The Breath of Life
Breathing is not as simple as it might seem. All human beings need lung surfactant, a complex mixture of lipids and proteins, to breathe. This biomaterial reduces the surface tension within the lungs’ air sacs, allowing the quiet inhaling and exhaling of breathing to be effortless.
Roughly 2 million premature infants are born every year without the essential lung surfactant, resulting in respiratory distress syndrome. The lungs cannot inflate. Most of these babies, primarily those in developing countries, die. The more fortunate are helped with an expensive treatment derived from animal protein.
RDS also can occur in adults due to disease or trauma. However, the replacement therapy that is effective with infants evokes an immune response in adults and therefore cannot be used.
When Ka Yee C. Lee, associate professor of chemistry at the University of Chicago, brought the lung surfactant problem to Northwestern assistant professor Annelise Barron’s attention in 1997, Barron realized she knew how to make molecules that had the potential to help infants and adults with RDS.
“Lung surfactant is mostly lipids, but the proteins are critical,” she says. “We now have made a synthetic molecule that behaves like the lung surfactant protein SP-C. This could lead to a therapeutic biomaterial that is safer, more reliable and less expensive to produce than animal-derived materials. Lower cost is especially important in developing countries.”
Once optimized, the novel material also could lead to new drugs for the treatment of other lung diseases, including pneumonia, tuberculosis, asthma and cystic fibrosis.
Using what Barron calls “very clever chemistry,” her collaborator Ronald Zuckerman, a chemist at pharmaceutical giant Chiron Corp., developed a protocol for synthesizing close mimics of natural proteins or peptides. Called peptoids, these synthetic molecules are closely related to the natural molecules they mimic, but they don’t degrade in the body. (The half-life of a natural peptide in the bloodstream is only about nine minutes.)
Barron first learned how to make peptoids while on a postdoctoral fellowship at Chiron in 1996 and later zeroed in on the lung surfactant protein because it was medically important and feasible to imitate.
“I made the supposition that if my students and I could mimic its structure, we could mimic its function,” says Barron. “So far this turns out to be true.” The National Institutes of Health and the National Science Foundation see the promise behind her team’s hypotheses and are backing her lung surfactant studies.
To mimic SP-C, which is a very small protein, Barron and her graduate student Cindy Wu (now at Amgen, a biotechnology company) used the same chemical “backbone” as that found in the natural protein, but they tweaked the sidechain chemistry. Their resulting peptoid has a similar helical structure but one that is extremely stable and therefore doesn’t unfold or degrade like the natural protein.
Barron’s graduate students, who can make a peptoid in about two days, are working on creating a mimic of the other important lung surfactant protein, SP-B, which has a slightly more complicated structure.
Barron is applying her peptoid knowledge to another problem and hoping for similar success. She is making mimics of anti-microbial peptides found in frog skin, proteins that are very potent in killing bacteria but don’t harm mammalian cells.
“If we can make peptoid mimics of anti-microbial peptides, which are nature’s antibiotic, we may have a totally new weapon to fight bacterial infections,” says Barron. — M.F.
wanted to be able to stand on my degree and on my own scruples,” she says. “Playing the sport has given me a grasp of the playing side. I understand what these guys go through in playing some 90 games a year, with all the travel and the demands on their time. If you can speak the speak and show them that respect, they respect you all the more.” — S.H.