Lethal Gas Plays Protective Role

New evidence from mouse lung tissue indicates that low levels of carbon monoxide (CO) enhance cell survival in an organ transplant model. The researchers, who reported their findings in the March 20 issue of Proceedings of the National Academy of Sciences, demonstrated that CO activates a variety of regulators of cell survival.

Leo Otterbein, HMS associate professor of surgery at Beth Israel Deaconess Medical Center, is used to skepticism when he describes CO as a therapy. But in low concentrations not used in previous studies, the gas can protect cells from death, Otterbein explained. For instance, in last year’s Sept. 4 Journal of Experimental Medicine, he and colleagues reported that low levels of CO reverse established pulmonary hypertension in rodent models. But the precise cellular targets for the gas remained unclear.

To investigate the targets, the researchers exposed lung macrophages to low concentrations of CO (<0.025 percent), finding that it induced the generation of reactive oxygen species, an inflammatory response signal. This increase appeared within five minutes of CO exposure and disappeared within an hour. “It’s on and off,” said Beek Chin, a toxicologist and HMS instructor in surgery at BID. “It’s the earliest CO signaling event that we know of.”

The team went on to show that a transcription factor activated by reactive oxygen species, hypoxia-inducible factor 1-alpha (HIF-1-alpha), rises in response to CO. Western blot analyses indicated that HIF-1-alpha, which regulates genes related to inflammation and cell survival, increased within 15 minutes of CO exposure. Because HIF-1-alpha regulates the wound healing cytokine TGF-beta, Otterbein and Chin wondered whether TGF-beta was also part of the pathway of CO’s cytoprotective effects. As they predicted, CO upregulated TGF-beta, a result they mimicked with a synthetic CO-releasing molecule.

The researchers then applied their findings to an animal model of organ transplantation, in which macrophages were deprived of oxygen for eight hours, followed by 16 hours of reoxygenation. The regimen killed about 20 percent of the cells. In contrast, only about five percent of cells died when the plate of macrophages was exposed to CO during reoxygenation. Otterbein and his collaborators at Yale University School of Medicine found similar cytoprotective effects of CO in mice. Breathing in CO prior to a temporary occlusion of a blood vessel to the lung protected against cell death. This protection was dependent on the ability of CO to increase HIF-1-alpha and TGF-beta expression.

Clinical trials later this year will evaluate CO use during organ transplantation. The gas could improve organ acceptance and accelerate function once transplanted.

—Molly McElroy

Risk of Asthma Raised By Domestic Violence

HSPH researchers have identified a new risk factor for asthma that seems to be as important as other well-known environmental threats. Domestic violence was associated with an increased risk for the respiratory disorder based on a survey performed in a nationally representative sample of more than 90,000 households in India. The risk posed by domestic violence prevailed even after other well-established asthma risks were held constant. The findings appeared online Feb. 28 in the International Journal of Epidemiology.

Some studies suggest that psychosocial stressors might explain the higher prevalence of asthma among lower socioeconomic groups. S.V. Subramanian, HSPH assistant professor of society, human development, and health; HSPH graduate students Leland Ackerson and Malavika Subramanyam; and Rosalind Wright, HMS assistant professor of medicine at Brigham and Women’s Hospital, used domestic violence as a marker of psychosocial stress and analyzed its relationship with asthma risk from data collected as part of the Indian National Family Health Survey from 1998 to 1999.

Women who were abused within the previous year had a 37 percent increase in their asthma risk. Abuse that occurred over a year before the survey was also linked to greater risk, indicating enduring adverse consequences of domestic violence.

“The magnitude of the risk is right up there with other well-known, well-established risk factors,” said Subramanian, referring, in part, to smoking cigarettes, which the survey found to increase asthma risk by 54 percent. The researchers held other asthma risk factors constant so their risk calculations would reflect an independent association between asthma and domestic violence.

The increased prevalence of asthma among family members exposed to domestic violence was not restricted to victims. All occupants of a household where abuse had occurred within the past year had a 19 percent increased risk. “If you live in a household with a woman being abused, everyone is at risk for asthma,” Subramanian said.

The researchers also estimated the way age alters asthma risk due to domestic violence. They found that children under 5 years old—a critical mark for asthma onset, Subramanian said—had a particularly strong association between asthma and domestic violence, with about a 20 percent increased risk.

Links between asthma and violence have also been identified in the United States and Australia. The field of research linking psychosocial stress and asthma holds some promise for explaining why asthma rates have been increasing in recent years, Subramanian said.

—Molly McElroy

Laureate Tells Tales of Science Coming and Going

A visit to the library, once commonplace, may seem a quaint custom these days. The library now comes to us. Yet something may be left behind—a huge trove of historical writing. “Where our ideas come from has been lost, especially in an age when we don’t read anything that’s not available in digital form on PubMed,” said Christopher A. Walsh, the Bullard professor of neurology at HMS and Beth Israel Deaconess Medical Center.

A recent lecture by the Nobel-prize winning scientist Paul Nurse was intended to change that. The talk, which Walsh introduced, was the first in the new Leaders in Biomedicine series sponsored by the MD–PhD program. Those fortunate enough to find a seat in the packed NRB auditorium on March 15 were treated to a tour of four great ideas in the history of biology—the cell, the gene, evolution by natural selection, and life as chemistry.

A masterful and genial storyteller, Nurse plunged back in time, illustrating each idea with pictures and anecdotes. He attributed the first idea, that of the cell, to the invention of the microscope. The instrument offered up secrets to such naturalists as Robert Hooke who, in 1665, observed fine pores or “cells” in a sliver of cork. Anton van Leeuwenhoek improved the technology. “Soon everybody was looking at cells,” said Nurse, who is president of Rockefeller University.

The middle of that century saw the birth of the second idea, the gene. Nurse gave full credit for the concept to Gregor Mendel. “Unlike most biologists of the day, he took a quantitative approach,” Nurse explained. He also hit upon the right model organism, the sweet pea. And yet Mendel’s “beautiful piece of work”—which was widely circulated, some say even to the great Charles Darwin—was entirely ignored. “Nobody took any notice of it,” Nurse recounted, until the turn of the 20th century.

Darwin’s primary achievement, of course, was to discover the concept of evolution by natural selection. “It’s probably the greatest idea in biology,” said Nurse. Yet the concept of change over long periods of time was something the young Charles learned from his grandfather, Erasmus Darwin. Clearly taken with the elder Darwin, a well-known, if idiosyncratic, physician and naturalist, Nurse described how Erasmus wrote his theories in rhyming couplets and had engraved on his carriage the then blasphemous slogan, “Everything from shells.” “He had to wipe out the motto from his coach after the vicar told rich patients they would be wicked to go to him,” said Nurse.

Antoine Lavoisier, an inventor of the idea that life is chemistry, made an even bigger sacrifice, though not for science. In his day job, Lavoisier was a tax collector for the Ancien Régime—two reasons to be reviled. In 1793, he was guillotined. While alive, he took a special interest in winemaking and proposed that fermentation was the result of a chemical reaction. Louis Pasteur, also a wine aficionado, having shown that bacteria and yeast produced the chemicals required for fermentation, argued that the chemicals were actually necessary for the life of the single-celled organisms.

Though biologists have spent much of the 20th century outlining the chemical reactions going on inside the cell, the time may have come to move on to understanding how individual reactions give rise to complex biological properties, such as sensation, adaptation, reproduction, community, and self-organization. “We need to move beyond simply describing chemical and physical processes,” Nurse asserted. The problem, he said, falls under the rubric of biological organization, a concept that touches on systems biology. “It could make some headway in being a great idea in biology, but I’m not sure.”

For that to happen, biologists might need to learn a new language, that of information processing. “We tend to live in a commonsense world,” Nurse explained. “Twenty-first century biology may have to move into a stranger world, a more abstract realm. Thinking in terms of information processing is certainly worth considering.”

—Misia Landau

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