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Respected doctors confront a tragedy
Experiment: With a research subject's death, two distinguished scientists confront what colleagues say is the worst imaginable outcome.
By Tom Pelton
Sun Staff
Originally published July 8, 2001

Dr. Solbert Permutt is a giant in the world of lung research, a gregarious, outspoken 76-year- old professor with the enthusiasm of a teen-ager, a flamboyant taste for large bow ties and a history of teaching generations of doctors at Johns Hopkins Medical School.

His friend, Dr. Alkis Togias, 43, is quiet and conservative, a scientist who doesn't mind dirtying his hands studying cockroaches as a possible cause of asthma in Baltimore's public housing.

For years, they've shared intellectual interests. Now they share a lawyer. They're tied together in what colleagues describe as the worst imaginable outcome of a medical experiment: the death of a research subject and a resulting federal investigation.

"This is the kind of catastrophe - the nightmare scenario - that everybody fears will happen in human experimentation," said Jeffrey J. Fredberg, director of the physiology program at the Harvard School of Public Health. "The feeling among many of us is, 'There but for the grace of God go I.'"

The death June 2 of Ellen Roche, a 24-year-old Reisterstown resident, has sent shock waves through Hopkins and out among scientists across the nation. It was the first death of a volunteer in a medical experiment at Hopkins in more than a decade.

The death was especially devastating to the doctors, colleagues say, because Roche worked with them as a lab technician at the Asthma and Allergy Center at the Bayview campus.

Roche was enrolled in a federally funded study overseen by Permutt and Togias into how the lungs of asthmatics and healthy people work differently. After inhaling a chemical, Roche developed a dry cough and flulike symptoms. Her lungs failed during a nearly monthlong hospitalization.

Last week, the federal Food and Drug Administration released a preliminary report that faulted Togias, the principal investigator in the experiment, saying that he neglected to follow several safety requirements.

These included failing to obtain FDA approval for using an unapproved drug and failing to adequately warn his volunteers of the risks. The consent forms signed by Roche and nine others warned of dizziness and temporary coughing, but did not mention any risk of death or say that a chemical used in the experiment was no longer approved as a drug by the FDA.

Medical journals in the 1950s and 1960s linked the chemical, hexamethonium, to rare cases of fatal lung disease. However, more recent articles have reported that inhaling small amounts of the chemical in experiments has not caused problems.

Along with the FDA, the federal Office of Human Research Protection is investigating the death, the cause of which is not yet known.

Daniel A. Kracov, an attorney with the Washington law firm Patton Boggs, said it would be inappropriate for his clients to talk publicly while the death is under investigation.

"They are obviously extremely upset and concerned about the situation, and are concerned about the family of the patient - that has always been their top concern," Kracov said.

Many of their fellow scientists say the suggestions of improper conduct are puzzling because Permutt and Togias have led distinguished careers.

"Here are two very serious, very sensible doctors who have contributed a great deal to science - it is very difficult to understand, and very sad," said Dr. Thomas A. E. Platts-Mills, chief of the asthma division at the University of Virginia.

Permutt was inspired to become a researcher when he was 5 years old, according to a 1994 book, "The Pulmonary Circulation and Gas Exchange," to which Permutt contributed a chapter that is partly biographical.

Permutt's mother took him to see the 1932 movie "Arrowsmith," based on a novel by Sinclair Lewis. The lead character, Dr. Martin Arrowsmith, tests a serum to prevent the spread of bubonic plague in the West Indies. When his wife dies of the plague in a laboratory accident, Arrowsmith denounces experimentation on human subjects. But then his serum proves successful, and he continues his research.

"From the time I saw that movie, I dreamed of becoming a medical scientist like Arrowsmith," Permutt wrote in the 1984 book. "Although the work might be dangerous, it would also be adventurous, and I was willing to take the risks in the same way that a policeman or a fireman does."

As a young student, Permutt became intoxicated by the "beautiful and mysterious" mathematical symbols he saw in books, he wrote.

After attending a year of college at the University of Alabama, Permutt was drafted into the Army in 1943 at the age of 18. The Army helped put him through college and medical school, and he earned his degree from the University of Southern California in 1949.

But he didn't want to treat patients. He wanted to explore the cutting edge of science, according to the book. So he joined the anatomy department at the University of Chicago, studying the substances that lie between cells in the body.

The Army drafted him again in 1953 for the Korean War. While running the tuberculosis ward at the Fitzsimmons Army Hospital in Denver, Permutt became fascinated with the lungs and decided to devote his life to pulmonary medicine.

But then Permutt ran into serious problems. While at the University of Chicago, he'd become involved in left-wing politics at the time Sen. Joseph McCarthy was conducting an inquisition against leftists. "My rather mild political activities, such as supporting friendship with the Soviet Union and China and outlawing the atom bomb, put me into direct conflict with Joe McCarthy and his ilk," he wrote.

During McCarthy's hearings in 1954 on Communists in the Army, the service threw Permutt out, giving him an undesirable discharge, Permutt wrote.

He had trouble finding work because of the taint of the discharge, Permutt noted. But then a former professor at the University of Chicago helped him get a job treating tuberculosis patients at Montefiore Hospital in New York.

Permutt studied the pressurization and elasticity of the lungs as a fellow at Johns Hopkins in 1956. After leaving for a few years, he returned to Baltimore in 1961 to become an associate professor in the Hopkins School of Public Health.

Over the four decades Permutt has worked at Hopkins, he has become well known for his papers - publishing 215 of them - which often challenge conventional theories about how the lungs work, according to his colleagues.

"Dr. Permutt is extremely well known - he has been a leading figure in pulmonary medicine for decades and is very well respected," said Dr. David Proud, a professor of physiology at the University of Calgary and a former colleague of Permutt's at Hopkins.

"He is incredibly enthusiastic - as enthusiastic as a teen-ager sometimes in understanding how things work," said Proud. "That's why he keeps working at an age when some people have retired."

Many scientists are studying the causes of asthma, which has become increasingly common over the past two decades and is now the most frequent cause of hospitalization among American children.

But while several of his colleagues have been studying air pollution as a possible cause for asthma, Permutt has been looking in the opposite direction - into the human body.

He and his partner, Togias, have theorized that the lungs of asthmatics and healthy people respond the same way when they breathe in dust or other irritants. The difference is that asthmatics can't relax their lungs after coughing, suggesting that an underlying cause of the disease might be an impairment of the muscles in the lungs.

Six years ago, Permutt and Togias published a paper in the Journal of Clinical Investigation that supported that theory.

Togias served as one of the volunteers in the 1995 study, inhaling a chemical designed to irritate his lungs. He said the experience opened his eyes to what his patients suffer, according to a New York Times article about the study.

"When you can't breathe, no matter how hard you try, you understand the feelings of anxiety and distress of asthmatics," Togias said. "It certainly gives you more empathy with patients."

The experiment that ended in Roche's death was similar to the 1995 study, but it went a step further by adding a second chemical irritant, hexamethonium.

"The purpose of this study is to find out how the tubes that carry air into the lungs can stay open even when we breathe all types of irritating chemicals," Roche and the other volunteers were told in the consent forms they signed.

In addition to collaborating with Permutt, Togias has also branched out into other areas of study, his fellow researchers say.

For example, Togias is also trying to understand why asthma is more prevalent among poor children than well-off ones. And he's looking into the relationship between allergies and asthma. He's working with the Housing Authority of Baltimore City to determine whether people living in public housing suffer from asthma more frequently because they're allergic to cockroaches living in their apartments.

A resident of Bethesda who speaks five languages, Togias was born in 1957 in Athens, Greece. He received his medical degree from the National and Kapodistrian University Medical School in Athens in 1983, and came to Johns Hopkins as a research fellow that year, according to his resume.

Dr. Robert Naclerio, a mentor to Togias at Hopkins, said Togias came to the United States to pursue opportunities in medical research not possible in his home country. "Even though he comes across as low key, he's very ambitious. He's got a kind of fire in his belly to learn and make discoveries," Naclerio said.

In 1989, Togias won an award from the Hopkins School of Medicine for excellence in postdoctoral clinical sciences. Hopkins named him an instructor in 1989 and promoted him to associate professor in 1996, according to his resume.

"He is a very careful, thoughtful, intelligent guy who has made very important contributions to the understanding of asthma," said Dr. Julian Solway, director of the asthma center at the University of Chicago. "He is not the kind of person who is haphazard in anything he does."

Friends of Togias' say he has been visibly distraught since the death of Roche. Naclerio said he last saw his former student on June 12 at a meeting in Chicago of consultants for the drug manufacturer Merck & Company.

"He seemed devastated to me," said Naclerio. "This type of situation, having a problem and somebody dying, is not part of why we came into medicine.

"It must be running through his mind, why did this situation arise?" Naclerio said. "Everybody is trying to figure it out and how to place blame."

Copyright © 2001, The Baltimore Sun

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