The disease that we now call respiratory distress syndrome of the newborn had many different names in the 1950s, including congenital aspiration pneumonia, asphyxial membrane disease, desquamative anaerosis, congenital alveolar dysplasia, vernix membrane disease, hyaline membrane disease, and hyaline atelectasis. Most doctors today can’t tell you what most of those words even mean. But the esoteric names sprang from the many theories of the syndrome’s cause, masking the unknown in obscure language. Some believed the infants were breathing fluid into the lungs as they passed through the birth canal. Others hypothesized a heart defect, which was causing fluid to back up into the lungs. Another theory proposed that pulmonary circulation was the source of the problem. Unsurprisingly, clinical trials for potential medicines in human subjects all came back negative.
Despite how far the entire field was from solving this problem, a few things were known. Autopsies noted that the alveoli, those small grapelike clusters where gas exchange takes place, were plugged up with dead inflammatory cells and protein waste, which were named hyaline membranes. This material had a slightly transparent, glassy look. The term hyaline membrane came from the Greek word hyalos, meaning “glass or transparent stone such as crystal.” Most scientists focused their research on this phenomenon.
Mary Ellen, now Dr. Avery, deliberately did not focus on hyaline membranes, or any other existing theory, freeing herself from all preconceptions and throwing herself into understanding the basic physiology of the lung. Her approach, like that of most of successful scientists, was to explore the mechanisms underlying a given process and not just to observe the output. She focused on the basic questions of what allowed the lung to expand and contract, over and over and over again, without being ripped apart or collapsing in on itself, on what gave this wonderful organ its resiliency and strength to breathe 20,160 times per day, moving some ten thousand liters of air, while an additional five liters of blood makes its way through the blood vessels of the lungs every minute. The heart is made of compact, strong muscle. The liver is a dense structure of channels and filters. The lung, by contrast, is mostly air. Under a microscope, it has a thin, lacy structure, delicate in appearance. Where its resiliency and strength came from was a mystery.
Dr. Avery studied the respiratory physiology of different animals from birth to a few weeks old, mapping their lung development and characteristics as they emerged into life. Away from the lab, she continued her clinical work at the Boston Lying-In Hospital, overseeing the care of the newborns. Obstetricians would hand the newborn babies to her, and she would start a stopwatch and write down the data as the baby inhaled for the first time, calculating an APGAR score and then taking blood samples. She ran from room to room, her mind on high alert for any clues about these babies’ lungs.
When babies died from mysterious lung illness, Dr. Avery was at their autopsies, going over their pathology, holding on to the slides for the day when she could make more of a connection between them. One thing that caught her attention during these autopsies was how dense with tissue these little baby lungs were, completely airless, resembling the liver more than the lung. They had failed to inflate.
Dr. Avery visited the library at the Massachusetts Institute of Technology (MIT) on weekends, seeking literature from fields outside of medicine, hunting for new ideas from the minds of chemists and mathematicians. On one of these visits she discovered a book by C. V. Boys entitled Soap Bubbles: Their Colours and Forces Which Mould Them.
First published in 1912 for English schoolboys, this slim volume was a primer on the physical properties that govern soap bubbles, filled with simple experiments that document the physical properties of liquids and their interaction with air, explaining how soap bubbles are able to stay intact, miraculously floating through the air. Dr. Avery saw a connection between soap bubbles and the alveoli in our lungs. Circular in shape, and needing to stay open to continue gas exchange, alveoli are governed by the same physical laws as those governing soap bubbles.
The key to soap bubbles staying spherical and not collapsing in on themselves lies in their surface tension. Any spherical structure, like a soap bubble or an alveolus in the lung, is bound by a simple law of physics. Formulated by French scientist Pierre-Simon Laplace and English mathematician Thomas Young in 1805, the law states that the pressure exerted on a circular structure is directly proportional to the surface tension in the sphere, and inversely proportional to the radius of the sphere. Extrapolated out, this means that larger bubbles are more stable and have less pressure on them than smaller bubbles, and they are more likely to stay intact. Similarly, a sphere with lower surface tension is more stable and is under less pressure than one with higher surface tension.
The radius of a sphere is simply the distance from the center of the sphere to any edge. Surface tension, however, is more complicated. At the interface between a liquid and a gas, the molecules in the liquid are more tightly bound together than in other areas of the liquid. For example, in a glass of water the water molecules at the surface are much more crowded together than the molecules in the middle of the glass, because there are no water molecules above them to exert a dispersing force. These tightly bunched water molecules at the surface cause tension, which produces the slight dip one can see at the top of a glass of water.
Different liquids have different tendencies to bunch together at the surface. Water has a relatively high surface tension, so molecules are bunched relatively tightly together at its surface. Consequently, water does not make a good bubble, and exists more easily in drops, like rain drops and drops of water in a sink. But if soap is added to water, the surface tension is dramatically lowered. The ends of soap molecules have different properties: one end attracts water (hydrophilic), and the other one repels water (hydrophobic). When placed in water, the hydrophobic ends of soap molecules push their way to the top, which causes the water molecules to separate from one another, lowering the tension and energy between them. This allows a spherical structure like a soap bubble to stay intact, until it dries out and bursts.
At the same time Dr. Avery was learning about bubbles and surface tension, a number of committed scientists, employed by the federal government at the height of the Cold War, were investigating properties of the lung in reaction to chemical warfare. The lungs are a typical entry point for poisonous gases, and understanding the effects of toxins on the lung and how to combat them was a priority. One of these researchers, Dr. John Clements, at the Army base in Bethesda, Maryland, undertook a series of experiments in the mid 1950s to quantitatively measure surface tension in the lung, which demonstrated that lung tissue had very low surface tension compared to other tissues. He then did something simple, which nobody had ever done: he measured pressure across extracted lung tissue with expansion and contraction. As mentioned, the pressure on a sphere like a soap bubble or a lung alveolus is proportional to its surface tension divided by its radius, and lower pressures will mean the bubble will have a greater chance of not collapsing in on itself. Remarkably, the pressure decreased significantly with lung contraction (as the alveoli in the lung were getting small with contraction, pressure should have increased as the radius decreased), and increased significantly with expansion (as the alveoli got bigger, pressure should have decreased as the radius increased). To explain this, Dr. Clements correctly postulated that something must be overcoming the effect of size on pressure, and the only variable left in Laplace’s equation was surface tension.42
Taking his hypothesis further, Dr. Clements imagined that something within the lung must be lowering surface tension so dramatically as to overcome the effect of size on pressure. He correctly postulated it was a soap-like foam, which exerted a dispersal effect as its molecules became more concentrated and the area became smaller, and lost this effect when the lung expanded and pulled the soap like foam molecules apart. The effect of this soap-like foam lowering surface tension would be more important than lung size in calculating pressure if it was a powerful substance (which it was, and is). John Clements later named this substance surfactant, from its effects on the surface tension.