Witlebsky, MD (son of Ernest Witebsky) look on. (Photo by Alison Bert)

"Too often in medicine, we take things at face value because they seem so logical," Dr. Rose said at the Golden Goose ceremony. "We frequently don't have evidence for them, or even any understanding as to how they could happen. And that's really where my story resides. ...

But at 26, he was not about to accept it as dogma. "Of course, being maybe a little rebellious at that point, a little skeptical, I began to work with this essential thyroid protein, thyroglobulin. And I found that thyroglobulins were very much the same in all animals we studied, including humans.

"I wondered, 'So how can, in this case, a rabbit but it might be you or me recognize all these other protein molecules but never the thyroglobulin of our own bodies. Horror toxicus told me that it won't.

"I thought, ‘Maybe I'll test it one of these days.' And by golly I did."

Rose injected thryroglobulin from rabbits back into the rabbits. The result shocked him — the rabbits produced antibodies that inflamed and even destroyed their own thyroid gland that houses the thyroglobulin. He then tested serum samples from patients with inflamed thyroids (termed Hashimoto thyroiditis) and showed that they had antibodies to thyroglobulin.

This was the first case of reproducing a well described human disease by immunization. “We call them autoimmune diseases — diseases  caused by a crazy, out-law immune system," Dr. Rose said.

Dr. Rose credits his mentor for responding with skepticism and demanding that he reproduce his results for what could be an important discovery.

"'Again, again!'" he said, "'Repeat it repeat it — you must have made a mistake.'"

But there was no mistake; this discovery would lead to an increased understanding of the more than 100 autoimmune diseases and while opening pathways to better diagnose and treat them.

Read about their research and watch a short film.

Read top-cited research by Drs. Rose and Witebsky published by Elsevier

• Rose et al: Defining criteria for autoimmune diseases (Witebsky's postulates revisited) S’ouvre dans une nouvelle fenêtre, Immunity Today(1993)

• Rose et al: Clinicopathoiogic description of myocarditis S’ouvre dans une nouvelle fenêtre, Journal of the American College of Cardiology (1991)

• Rose: The discovery of thyroid immunology S’ouvre dans une nouvelle fenêtre, Immunology Today (1991)

• Rose and Witebsky et al: Penicillin allergy and desensitization S’ouvre dans une nouvelle fenêtre, Journal of Allergy (1962)

• Rose and Witebsky et al: Serum sickness: II. Demonstration and characteristics of antibodies S’ouvre dans une nouvelle fenêtre, Journal of Allergy (1961)

• Witebsky: The Autoantibody Nature of the Thyroiditis Antibody and the Role of the Thyroglobulin in the Reaction S’ouvre dans une nouvelle fenêtre, The Lancet (1958)

2. "Take the science to where the problem is."

"Dr. Weller told us, ‘If every one of the dollars spent in federally sponsored research ... worked, we might have the success of extending the average life expectancy in the United States, say, from 68.7 to 69.1.

"If 10 cents of each dollar — one 10^th of that amount — were spent in the developing world, we might have the success of extending the potential life expectancy from age 40 to age 60.’

"And I was hooked."

He went to his chief of medicine at Beth Israel Hospital in Boston and told him of his decision to join the US Public Health Service — one of the seven uniformed services in the US.

"I said, 'Look, we all have to serve two years of government service as physicians. Many of my colleagues are going to the NIH in Bethesda or to the Naval Hospital or the Walter Reed Army Institute of Research in Washington, and that’s wonderful. But that’s not how I want to spend my two years in government service.

"I want to go to the developing world and save the world."

"My friends at Harvard said, 'Oh that’s great. When you come back from East Pakistan, you can treat all the cholera patients in Boston — as though if it didn’t exist in Boston, it didn’t exist, it didn’t matter. But it mattered."

In East Pakistan, now Bangladesh, Dr. Sachar devised an unusual method to better understand the intenstinal activity in cholera patients. After adapting standard methods for measuring electric potential across biological membranes – like frog skin – in the laboratory, he devised a novel technique for measuring electric charge across the intentinal wall in intact humans. Applying this technique to cholera patients in East Pakistan, Dr. Sachar showed that intestinal absorptive function was normal in cholera and was accelerated normally in the presence of sugar. That realization formed the basis for oral rehydration therapy (ORT) for diarrheal disease, widely credited with saving over 50 million lives worldwide.

Dr. Sachar went on to become a Clinical Professor of Gastroenterology at Mount Sinai School of Medicine in New York.

Read about his research and watch a short film.

Dr. Sachar's advice for young scientists

"In order to achieve success with the translation of basic scientific research to useful beneficial application," he said, "you have to take the science to where the problem is.

"I could have sat for years at the laboratory bench in Copenhagen studying the electric potential across the frog skin – forever.

"Until you are ready to seek out the place where the problem is occurring, the place where the disease is committing its ravages, you’re not going to achieve the ultimate goal of saving lives and enhancing social welfare."

Read top-cited research by Dr. Sachar published by Elsevier

• Sachar et al: Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis S’ouvre dans une nouvelle fenêtre, Gastroenterology(2003)

• Sachar et al: Cancer in Crohn's disease after diversionary surgery: A report of seven carcinomas occurring in excluded bowel S’ouvre dans une nouvelle fenêtre,The American Journal of Surgery (1978)

• Sachar et al: Intestinal Transmural Electric Potential and its Response to Glucose in Acute and Convalescent Cholera S’ouvre dans une nouvelle fenêtre,Gastroenterology (1969)

3. Don't let your goals and expectations get in the way of good science.

Dr. Jack Levin, Professor of Laboratory Medicine at the University of California San Francisco School of Medicine, admits he's "prejudiced" when it comes to basic research. After all, it's what he'd done for more than six decades — with remarkable results.

But the reason he favors it over applied research may seen counterintuitive.

"I think basic research is likely to have a much greater impact over the long term than applied research," he said. "In addition, applied research traps you into a goal which may or may not be realistic and narrows your focus.”

"So I think research that is not overly focused in terms of a specific end has the ability to amplify its results not only in the field in which the person is working but in fields that do not seem to be relevant at that point."

That was indeed the case with the research he and the late pathobiologist Frederik "Fred" Bang S’ouvre dans une nouvelle fenêtre were honored for with the Golden Goose Award.

Studying the blood of the horseshoe crab leads to a lifesaving medical discovery

In the 1950s, Dr. Bang was studying the circulatory system of the horseshoe crab when he discovered that an unknown infection was causing their blood to clot. A decade later, he called on Dr. Levin for his hematology expertise.

Through his experiments, Dr. Levin identified the culprit: a bacterial endotoxin. Bacterial endotoxin is a component of the cell wall of Gram-negative bacteria such as E. coli and Salmonella and can cause serious illness.

Dr. Levin then used the blood of the horseshoe crab to develop a new way to screen for bacterial endotoxins. Today, the Limulus amebocyte lysate (LAL) test is the standard way to screen intravenous fluids, parenteral drugs, and implantable medical devices for endotoxins.

"I think that my work is an excellent example of the importance of conducting and supporting basic biological research, even when there's no obvious practical benefit at the time," Dr. Levin told the audience at the Golden Goose ceremony. "And certainly, the history of investigative science indicates that early failure was a common feature of many discoveries, which turned out to be very important."

Read about their research and watch a short film.

Read top-cited research by Drs. Levin and Bang published by Elsevier

• Bang: Comparative pathology of marine invertebrates and the study of human disease S’ouvre dans une nouvelle fenêtre, The Journal of Pediatrics (1975)

• Bang et al: Ciliate infection of the blood of the edible crab, Cancer pagurus, in holding tanks in Brittany, France S’ouvre dans une nouvelle fenêtre, Journal of Invertebrate Pathology (1972)

• Bang et al: Protein and Colorie Malnutrition, Cell-Mediated Immunity, and B.C.G. Vaccination in Children from Rural West Bengal S’ouvre dans une nouvelle fenêtre, The Lancet (1976)

• Bang et al: Long-term growth of chicken fibroblasts on a collagen substrate S’ouvre dans une nouvelle fenêtre, Experimental Cell Research (1974)