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Historical Perspectives: Beyond the First Breath: Hyaline Membrane Disease and Constructing the Neonatal Patient, 1959–1975

2018; American Academy of Pediatrics; Volume: 19; Issue: 11 Linguagem: Inglês

10.1542/neo.19-11-e636

1526-9906

Deniz Cataltepe,

Congenital Diaphragmatic Hernia Studies

How do the lungs of newborns support their first breaths, and why do some infants develop respiratory distress? This crucial research question emerged in the 1950s and was investigated by numerous physicians and scientists, including the American pediatrician Mary Ellen Avery, who devoted her career to the regulation of infant respiration. In a 1964 lecture, Avery drew a distinction between the intrauterine and extrauterine environments stating that "It is clearly at birth that regular rhythmic respiration begins. Something is turned on, something must be different just after birth from the way it was before, and this something must be essential to the regulation of respiration."(1)Although Avery was a physician by training and not a scientist, research played a significant role in her career and led to her prominence as one of the investigational leaders of respiratory distress syndrome, which was known as hyaline membrane disease (HMD) during the time of Avery's research. Avery focused on the role of surfactant, specifically its deficiency in HMD, challenging the accepted view at the time that HMD was caused by an obstruction in the lungs due to the aspiration of hyaline membranes. (2)(3)(4) Avery's act of shifting the understanding of HMD from an obstructive disease to one of a biochemical deficiency was all the more striking given her role as a pediatrician and not a formally trained laboratory scientist. Biographers have estimated that her findings on HMD and their subsequent translation to treatment in the form of surfactant replacement have saved the lives of more than 800,000 infants. (2)The discovery of surfactant deficiency as the cause of HMD in 1959 not only challenged the accepted understanding of the disease at the time, but it also redefined the relationship among multiple medical specialties, including pediatrics, obstetrics, and physiology, as they pertained to the premature infant population. In addition, the research initiative surrounding HMD lay the groundwork for the development of neonatology as a new medical specialty that valued both the clinic and laboratory.Through an investigation of Avery's lectures, correspondence, and published work on HMD, an excerpt from the author's dissertation (5) aims to show that Avery's research on the disease ushered in a new era of newborn medicine, one that was particularly focused on the premature infant. Through her collaborations with physiologists and her physical-chemical approach to a problem that had historically been tackled with a "clinicoanatomic" focus, Avery's research on HMD became the foundation on which the care of the neonatal patient was shaped during the 1960s and 1970s. (6) Moreover, by translating these concepts for clinicians, Avery created a practical role for herself as an "introducer" between fields during the early years of her career as a woman in medicine. The influence of Avery's research on HMD in the neonate culminated in the development of NICUs during this period, which were highly technical spaces in which physicians, physician-scientists, basic scientists, and other medical practitioners held a stake.Leading up to the mid-20th century, both pediatricians and obstetricians focused on clinical care of the newborn. At the Johns Hopkins University School of Medicine and Harvard Medical School, prominent medical centers at which Avery would later train and work, the departments of pediatrics and obstetrics were each tactful in their engagement with research and the types of investigative methods associated with their specialties. The field of pediatrics was becoming increasingly responsible for newborns, a patient population whose care presented an urgency, given the high infant mortality rate in the late 19th-century United States (estimated at 15%-20% in the first year after birth). (7) The involvement of pediatricians in newborn care, as well as the biochemical and basic science expertise they were continually refining, led to the framing of the newborn as a distinct "patient" whose care was provided at children's hospitals through specialized technologies.In 1910, premature birth was found to be the leading cause of infant mortality in the United States, leading to an urgency to investigate diseases in the premature infant. This contributed to a burgeoning infant welfare movement beginning in 1914 that was led by a group of obstetricians including John Whitridge Williams, who was the chief of obstetrics at Johns Hopkins. (7)(8) As the professional reputation of obstetrics was dwindling at this time, Williams put forth a concerted effort to legitimize his specialty by appealing to the necessity of skill in childbirth and placing value on the technical training of obstetricians. (6)(7) Williams was not only concerned with infant welfare as a means of promoting his professional ambitions for obstetrics in the early 20th century, he was also interested in the type of research being conducted on pregnancy. In 1919, Williams was elected chairman of the Johns Hopkins' Department of Obstetrics, which was the first of its kind in the country. He championed research in obstetrical and gynecological pathology while also encouraging "the use of other approaches and laboratory methods, especially physiology and chemistry."(8) The pathological studies being conducted by the gynecological-obstetrical staff at Johns Hopkins reflected the clinicoanatomical approach to research, in which observations and materials gathered in the clinic were correlated to anatomical findings. (6)(8) Williams encouraged exploration of the "biological and biochemical aspects of pregnancy," which he found were insufficiently investigated and thus stunting the advancement of obstetrical knowledge. (8) The Department of Obstetrics and Gynecology at Harvard Medical School practiced a similar, highly technical approach to obstetrical training during the 1910s and 1920s. (9)Although Williams was unable to launch a physical-chemical approach in obstetrical research during the early 20th century, his pediatric colleagues at Johns Hopkins were able to find more success in their biochemical endeavors. In 1912, the first chair of the department of pediatrics, John Howland, arrived at Johns Hopkins and was credited with reforming pediatrics by "substituting bedside observation and conjecture" for the "study of disease through laboratory methods and experiments."(8) Biochemistry was thought to have flourished for the 15 years following Howland's appointment, a period in which he strengthened the relationship between this scientific discipline and pediatrics and changed the culture of Johns Hopkins' Department of Pediatrics. (8) Students and physicians who passed through Howland's department were almost always "drawn into [his] vortex of biochemical research."(8) The network of physicians moving between Johns Hopkins and Harvard Medical School in the early 20th century transferred and perpetuated the strong relationship between biochemistry and pediatrics, leading to a linkage of clinical practice and physical-chemical research methods that was unable to be attained in obstetrics.While pediatricians were investigating the chemical mechanisms of disease in the early 20th century, they were also devoting increased attention to the clinical care of the newborn. A particularly notable development in the first half of the 20th century between pediatrics and the care of newborns was at the Sarah Morris Children's Hospital in Chicago, where the pediatrician Julian Hess used technology and specialized staff to craft a specific space within the hospital for this patient population. (10) Hess was well known for designing the "Hess incubator," which shared features with an oxygen chamber and was used to create an artificial environment and deliver oxygen therapy to premature infants. (11) He was also renowned for his book, The Premature Infant: Its Medical and Nursing Care, first published in 1941. Hess prioritized the role of the nursing staff in the premature infant nursery; Evelyn Lundeen, his nursing director, was the coauthor of the book. (10)(11) In the preface, Hess and Lundeen wrote that "Since it is our conviction that untiring, unremitting care has no substitute in the care of the premature infant, we have deemed it essential to give equal prominence to the role of the nurse," highlighting the significant value they placed in local, skill-based clinical knowledge in the care of this patient population. (10)By completing medical school and her pediatrics residency at Johns Hopkins before heading to Harvard Medical School for a fellowship in the late 1950s, Avery would become both a product and perpetuator of the interdisciplinary transfer of knowledge between basic sciences in the laboratory and clinical practice in the hospital. She commented that, during her medical school years, the encouraging environment and value placed on research at Johns Hopkins helped her realize the potential to conduct clinical and "bench to bedside" research throughout her career. (12) Compounded with the need for more specialized, interdisciplinary care for newborns, this interface between the laboratory and clinic would lay the grounds for the fruitful collaboration that would emerge in the mid-20th century.Avery's curiosity about infant respiration and research on HMD was made possible by a wide-ranging network, encompassing pediatricians, obstetricians, physiologists, and other medical professionals, which focused on respiratory mechanics in the mid-20th century. Her interest in the lung arose from her personal experience with illness; in the early 1950s, after graduating from Johns Hopkins Medical School, Avery contracted tuberculosis. During her 2-year bout of illness, she grew intensely curious about the physiology of the lung, and HMD caught her attention. (2) She was inspired by the book Physiology of the Newborn Infant by the Harvard pediatrician Clement A. Smith, which covered newborn development and adaptations at birth as well as their effects on the establishment of regular respiratory processes. (9)(13) Avery would later train under Smith during her fellowship at Harvard Medical School, adapting his approach of combining pediatrics, physiology, and basic science endeavors to investigate breathing in newborns.In 1957, Avery moved to Boston to undertake a fellowship at Harvard Medical School that was funded by the National Institutes of Health (NIH) and joined the research laboratory of Jeremiah Mead, Professor of Environmental Physiology at the Harvard School of Public Health. (1)(4)(14)(15) His laboratory had recently discovered that the surface forces of the lung were responsible for its elastic recoil, which led them to calculate a new value for the lung's surface area. (4)(16) In 1959, Avery and Mead published an article entitled "Surface properties in relation to atelectasis and hyaline membrane disease," which demonstrated surfactant deficiency to be the cause of HMD. (17) The article was published in the American Journal of Diseases of Children because Richard Day—then chairman of pediatrics at the University of Pittsburgh and Avery's friend of many years—was the editor of the journal and was excited about the connection between surface tension and lung function. He personally asked Avery to publish the article in his journal even though it had a significant physical-chemical focus and clinical research methodology was lacking. (12)Avery's collaboration with Mead built on the work of pioneer physiologists such as the Swiss physician Fritz Rohrer, who, beginning in 1915, developed quantitative measurements for use in various areas of respiratory mechanics. (18) In the 1940s, Sir Joseph Barcroft, a British physiologist, advanced the understanding of the fetus' transition from "placental to pulmonary respiration."(6) In addition, Avery was inspired by the body of work conducted by Wallace Fenn, Hermann Rahn, and Arthur Otis at the University of Rochester between 1941 and 1956. (18)(19)(20) Although it was not their initial area of interest, these 3 Rochester physiologists were motivated to study respiratory issues because of the use of chemical gases during wartime. They undertook studies that elucidated the mechanisms behind pulmonary gas exchange; the effects of altitude, hyperventilation, and pressure breathing; and identified the relationship between pressure and volume as they related to the lung and chest wall. (21) In a lecture entitled "First Breath," which she delivered in 1959, Avery commented on the work of these physiologists and others, noting that their efforts "had an impact on pediatrics in recent years as those concerned with resuscitation of newborn infants have become aware of the concepts and tools recently applied." She explained that "Paralleling the intellectual revolution in respiratory physiology and the technological advances, pediatricians interested in newborn infants and pathologists have become aware of the frequency of respiratory failure as a cause of neonatal death." (19) This respiratory failure became a research interest for medical practitioners with a range of backgrounds.The concept of research collaborations across the demarcations of medical specialties was becoming commonplace during the time of Avery's work, with neonatal centers being generously funded by sources including the NIH, the March of Dimes, and the Robert Wood Johnson Foundation. (22) This shift in investigational approaches to neonatal diseases was made possible by what Avery described as "the changing status of medical investigation in this country" in the preface to her 1964 monograph on the newborn lung, The Lung and its Disorders in the Newborn Infant. (15) Avery implied that the research of her predecessors was stringently regulated by the objectives of their preexisting research programs or clinical practices. In contrast, Avery felt that she was not bound to any such research agenda: "I have been relatively free to pursue investigations as they seemed appropriate, and to read at length, with only as many clinical and teaching responsibilities as were important to stimulate the investigative ones."(15)Avery's inclination to follow diverse research leads during her time at Harvard was exemplified by her visit in 1957 to John Clements' laboratory at the Edgewood Arsenal in Maryland—an army research facility focused on basic sciences. The immediate impetus for Clements' research was the Soviet threat of using chemical weapons, which led to the military's studies on how nerve gases affect the human lung. Before Avery joined the Mead laboratory, Clements had heard of the group's findings on calculated lung surface area and was inspired to investigate surface tension in the lungs as well as the material that he believed maintained low surface tension in the alveoli. (4)(23) In addition to Clements, Avery carefully followed the work of Richard Pattle, a researcher at the Chemical Defense Establishment in England who, like Clements, based his investigations on gases used in war and their impact on the human lung. (4) While studying pulmonary edema, Pattle found that the healthy lung contained particularly stable "bubbles," leading him to the conclusion that the lung's internal surface was covered with a substance that had low surface tension. (4)(24) Clements used Pattle's findings in the mid-1950s and integrated them with the Mead group's calculation of lung surface area to determine the surface tension of the substance, which he ultimately termed surfactant. (4)(25) This back and forth among Clements, Pattle, and Avery and Mead crossed the borders between science aimed at biomedical cures and military research. Furthermore, it shaped the language used by the medical community when discussing surfactant and its vital role in HMD.As Avery continued to adopt methodology and scientific insight from respiratory physiologists in the late 1950s, she also embraced their language and style of explaining experimental results. The physical-chemical method strongly influenced the ways in which she would present her work and the body of literature on lung surface tension, surfactant, and HMD to medical audiences. Delivering a talk in New Haven in April 1959, only 1 month ahead of her publication with Mead on the relation of surface properties of the lung to HMD, Avery concentrated on the subject of surface forces and included figures, such as pressure-volume curves, as well as multiple references to the Laplace equation to illustrate the relationship between surface tension and inflation of the alveoli. Although her notes were heavily grounded in basic science, Avery was careful to make periodic allusions to the subject matter's relevance to pediatrics and to remind herself to "translate" the topic for her audience of pediatricians. (26) While Avery's multiple connections between the physical-chemical presentation of her topic and the field of pediatrics might have served to bolster the audience's interest in her talk, it also demonstrated how pediatric medicine had gained a foothold in the 1950s as the medical specialty that held the most authority over the respiratory physiology of the neonate.To isolate the factors that led to Avery's success in her research and the ultimate discovery of surfactant deficiency as the cause of HMD, one can look to Ian Donald, the Scottish obstetrician who initiated the use of diagnostic ultrasonography in the mid-1950s. (6) Although Donald's use of ultrasound technology was an important contribution to newborn medicine, his earlier work on tackling the breathing difficulties of neonates was less successful. During his time at the Department of Obstetrics at St Thomas' Hospital in London, Donald worked with Maureen Young, a protégé of the physiologist Sir Joseph Barcroft. Eventually, they developed an "automatic respiratory amplifier," which was designed to inflate the lungs by following the natural rhythm of the infant's breathing. The amplifier served as Donald's first major contribution to the field of respiratory physiology as a clinician-scientist, priming his subsequent ventures into neonatal respiratory distress and HMD. (6)Donald's focus on HMD began in the early 1950s, after he joined the staff of the Royal Postgraduate Medical School at Hammersmith Hospital. Donald collaborated with Albert Claireaux, a pathologist at Hammersmith whose histologic observations of HMD helped elucidate its cellular pathology. (6) At the time, it was only possible to diagnose HMD on postmortem examination because the symptom of respiratory distress could also be related to primary atelectasis, among other causes. Ahead of his ultrasound investigations, Donald used his curiosity with medical imaging, specifically radiography, to test whether there were anatomic changes in the lungs of neonates that corresponded to the development of HMD. It was ultimately the lack of collaborations with those trained in biochemistry and physiology that caused Donald's research on HMD to be futile. Nonetheless, he and Claireaux concluded that a certain "mottling" of the lungs, distinguishable on radiographic imaging, correlated with the initial phases of HMD. (6)The network of neonatal clinicians and researchers that emerged during the 1950s, which has been charted by Rachel McAdams, illustrates a web of collaborators that all shared a basic interest or formal training in pediatric medicine. (27) As Nicolson and Fleming assert in their textbook on ultrasonography, "The time when an obstetrician, working in the clinic, could provide leadership in the treatment of sick babies was rapidly passing."(6) In the context of research on neonatal respiratory distress in the 1950s, flexibility in methodology and collaboration across disciplines, which pediatricians were practicing, was as important as the research question being posed. While Donald took a clinico-anatomic approach to his studies, Avery's physical-chemical method, which was inspired by military scientists as well as classically trained physiologists, focused her interests on the inner workings of the lung. She transformed the clinician's understanding of this organ into an amalgamation of physical properties, allowing "surface tension," "surface area," and "elastic recoil" to become common terms shared with the audiences of her lectures and readers of her articles.Just as the 1950s witnessed the development of a tightly knit neonatal network, the type of language used by this network changed in parallel. Avery recognized the need for a common language and clear communication between the different medical practitioners involved in this network, and appeared willing to fill the role of translator among the various groups. In the 1960 Ross Conference on Pediatric Research, she delivered a talk on the relationship between pulmonary mechanics and infant age and size. Commenting on the frequent partnership between pediatricians and physiologists that characterized research on neonatal respiration at the time, she asserted that:Avery positioned physiologists as having much to learn from pediatrics as far as their interest in neonatal respiration was concerned. Her explicit reference to pulmonary mechanics and their relation to the growing newborn as being the "reason-to-be" of pediatric medicine placed the research topic squarely within the jurisdiction of pediatrics, with physiology providing the necessary methodologic assistance for investigations. As a female physician and researcher in the 1950s and 1960s, Avery had to navigate a male-dominated field in a tactful way for her voice and work to be granted attention. As she explained, "It's been the pattern of my life to go ferret out people who are smarter than I am, and then sit around and learn what they have to say, and put it together." In the case of her work on surfactant deficiency, Avery prided herself on being "the glue for all of this," asserting that "the ideas were all there waiting to be glued together. I think of it as analogous to a jigsaw puzzle [...]." (12) Although serving as the glue required a substantial amount of explanatory labor on Avery's part, taking on this role at medical conferences and through collaborations in her work allowed for networking and professional growth as a young female physician at this time.Apart from shaping the direction and output of Avery's research, the neonatal research network also enabled the refinement of the clinical subject of its research projects: the neonatal patient. Despite its later prominence, it was initially difficult to convince the medical community of the findings in Avery and Mead's 1959 article that declared the association between surfactant deficiency and HMD. Their results represented a marked departure from the view at the time of HMD as an obstructive disease caused by the presence of membranes in the airways. Thus, there was a hesitation to affirm that the article demonstrated a cause-and-effect relationship between surfactant deficiency and HMD. (4)(12)(17) As word of Avery's findings spread during the 1960s, she was proactive in conducting follow-up studies to definitively draw the line between the surfactant system and its necessity in maintaining homeostasis in the lung. At the same time, she traveled across the world delivering lectures to convince the scientific community of the validity of her research. (4) These roles catapulted her to the forefront of the emerging field of newborn medicine, consisting of "clinicians, clinician-scientists, and basic scientists."(4) Moreover, her ability to serve as an introducer and translate specialized knowledge between these different groups added value to her professional reputation. With increasing recognition of Avery as a leading expert in HMD, or as it was increasingly beginning to be known, "respiratory distress syndrome," she played a role in shaping new understandings of the neonatal patient. As this modification of the neonate took place during the 1960s and 1970s, the field of neonatology and its practitioner, the neonatologist, was born. (27)Between 1960 and 1966, Avery participated in a number of conferences and informal colloquia organized around pediatric research topics as well as those in adult medicine and professional development. Avery was asked to introduce the topic of "Mechanics of Respiration" at the 37th Ross Conference on Pediatric Research in 1960, only 1 year after publication of her widely cited article with Mead. During these conferences, the Ross Laboratories of Columbus, OH, sought to shift the relationship between the pharmaceutical industry and the medical community by "assist[ing] in the correlation of the latest information from research on subjects of general interest in the practice of pediatrics, and to stimulate further research by the exchange of information."(29) The Ross Laboratories' lack of a personal stake in the conference topics allowed the academic medical centers to mold the direction of the talks, and, in turn, the larger trends in pediatric medicine at the time.In 1959, 2 months after Avery's publication, an "informal discussion" on the proper name for HMD took place among participants at the IX International Congress of Pediatrics in Montreal, Canada. Clement A. Smith, the physician with whom Avery had worked during her NIH fellowship in Boston, was one of the chairs of the discussion. Despite being in attendance, as well as having her name and work on surfactant referenced several times, Avery did not voice her opinions during the discussion. This was likely because she was 1 of only 7 women in a room of 35 physicians and did not want to speak out of turn as a junior physician, despite her expertise. (30) Ultimately, "idiopathic respiratory distress of the newborn" was the frontrunner classification after the physicians voted.In 1963, Avery used the term pulmonary distress syndrome at the "Advanced Seminar in Pediatrics: Fetus, Premature, and Newborn Infant" conference that was hosted by the University of California, Los Angeles (UCLA) School of Medicine. (31) Her terminology removed the "newborn" designation while retaining the term "distress"—2 decisions that subtly shifted the disease away from being understood as applicable to all newborns, as well as assigning "distress" to the patient it affected. The UCLA conference was also significant for its explicit reference to the distinction between fetuses, premature newborns, and term newborns, placing these patients on a differentiated, chronologic timeline of development. Although the conference predated the politics behind defining fetal personhood, it presented the fetus as a discrete phase of development and separated the schedule of talks into the following categories: "Maternal-Fetal Relationships," "Normal Newborn Physiology," "Diseases of the Newborn Prematurity," and "Diseases of the Newborn." (31)(32)Avery also participated in the National Institute of Child Health and Human Development's "Interdisciplinary Conference on Neonatal Respiratory Adaptation" in 1963. This conference brought together pediatricians, obstetricians, physiologists, and other researchers to discuss intrauterine events, the transition from intrauterine to extrauterine life, and postnatal adaptations. (33) Avery's mentor during her Boston fellowship, Clement A. Smith, was the discussion leader for the "Postdelivery Adaptation and Maladaptation" session, and asked her to contribute to the session by "starting off from [her] analogies with space medicine as gravitational changes affect the movement of water in the body." (34) The space medicine analogies that Smith referred to were part of a prior talk in which Avery had declared that "we who are concerned with newborn infants have much to learn from space research" due to the need to "ponder hydrostatic mechanisms in the lung and their role in the formation of atelectasis and edema, to relate oxygen toxicity to the duration of exposure and to the Po2 in the blood, [and] to worry about perceptual deprivation" that existed in both lines of work. (35)(36) In asking Avery to use this analogy again, Smith spoke to the success of the analogy in inciting audience interest.Avery's reputation extended beyond the medical community; in 1963, Patrick Bouvier Kennedy was born 5½ weeks premature to President John F. Kennedy and Jacqueline Kennedy Onassis. Kennedy lived for only 39 hours after delivery and, for the majority of lay people, he was their first encounter with HMD. Following the news of Kennedy's premature birth, Avery was consulted by journalists across the country. (37)(38) She explained that "the respiratory disease hyaline membrane usually increases in severity over the first 24 to 48 hours, then either leads to death or gradual recovery," thereby providing an expert opinion on the Kennedy infant's prognosis. (38) Although Avery took the opportunity to assert the severity and significance of HMD, she was surprisingly wary of citing findings from her own research that linked the cause of HMD to surfactant deficiency.One space in which Avery had complete control over the presentation of the neonate was in her monograph, The Lung and its Disorders in the Newborn Infant. The first edition of the book was published in 1964 while Avery was an assistant professor at Johns Hopkins. By this point, the pediatrician Alexander Schaffer—who wrote the foreword for Avery's book and was also the consulting editor—had already coined the terms "neonatology" and "neonatologist." (15)(27) His definition deemed neonatology to be the specialty that "designates the art and science of diagnosis and treatment of disorders of the newborn infant," a description that Avery's book clearly matched, specifically through its investigation of matters related to the lung. (39)The late 1960s to mid-1970s also led to the creation of physical spaces in hospitals that further demarcated the neonatal patient population. The concept of a space dedicated to the interprofessional care of newborns was not necessarily new; Julian Hess had previously constructed a premature infant nursery in 1922 at Sarah Morris Children's Hospital in Chicago. The nursery was renowned for its 28 incubators, which were considered to be the most sophisticated of their kind, as well as its integration of nurses in the care of the premature infants. (11) By relabeling the premature infant nurseries as "intensive care" units, hospitals conveyed the idea that they placed a significant value on the neonatal patient and the type of clinical work that was being done in these units. As the neonatal patient population became more clearly defined, the neonates received care "based on age and unique medical needs rather than diagnosis." (40) The expansion of NICUs in the United States aligns with the increased research interest and efforts directed at HMD. With their abundance of ventilators to provide oxygen support as well as other highly technical medical equipment, these NICUs became areas for the treatment of neonates whose specialized needs were being defined in tandem with the development of new research and medical therapies. (40)Between 1974 and 1985, Avery served as the first female physician-in-chief of Boston Children's Hospital. (14) As a pediatrician and researcher, Avery focused on the neonatal patient population in her work, and as she rose to prominence for her findings, she reinforced the placement of the care of this patient within the realm of pediatrics. Avery was never deemed a neonatologist, because the specialty did not officially exist until 1975, when the American Board of Pediatrics created the Subspecialty Board of Neonatology. Her work on HMD, coupled with the new technological advances in hospital-based medicine in the late 20th century including prenatal diagnostic techniques such as amniocentesis and fetal ultrasonography, framed newborns as distinct, vulnerable patients in need of hospital-based care, and whose diseases ought to be subject to biomedical investigations. The refinement of this patient population in the United States during the early 1960s gave way to the creation of a new space for premature and ill full-term newborns: the NICU. (41)Avery's frequent collaborations with physiologists and basic science researchers perpetuated a culture of interdisciplinary collaboration within newborn medicine, a culture that was instrumental in "biomedicalizing" the care of neonates. As a young female physician, Avery operated within her professional settings in a unique way that allowed her to make an impact without challenging senior physicians, which facilitated her contributions to neonatology and respiratory physiology. By being involved in a number of steps in the research process—from studying minced lungs to being present for a newborn's first breath in the delivery room—Avery integrated the work being done in the laboratory with that being done in the clinic. (12) She shared her insights with medical audiences at conferences, framing her role as that of a translator between both pediatricians and physiologists, as well as between those who practiced the physical-chemical methods of investigation and others who preferred the more traditional, clinicoanatomic ones. Mary Ellen Avery's research in HMD made her a well-known figure in medicine, facilitating her contributions to the development of the clinical field of neonatology and the critical practice of applying basic science research to the patient.I wish to thank my dissertation supervisor, Dr. Salim Al-Gailani, for his insight and help with my research and writing processes, especially for guiding me through 20th-century histories of pregnancy and infant care and providing invaluable feedback on my work.