IN MEMORY OF MARY ELLEN AVERY

Topic Editor John Steven Torday

PEDIATRICS FRONTIERS COPYRIGHT STATEMENT ABOUT FRONTIERS © Copyright 2007-2014 Frontiers is more than just an open-access publisher of scholarly articles: it is a pioneering Frontiers Media SA. All rights reserved. approach to the world of academia, radically improving the way scholarly research is managed. All content included on this site, such as The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share text, graphics, logos, button icons, images, and generate knowledge. Frontiers provides immediate and permanent online open access to all video/audio clips, downloads, data compilations and software, is the property its publications, but this alone is not enough to realize our grand goals. of or is licensed to Frontiers Media SA (“Frontiers”) or its licensees and/or subcontractors. The copyright in the text of individual articles is the property of their FRONTIERS JOURNAL SERIES respective authors, subject to a license granted to Frontiers. The Frontiers Journal Series is a multi-tier and interdisciplinary set of open-access, online The compilation of articles constituting journals, promising a paradigm shift from the current review, selection and dissemination this e-book, wherever published, as well as the compilation of all other content on processes in academic publishing. this site, is the exclusive property of All Frontiers journals are driven by researchers for researchers; therefore, they constitute a service Frontiers. For the conditions for downloading and copying of e-books from to the scholarly community. At the same time, the Frontiers Journal Series operates on a revo- Frontiers’ website, please see the Terms lutionary invention, the tiered publishing system, initially addressing specific communities of for Website Use. If purchasing Frontiers e-books from other websites or sources, scholars, and gradually climbing up to broader public understanding, thus serving the interests the conditions of the website concerned of the lay society, too. apply. Images and graphics not forming part of user-contributed materials may not be downloaded or copied without permission. DEDICATION TO QUALITY Individual articles may be downloaded Each Frontiers article is a landmark of the highest quality, thanks to genuinely collaborative interac- and reproduced in accordance with the principles of the CC-BY licence subject to tions between authors and review editors, who include some of the world’s best academicians. any copyright or other notices. They may Research must be certified by peers before entering a stream of knowledge that may eventually not be re-sold as an e-book. reach the public - and shape society; therefore, Frontiers only applies the most rigorous and As author or other contributor you grant a CC-BY licence to others to reproduce unbiased reviews. your articles, including any graphics and Frontiers revolutionizes research publishing by freely delivering the most outstanding research, third-party materials supplied by you, in accordance with the Conditions for evaluated with no bias from both the academic and social point of view. Website Use and subject to any copyright By applying the most advanced information technologies, Frontiers is catapulting scholarly notices which you include in connection with your articles and materials. publishing into a new generation. All copyright, and all rights therein, are protected by national and international copyright laws. The above represents a summary only. WHAT ARE FRONTIERS RESEARCH TOPICS? For the full conditions see the Conditions Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are for Authors and the Conditions for Website Use. collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot ISSN 1664-8714 research area! ISBN 978-2-88919-363-9 Find out more on how to host your own Frontiers Research Topic or contribute to one as an DOI 10.3389/978-2-88919-363-9 author by contacting the Frontiers Editorial Office: [email protected]

Frontiers in Pediatrics December 2014 | In Memory of Mary Ellen Avery | 1 IN MEMORY OF MARY ELLEN AVERY

Topic Editor: John Steven Torday, University of California- Los Angeles, USA

Image taken from Stark, A. R. My tribute to Mary Ellen Avery. Frontiers in Pediatrics (2014) doi: 10.3389/fped.2014.00050.

Mary Ellen Avery was the driving force behind the discipline of Neonatology. She fought against convention when she published her ground-breaking paper in 1959 showing that Hyaline Membrane Disease was caused by lung surfactant deficiency. Up until then it was thought to be an due to amniotic fluid aspiration, as suggested by Hoccheim in 1903. She encouraged her students to think out of the box, as long as we were studying ‘something that you couldn’t live without’. In addition to being a great clinician-researcher she was a mentor. The article is by her former students writing about their personal experiences under the tutelage of Mel Avery.

Frontiers in Pediatrics December 2014 | In Memory of Mary Ellen Avery | 2 Table of Contents

04 Mary Ellen Avery’s Research Career – Remembrance of Things Past John Steven Torday 08 Mel – Personal Reminiscence H. William Taeusch 10 My Tribute to Mary Ellen Avery Ann R. Stark 12 My Personal Tribute to Dr. Mary Ellen Avery Ilene R. S. Sosenko 13 “PADding” My Career with Dr. Mary Ellen Avery Heber C. Nielsen 15 My Tribute to Mary Ellen Avery John Steven Torday 17 How Mary Ellen Avery Influenced My Career as an Investigator Cynthia Frances Bearer 19 Mel Avery: Mentor, Role Model, Friend, Mother of Us all Mary E. Sunday 22 In Remembrance of Dr. Mary Ellen Avery Joanna Floros 23 A Remembrance of Mary Ellen Avery, M.D. Julie R. Ingelfinger

Frontiers in Pediatrics December 2014 | In Memory of Mary Ellen Avery | 3 MINI REVIEW ARTICLE published: 28 April 2014 PEDIATRICS doi: 10.3389/fped.2014.00034 Mary Ellen Avery’s research career – remembrance of things past

John StevenTorday*

Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA

Edited by: Mary Ellen Avery’s research is recognized as a milestone in biomedical research. She had David Warburton, Children’s Hospital discovered the underlying cause of hyaline membrane disease, surfactant deficiency, fos- Los Angeles, USA tering ever more vigorous efforts to reduce neonatal mortality in the burgeoning practice Reviewed by: David Warburton, Children’s Hospital of Neonatology. Neonatology is the only clinical discipline that began as an experiment, Los Angeles, USA making it a model for biomedical research. Avery knew that the concerted effort to treat Megan Jane Wallace, Monash preterm newborns could potentially do more harm than good, violating her oath to Hip- University, Australia pocrates, if not held to the highest scientific standards. She remained true to that pledge Martin Post, The Hospital for Sick Children, Canada throughout her career, as recounted in this Review. *Correspondence: Keywords: Mary Ellen Avery, lung surfactant, respiratory distress syndrome, evidence-based medicine, leadership John Steven Torday, Department of Pediatrics/Neonatology, University of California Los Angeles, 1124 West Carson Street, Torrance, CA, USA e-mail: [email protected]

INTRODUCTION in conjunction with a Fellowship to study newborn infants with I feel like the narrator recounting his tale at the wedding banquet Clement Smith at the Boston Lying-In Hospital. in Coleridge’s epic poem “The Rime of the Ancient Mariner.” Of Mead’s laboratory had discovered that if the lung was filled course anyone can go to PubMed and retrieve Mary Ellen Avery’s with air it had greater elastic recoil than if it were filled with saline, publications, totaling 146 peer-reviewed papers, but the back story leading to the realization that the surface forces of the lung, which is what I am going to relate, largely based on my personal recall are greater at an air–liquid interface than at a liquid–liquid inter- under her tutelage for 25 years. face, caused the elastic recoil of the lung. Mead’s group used these Her interest in the breathing problems of newborn infants had observations to calculate lung surface area,which differed substan- been piqued by the awareness that the most common finding in tially from that estimated by the morphologists. That observation the lungs of premature infants born alive who died shortly there- prompted Clements to measure the surface tension of material after, was atelectasis and hyaline membranes. The pathology had expressed from the lung. Clements, tried to reconcile the Mead been well-described by both George Anderson and Peter Gru- laboratory data with Pattle’s findings of stable bubbles expressed enwald at Johns Hopkins. They both emphasized the lack of a from lungs having zero surface tension. Whittenberger at the Har- clinical description of the course of the disease. In 1947, Gruen- vard School of Public Health, a research advisor to Clements at wald (1) described the unusual expansion patterns of the lungs of Edgewood Arsenal, Maryland communicated Clements’ findings premature infants. He hypothesized that an unusually high surface to Mead and Avery back in Boston. Clements had reasoned that a tension could account for the high pressure necessary to introduce dynamic method of measurement of surface tension would better air into the lungs, but also that air was trapped in the lungs in a reflect conditions in the lung, so he designed a modified Wil- Swiss cheese-like pattern, as predicted by the Law of LaPlace. helmy surface film balance to study changes in surface tension with Richard Pattle (2) was studying the foam of pulmonary edema area. His striking observation established the important feature of in the Chemical Defense Establishment in Porton, England, since the alveolar lining layer, namely a change in surface tension with some gases used in wartime such as phosgene induce lung edema, area, so that at large lung volumes surface tension is high, and at so antidotes were being sought. The unusual stability of bubbles low lung volumes it approaches zero. He named the material pre- expressed from normal lungs led Pattle to conclude that the inter- sumed to be at the alveolar–air interface “pulmonary surfactant,” nal surface of the lung must be covered with a lining layer of very and commented on its central role as an anti-atelectatic factor. low surface tension. He suggested that absence of the lining sub- Avery visited Clements’ lab at the Edgewood Arsenal in Decem- stance of the alveoli might play a role in causing atelectasis. The ber, 1957 to see the surface film balance. On her return to Boston, appearance of hyaline membranes might be due to a defective Mead proposed a way to modify the method to allow them to study lining layer causing transudation from the blood, or to excessive minced extracts from lungs of human infants. Samples of lungs secretion of the lining substance itself. were obtained courtesy of Kurt Benirshke, the chief of pathol- Dr. Avery had completed her pediatric residency at Johns Hop- ogy at the Boston Lying-In Hospital at that time. The absence of kins in the 1950s, so she went off to Boston to study respiratory foam in the lungs at autopsy was a prominent observation that physiology at the Harvard School of Public Health with Jere Mead, might have led to the conclusion that these lungs were deficient

www.frontiersin.org April 2014 | Volume 2 | Article 34 | 4 Torday Mary Ellen Avery’s research career

FIGURE 1 |The Joint Program in Neonatology (JPN), 1984, in front of the 1974, gathered for a group picture with her in front of the administration Administration Building (Building C), Harvard Medical School. In 1984, on building at Harvard Medical School. Those in attendance were clinicians, the 25th anniversary of the publication of the Avery and Mead paper, clinician-scientists, and basic scientists alike as the embodiment of Dr. members of the Joint Program in Neonatology, which Dr. Avery had created in Avery’s eternal effort “to do no harm.” in surfactant even in the absence of measurements on the sur- RESPIRATORY DISTRESS SYNDROME AS SURFACTANT face film balance. The first measurements were made before Pattle DEFICIENCY – EVIDENCE-BASED MEDICINE had published his observations in 1958. His finding that the bub- The first four peer-reviewed papers Avery published were case bles expressed from lungs of immature guinea pigs were unstable reports, beginning in 1955 (4). But then there was that watershed reassured Avery that she was on the right track in her stud- year of 1959 when she and Jere Mead published their ground- ies of the lungs of infants who had died of hyaline membrane breaking paper on HMD as surfactant deficiency (5). She would disease (HMD). tell her students how difficult it was to publish this manuscript There were multiple theories for the pathogenesis of HMD because it went against convention – Hochheim had declared that when Avery began her study of lung surfactant. In the first edi- HMD was an obstructive disease due to the eosinophilic mem- tion of her book The Lung and its Disorders in the Newborn Infant branes found in the airways of the newborns who had died of this (3), she objectively presented what was known at the time, and, disease. But Avery was aware of the studies done by Von Neergaard although she presented observations on the possible role of surface and Pattle, showing that there was surface tension reducing activ- forces, she admitted that the etiology of HMD was unknown. She ity in the alveoli of the mammalian lung. She reasoned that if these recapped the arguments for the primacy of aspiration, asphyxia, infants were surfactant deficient that that would have accounted heart failure, shock, disturbed autonomic regulation, fibrinolytic for the atelectasis and exudation of fluid across the alveolar wall, enzyme defect,prolonged acid–base derangements,and low serum producing the hyaline membranes. If she was right, there was an proteins. Over the ensuing years these variables have been elim- opportunity to correct the disease, in contrast to the assumed inated one by one, bringing ever-greater clarity to the ultimate intrauterine obstructive mechanism associated with HMD. From role of surfactant deficiency. The first time Avery unequivocally that point forward Dr. Avery published another 141 papers, but of stated that HMD was due to surfactant deficiency was in the fourth those there were 26 that would plot her arc as the clinician-scientist edition of her textbook in 1981. who conquered HMD. I would like to recount those studies within

Frontiers in Pediatrics | Neonatology April 2014 | Volume 2 | Article 34 | 5 Torday Mary Ellen Avery’s research career

the context of Dr. Avery’s effort to validate HMD as Respiratory as the first woman ever to have become the Chair of a clinical Distress Syndrome, or surfactant deficiency disease. In early stud- department at Harvard Medical School. When she was applying ies excised lungs of human newborns were used (6) in tandem to medical school she was rejected by Harvard Medical School with animal models to establish the relationship between surfac- because of their policy of excluding women – always the student tant and lung function (7), and the expression of lamellar bodies of history, fighting the hard fight for what was right despite the in alveolar type II cells as a function of development (8). And prevailing attitudes, whether in science or social justice. since the functional surfactant was predicated on its secretion by Dr. Avery’s last cited paper, entitled “What is good for children the alveolar type II cell, an elegant histologic study was published is good for mankind: the role of imagination in discovery” was demonstrating this property of the alveolar epithelium (9). In a her formal Address to the American Association for the Advance- series of follow-up studies,Avery and her colleagues demonstrated ment of Science as the President of the society in the year 2004 relationships between conventional knowledge of pulmonary alve- (31). In her speech, she emphasized the power of the imagination olar homeostasis and lung surfactant at the cellular, functional, to overcome mankind’s problems. She certainly demonstrated her and pathophysiologic levels (10–15) to further convince the sci- own ability to achieve that goal, and even surpassed it through her entific community of the mechanistic relevance of the surfactant leadership and mentoring. system to alveolar homeostasis. Subsequent studies were designed I can only hope that her spirit will marshal on. to try and identify factors that might accelerate the appearance and activity of surfactant in order to prevent RDS (15), including REFERENCES observations that hormonal acceleration of lung maturation was 1. Gruenwald P. Surface tension as a factor in the resistance of neonatal lungs to physiologic in nature (16). Such studies were done in conjunction aeration. Am J Obstet Gynecol (1947) 53(6):996–1007. with the further elucidation of those factors that merely caused res- 2. Pattle RE. Properties, function and origin of the alveolar lining layer. Nature piratory distress, such as edema (17) and retained fetal lung fluid (1955) 175(4469):1125–6. doi:10.1038/1751125b0 (18), versus those that specifically caused RDS as surfactant defi- 3. Clements JA. Surface tension of lung extracts. Proc Soc Exp Biol Med (1957) 95(1):170–2. doi:10.3181/00379727-95-23156 ciency disease, strictly defined as dependence on oxygen support 4. Josephs HW, Avery ME. Hereditary elliptocytosis associated with increased in association with grunting, flaring, and retracting of the thorax, hemolysis. Pediatrics (1955) 16(6):741–52. and a ground-glass appearance of the lung on x-ray examination. 5. Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline mem- The breakthrough in the treatment of surfactant deficiency brane disease. AMA J Dis Child (1959) 97(5, Pt 1):517–23. in utero came when Liggins discovered that antenatal gluco- 6. Gribetz I, Frank NR,Avery ME. Static volume-pressure relations of excised lungs of infants with hyaline membrane disease, newborn and stillborn infants. J Clin corticoids could accelerate lung maturation. Avery’s laboratory Invest (1959) 38:2168–75. doi:10.1172/JCI103996 performed a systematic series of studies to demonstrate the phys- 7. Avery ME, Cook CD. Volume-pressure relationships of lungs and thorax in fetal, iologic effect of glucocorticoids on lung surfactant production in newborn, and adult goats. J Appl Physiol (1961) 16:1034–8. both rabbits (19–23) and lambs (24), including untoward effects 8. Buckingham S, Avery ME. Time of appearance of lung surfactant in the foetal like the inhibition of lung growth (25) for “full disclosure” – Avery mouse. Nature (1962) 193:688–9. doi:10.1038/193688a0 9. Bensch K, Schaefer K, Avery ME. Granular pneumocytes: electron micro- wanted her colleagues to be totally informed about this emerg- scope evidence of their exocrine function. Science (1964) 145(3638):1318–9. ing therapy. Subsequent studies filled in gaps in the relationships doi:10.1126/science.145.3638.1318-a between physiologic and pathophysiologic agents and surfactant 10. Schaefer KE, Avery ME, Bensch K. Time course of changes in surface tension dynamics (26, 27) so as to further elaborate on the basic and clin- and morphology of alveolar epithelial cells in CO2-induced hyaline membrane disease. J Clin Invest (1964) 43:2080–93. doi:10.1172/JCI105082 ical aspects of surfactant biology for the scientific community. 11. Said SI, Avery ME, Davis RK, Banerjee CM, El-Gohary M. Pulmonary sur- Among these was the study by Wyszogrodski (28) showing that face activity in induced pulmonary edema. J Clin Invest (1965) 44:458–64. beta adrenergic agents caused surfactant secretion, an important doi:10.1172/JCI105159 observation for both basic and clinical understanding of surfac- 12. Howatt WF, Avery ME, Humphreys PW, Normand IC, Reid L, Strang LB. Fac- tant’s properties. The last scientific peer-reviewed paper that was tors affecting pulmonary surface properties in the foetal lamb. Clin Sci (1965) 29(2):239–48. co-authored by Dr. Avery was the demonstration of the sexual 13. Brumley GW, Hodson WA, Avery ME. Lung phospholipids and surface tension dimorphism in the rate of lung maturation during human fetal correlations in infants with and without hyaline membrane disease and in adults. development (29), capping a series of animal studies conducted in Pediatrics (1967) 40(1):13–9. my laboratory with Heber C. Nielsen. Those studies were designed 14. DeLemos R, Wolfsdorf J, Nachman R, Block AJ, Leiby G, Wilkinson HA, et al. to determine why males were not as responsive to antenatal glu- Lung injury from oxygen in lambs: the role of artificial ventilation. Anesthesiol- ogy (1969) 30(6):609–18. doi:10.1097/00000542-196906000-00007 cocorticoids as females, an observation first reported by Kotas and 15. Kotas RV,Fletcher BD, Torday J, Avery ME. Evidence for independent regulators Avery (30). of organ maturation in fetal rabbits. Pediatrics (1971) 47(1):57–64. In 1984, on the 25th anniversary of the publication of the Avery 16. Wang NS, Kotas RV, Avery ME, Thurlbeck WM. Accelerated appearance of and Mead paper, members of the Joint Program in Neonatology, osmiophilic bodies in fetal lungs following steroid injection. J Appl Physiol which Dr. Avery had created in 1974, gathered for a group picture (1971) 30(3):362–5. 17. Said SI, Banerjee CM, Harlan WR Jr, Avery ME. Pulmonary edema as a cause of with her in front of the Administration Building at Harvard Med- surfactant deficiency. Jpn Heart J (1967) 8(6):742–3. doi:10.1536/ihj.8.742 ical School (see Figure 1). Those in attendance were clinicians, 18. Avery ME, Gatewood OB, Brumley G. Transient tachypnea of newborn. Possi- clinician-scientists, and basic scientists alike as the embodiment ble delayed resorption of fluid at birth. Am J Dis Child (1966) 111(4):380–5. of Dr. Avery’s eternal effort “to do no harm.” doi:10.1001/archpedi.1966.02090070078010 19. Kotas RV, Avery ME. Accelerated appearance of pulmonary surfactant in the In addition to her research efforts, Dr. Avery was a champion fetal rabbit. J Appl Physiol (1971) 30(3):358–61. for women in the field of medicine. Along with Lynn Reid and 20. Taeusch HW Jr, Wang NS, Avery ME. Studies on organ maturation: “skin age” Mary Ellen Wohl, she strongly advocated for a level playing field as an indicator of “lung age” in fetal rabbits. Pediatrics (1972) 49(3):400–5. www.frontiersin.org April 2014 | Volume 2 | Article 34 | 6 Torday Mary Ellen Avery’s research career

21. Taeusch HW Jr, Heitner M, Avery ME. Accelerated lung maturation and 29. Torday JS, Nielsen HC, Fencl Mde M, Avery ME. Sex differences in fetal lung increased survival in premature rabbits treated with hydrocortisone. Am Rev maturation. Am Rev Respir Dis (1981) 123(2):205–8. Respir Dis (1972) 105(6):971–3. 30. Kotas RV, Avery ME. The influence of sex on fetal rabbit lung maturation 22. Wang NS, Taeusch HW Jr, Thurlbeck WW,Avery ME. A combined scanning and and on the response to glucocorticoid. Am Rev Respir Dis (1980) 121(2): transmission electron microscopic study of alveolar epithelial development of 377–80. the fetal rabbit lung. Am J Pathol (1973) 73(2):365–76. 31. Avery ME. Presidential address. What is good for children is good for mankind: 23. Taeusch HW Jr, Wyszogrodski I, Wang NS, Avery ME. Pulmonary pressure- the role of imagination in discovery. Science (2004) 306(5705):2212–3. doi:10. volume relationships in premature fetal and newborn rabbits. J Appl Physiol 1126/science.306.5705.2212 (1974) 37(6):809–13. 24. Tauesch HW Jr, Avery ME, Sugg J. Premature delivery without accelerated lung Conflict of Interest Statement: The author declares that the research was conducted development in fetal lambs treated with long-acting methylprednisolone. Biol in the absence of any commercial or financial relationships that could be construed Neonate (1972) 20(1):85–92. doi:10.1159/000240450 as a potential conflict of interest. 25. Carson SH, Taeusch HW Jr, Avery ME. Inhibition of lung cell division after hydrocortisone injection into fetal rabbits. J Appl Physiol (1973) 34(5):660–3. Received: 04 March 2014; accepted: 04 April 2014; published online: 28 April 2014. 26. Taeusch HW Jr, Carson SH, Wang NS, Avery ME. Heroin induction of lung mat- Citation: Torday JS (2014) Mary Ellen Avery’s research career – remembrance of things uration and growth retardation in fetal rabbits. J Pediatr (1973) 82(5):869–75. past. Front. Pediatr. 2:34. doi: 10.3389/fped.2014.00034 doi:10.1016/S0022-3476(73)80086-1 This article was submitted to Neonatology, a section of the journal Frontiers in 27. Kyei-Aboagye K, Hazucha M, Wyszogrodski I, Rubinstein D, Avery ME. The Pediatrics. effect of ozone exposure in vivo on the appearance of lung tissue lipids in Copyright © 2014 Torday. This is an open-access article distributed under the terms the endobronchial lavage of rabbits. Biochem Biophys Res Commun (1973) of the Creative Commons Attribution License (CC BY). The use, distribution or repro- 54(3):907–13. doi:10.1016/0006-291X(73)90780-8 duction in other forums is permitted, provided the original author(s) or licensor are 28. Wyszogrodski I, Taeusch HW Jr, Avery ME. Isoxsuprine-induced alterations of credited and that the original publication in this journal is cited, in accordance with pulmonary pressure-volume relationships in premature rabbits. Am J Obstet accepted academic practice. No use, distribution or reproduction is permitted which Gynecol (1974) 119(8):1107–11. does not comply with these terms.

Frontiers in Pediatrics | Neonatology April 2014 | Volume 2 | Article 34 | 7 OPINION ARTICLE published: 03 July 2014 PEDIATRICS doi: 10.3389/fped.2014.00049 Mel – personal reminiscence†

H. WilliamTaeusch*

Department of Pediatrics, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA *Correspondence: [email protected] Edited by: Henry J. Rozycki, Children’s Hospital of Richmond at Virginia Commonwealth University, USA Reviewed by: Martin Keszler, Alpert Medical School of Brown University, USA William Oh, Alpert Medical School of Brown University, USA Rita Marie Ryan, Medical University of South Carolina, USA Ilene R. S. Sosenko, University of Miami Miller School of Medicine, USA

Keywords: Avery, lung, pulmonary, surfactants, neonatology, medical research, lungs

On July 1, 1970, I started my fellowship for life, she was generous enough to push regardless of gender. Her sole criterion for in neonatology under the tutelage of Mary me to learn from others with talents in accepting someone was enthusiasm for the Ellen Avery. I entered her lab in the MacIn- some areas that exceeded her own (Jere task. When a female trainee was paged to tyre Building at McGill University in Mon- Mead, David Bates, Joseph Milic-Emili, leave a research conference for a sick child, treal. There were no other fellows or techs Peter Macklem, and John Clements, the Mel loudly asked, “Where’s her husband?” working in her lab at the time. The lab was first Mel Avery awardee of the Pediatric The under representation of women in spacious but sparsely furnished. In one cor- Academic Societies, Vancouver, 2014). Mel medicine, however, affronted Mel’s sense ner was a pneumatic surface balance, hand- believed that cross-disciplinary collabora- of fairness, and she made sure oppor- built, from the design of John Clements. tive research was key for major develop- tunities were made known to qualified A lab book lay on the bench with entries ments in the field, long before medical cen- women. dated June, 1970, by Bob Kotas, my pre- ters dressed up this concept as a novel way Mel was loyal to a fault, but unaccept- decessor, who had neatly recorded data on to get funding. She was impatient of “me- ing of excuses used to explain an absence lungs from fetal rabbits. I was alone and too”research. She recognized and rewarded of productivity, however measured. My knew no one in the building. Mel’s office those that could produce results fitting favorite excuse was too much clinical time, was several miles away at Montreal Chil- her Venn diagram (new, true, and use- until she pointed out that in another divi- dren’s Hospital where she was, surprisingly, ful). Her curiosity extended from the Eski- sion, there were some with more clinical the new Chief of Pediatrics (An American! mos in Baffin Bay to hibernating turtles in responsibilities, and with a greater research A Woman!). Newfoundland to prematurely born sheep output. She was readily accessible in her hos- in New Zealand. She pored through my She could blow through thickets of ver- pital office but came to the lab only on novel (about a mother deciding whether to biage to find and state the truth. One Wednesday afternoons. There we sat nose allow surgery on her Down Syndrome new- famous example was a seminar where to nose for 3 h while she reviewed my week’s born with multiple life-threatening anom- one of us (a hapless unnamed research work. Not yet trained in the academic art alies) as if it were an NIH grant appli- trainee with the initials JT) was expound- of self-promotion, I once told her in three cation (Even those have more chance of ing his research results while Mel held the brief sentences of my past week’s efforts. approval these days). She did all this with switch that advanced his slides (remem- She waited for more and then looked star- an irrepressible optimism, a robust sense ber slides?) on the projector. Impatiently tled when I remained quiet. With her usual of humor, and an appreciation of her own she advanced his slides faster and faster candor she said that after she returned to foibles. Robert Usher once introduced Mel in search of the main point. He stood in her office at 5 p.m., by the end of her work- as unique in her ability to sense which path front of the rest of us talking faster and day, she would have completed more, much to choose when she came to a research faster as his slides flew by on the screen. more, than I had managed to do in a week. crossroad. A larger example was her consultancy to In heated response I blatted out all of my Her principles colored her femi- the UN where it was politically correct in week’s successes and failures in extenso. She nism. Men and women were unequal – some quarters to defend female circumci- smiled and said,“Well that’s better. You not women in medicine had heavier bur- sion on religious principle. Mel called it only have to do well, you have to show that dens to shoulder – often, kids and hus- by its right name – child abuse akin to you are doing well.” (Figure 1). bands. Nonetheless Mel expected the time torture. One of my many learned lessons at her expended/results achieved ratio to be equal Mel’s interests when I first met her knee. Not only has she been my mentor for those she chose to work with her, were the two subjects I disliked most in

† For those interested, Bojan Jennings completed a biography entitled, Mel: A Biography of Mary Ellen Avery, not long before Mel died. Unfortunately, it is no longer available from CreateSpace. Currently, Dr. Jennings is considering republishing it as an eBook. She can be reached at [email protected].

www.frontiersin.org July 2014 | Volume 2 | Article 49 | 8 Taeusch Personal reminiscence of Mel Avery

measure she added me as a coauthor on a Scientific American article (2). Mel’s wisdom included the ability to integrate disparate findings for the benefit of babies. She also had the ability to sweep up skeptics and attract new trainees with her keenness. She tutored and encouraged her loyal recruits to take on tasks that they themselves had no idea they could accom- plish. The wisest (maybe luckiest) decision of my life (and the moral of this tale) was to choose the most inspiring teacher to work with, rather than a merely interesting subject.

REFERENCES 1. Taeusch HW,Wang NS, Avery ME. Studies on organ maturation: “skin age” as an indicator of “lung age” in fetal rabbits. Pediatrics (1972) 49:400. 2. Avery ME, Wang NS, Taeusch HW. The lung of the newborn infant. Sci Am (1972) 228:74. doi:10.1038/ FIGURE 1 | Montreal lab, about 1970. Arrayed around Mel from left to right are Nai San Wang, Izzy scientificamerican0473-74 Wyszogrodski, Kwabena Kyei-Aboagye, and the author (with the bashful bunny). When the sequence of authorship for a paper arose for discussion, Mel, even though she merited being listed first, said, “Put my name last and I’ll still get all the credit, because nobody can remember the names of you Conflict of Interest Statement: The author declares jokers.” that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. medical school: pulmonary physiology and distinguish fetal lung maturity by looking steroid biochemistry. So for a time, alone at the H&E slides from newborn rabbits Received: 18 March 2014; accepted: 18 May 2014; published online: 03 July 2014. in her lab I injected rabbit fetuses with born by cesarean section at different late Citation: Taeusch HW (2014) Mel – per- glucocorticoids or saline, then recorded days in late gestation. That was easy for sonal reminiscence. Front. Pediatr. 2:49. doi: pulmonary volume curves on lungs from any pathologist. But Mel forced him to 10.3389/fped.2014.00049 the prematurely born rabbits. After about break down the attributes that determined This article was submitted to Neonatology, a section of 5 months of this, I complained to Mel maturity and we spent the afternoon scor- the journal Frontiers in Pediatrics. Copyright © 2014 Taeusch. This is an open-access arti- that I had not yet published a research ing lung maturity of steroid injected and cle distributed under the terms of the Creative Commons paper (I was young). Mel hid her amuse- saline-injected fetal rabbits. The next week Attribution License (CC BY). The use, distribution or ment, almost completely, and said that we did the same thing for the skin spec- reproduction in other forums is permitted, provided the she appreciated my enthusiasm. The next imens from the same rabbit fetuses. And original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance week she showed up with a young pathol- voila! I helped author a paper that indi- with accepted academic practice. No use, distribution or ogist, Nai San Wang. She sat him down at cated a discordance in maturational rates reproduction is permitted which does not comply with a microscope and asked him if he could of fetal skin and lungs (1). Just for good these terms.

Frontiers in Pediatrics | Neonatology July 2014 | Volume 2 | Article 49 | 9 OPINION ARTICLE published: 02 June 2014 PEDIATRICS doi: 10.3389/fped.2014.00050 My tribute to Mary Ellen Avery

Ann R. Stark*

Division of Neonatology, Department of Pediatrics, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA *Correspondence: [email protected] Edited by: John Steven Torday, University of California Los Angeles, USA Reviewed by: Lynne Smith, Harbor-UCLA Medical Center, USA

Keywords: respiratory distress syndrome, newborn, surfactant, antenatal glucocorticoids, hyaline membrane disease, surface tension

I was so pleased to learn that the inaugural respiratory physiology with Jere Mead They concluded that HMD is caused by the issue of the neonatology specialty section in the Department of Physiology at the absence or delayed appearance of a sub- of Frontiers in Neonatology would high- Harvard School of Public Health and to stance that, when present, would result in a light Mary Ellen “Mel” Avery’s contribu- learn more about newborn infants from low surface tension at low lung volume and tions to decades of neonatal research. Mel the pediatrician and physiologist Clement thus prevent alveolar collapse. was my mentor and friend for more than Smith who worked across the street at the A second key contribution was Mel’s 30 years, and it is a great honor for me to Boston Lying-In Hospital. Military fund- role in the translation of her discovery write about some of her substantial accom- ing targeted at chemical warfare, especially of surfactant deficiency in HMD to its plishments. Among her many contribu- the effects of nerve gas on the lung, sup- clinical application, treatment of affected tions, three are especially notable because ported many laboratories, including those newborns with artificial surfactant. In the they have saved the lives and improved the of Jere Mead, who was studying pulmonary 1970s, Dr. Tetsuro Fujiwara studied sur- health of countless newborns: identifica- edema, and John Clements, who was inter- factant biology with Forrest Adams in Los tion of surfactant deficiency as the cause of ested in surface properties of lung extracts. Angeles before he returned to Japan to con- respiratory distress syndrome (RDS), treat- Clements had modified a surface balance tinue his study of experimental surfactant ment of RDS with artificial surfactant, and in order to measure changes in surface ten- replacement. Hearing about his work, Mel prevention of RDS with antenatal steroids. sion with changes in area, as occurs during visited Fujiwara in Japan in 1979. At the In a paper she wrote about how it really breathing. He found that surface tension time, he was working with a pharmaceuti- happened,Mel dated her interest in respira- of the lung extracts was high when the cal company to develop an artificial surfac- tory physiology to the start of her pediatric area was large, corresponding to higher tant from bovine lungs. He subsequently internship at Johns Hopkins in 1952 (1). lung volumes, and very low when the area performed the first study of surfactant Only 1 month after she began her training, was small, similar to low lung volumes (3). replacement in human infants, reported a routine tuberculin skin test that was pos- This was due to a saline extractable surface- the next year (5). Mel returned to Boston to itive and a small upper lobe infiltrate on active material at the alveolar air interface help plan a randomized trial of surfactant a chest radiograph consistent with tuber- that he named pulmonary surfactant. replacement in the US, using the product culosis prompted a course of antibiotics Mel visited Clements in Maryland soon characterized by Fujiwara (6). and a prescription for 6 months of bed rest. after his publication to learn his tech- That study and others at the time led to a During this period, questions about her niques. When she returned to Boston, new era in neonatology. Between 1989 and own treatment spurred her quest for more she and Mead modified Clements’ method 1990, infant mortality in the US declined knowledge of respiratory physiology. to enable them to study minced extracts more rapidly than any other year since Returning to her pediatric residency at of lungs from human infants that they 1977, when the rate was much higher. Most Johns Hopkins, Mel cared for many pre- obtained from Kurt Benirshke, chief of of the decline was in neonatal mortality mature infants with a lung condition then pathology at the Boston Lying-In Hospital. which accounts for about two-thirds of called hyaline membrane disease (HMD), Their observations led to their landmark infant deaths, and most in the categories and now known as RDS. Nearly half of publication (4). Using the modified sur- involving respiration. This was clearly due the affected infants died, usually in the face balance, Avery and Mead measured to the wide availability of surfactant begin- first 3 or 4 days, with pathology character- the lowest surface tension obtained with ning in July 1989 and followed by rapid ized by atelectasis and hyaline membranes compression of lung extracts from infants FDA approval in 1990. (2). Infants who survived the first few days who died of HMD and infants who died A third key contribution was Mel’s work typically made a complete recovery. of other causes. They found low values on prevention of HMD. At a conference in Mel wanted to learn more about in lung extracts from the larger infants New Zealand in 1968, she reported that the lungs of newborn infants, especially without HMD, similar to older children lungs of fetal lambs less than approxi- those with HMD. In 1957, following her or adults, and high values in infants who mately 126 days gestation (146 days is full residency, she moved to Boston to study died with HMD and in the smallest infants. term) did not retain air. At the same

www.frontiersin.org June 2014 | Volume 2 | Article 50 | 10 Stark Tribute to Mary Ellen Avery

others (Figure 1). Those of us who had the good fortune to work with Mel treasure her critical insights, imaginative approach, and personal support. REFERENCES 1. Avery ME. Surfactant deficiency in hyaline mem- brane disease. Am J Respir Crit Care Med (2000) 161:1074–5. doi:10.1164/ajrccm.161.4.16142 2. Gruenwald P.Pathologic aspects of lung expansion in mature and premature newborn infants. Bull N Y Acad Med (1956) 32:689–92. 3. Clements JA. Surface tension of lung extracts. Proc Soc Exp Biol Med (1957) 95:170–2. doi:10.3181/ 00379727-95-23156 4. Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child (1959) 97:517–23. 5. Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T. Artificial surfactant therapy in hyaline- membrane disease. Lancet (1980) 1:55–9. doi:10. 1016/S0140-6736(80)90489-4 6. Gitlin JD, Soll RF, Parad RB, Horbar JD, Feldman HA, Lucey JF, et al. Randomized controlled trial of artificial surfactant for the treatment of hyaline membrane disease. Pediatrics (1987) 79:31–7. 7. DeLemos RA, Shermeta DW, Knelson JH, Kotas R, Avery ME. Acceleration of appearance of pul- monary surfactant in the fetal lamb by administra- tion of corticosteroids. Am Rev Respir Dis (1970) 102:459–61. 8. Wang NS, Kotas RV, Avery ME, Thurlbeck WM. Accelerated appearance of osmiophilic bodies in fetal lungs following steroid injection. J Appl Phys- iol (1971) 30:362–5. 9. Kotas RV, Avery ME. Accelerated appearance of pulmonary surfactant in the fetal rabbit. J Appl Physiol (1971) 30:358–61. FIGURE 1 | Bronchopulmonary tree illustrating Dr. Avery’s trainees through 1984. 10. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for pre- vention of the respiratory distress syndrome meeting, she heard the obstetrician Gra- women with anticipated preterm birth, in premature infants. Pediatrics (1972) 50: ham “Mont” Liggins report treating preg- as well as other accomplishments. These 515–25. nant ewes with corticosteroids to stimulate included the Edward Livingston Trudeau 11. Taeusch HW, Frigoletto F, Kitzmiller J, Avery ME, Hehre A, Fromm B, et al. Risk of respiratory early labor. The resultant lambs were born Medal from the American Lung Associ- distress syndrome after prenatal dexamethasone at a slightly earlier gestational age than ation, the E. Mead Johnson Award from treatment. Pediatrics (1979) 63:64–72. Mel’s (117–123 days) and had well-aerated the Society for Pediatric Research, the John Conflict of Interest Statement: The author declares lungs, suggesting accelerated appearance of Howland Award from the American Pedi- that the research was conducted in the absence of any surfactant, possibly induced by the cor- atric Society, and the Virginia Apgar Award commercial or financial relationships that could be ticosteroids. With others, she confirmed from the American Academy of Pediatrics. construed as a potential conflict of interest. Liggins’ finding of accelerated lung matu- In addition, she was the first pediatrician to ration with antenatal steroid administra- receive the National Medal of Science. Received: 19 March 2014; accepted: 19 May 2014; published online: 02 June 2014. tion in lambs and rabbits (7–9). Liggins In summary, Mary Ellen Avery was an Citation: Stark AR (2014) My tribute to and Howie performed the first randomized outstanding leader in pediatrics for both Mary Ellen Avery. Front. Pediatr. 2:50. doi: trial of antenatal steroids in humans in her scientific contributions and her sus- 10.3389/fped.2014.00050 New Zealand (10), and with Bill Taeusch, tained efforts to improve health of new- This article was submitted to Neonatology, a section of Mel participated in an early US human borns and children in the US and around the journal Frontiers in Pediatrics. Copyright © 2014 Stark. This is an open-access article trial (11). the world. In addition, her support and distributed under the terms of the Creative Commons Mel received many awards for her continued encouragement of the next gen- Attribution License (CC BY). The use, distribution or extraordinary contributions that led to eration provides another enduring legacy. reproduction in other forums is permitted, provided the understanding the mechanism of RDS Mel directly mentored at least 75 individ- original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance as surfactant deficiency, treatment with uals and influenced many more scientists with accepted academic practice. No use, distribution or surfactant replacement, and prevention and clinicians who have made and continue reproduction is permitted which does not comply with by antenatal corticosteroid treatment of to make important contributions and train these terms.

Frontiers in Pediatrics | Neonatology June 2014 | Volume 2 | Article 50 | 11 OPINION ARTICLE published: 24 March 2014 PEDIATRICS doi: 10.3389/fped.2014.00023

My personal tribute to Dr. Mary Ellen Avery

Ilene R. S. Sosenko* Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA *Correspondence: [email protected] Edited and reviewed by: John Steven Torday, University of California Los Angeles, USA Keywords: neonatology, research, IDM, mentor, Mary Ellen Avery

Because my husband was planning to pur- of their offspring (3–7). I remember her REFERENCES sue a fellowship in adolescent medicine delight when I presented my findings at 1. Robert MF, Neff RK, Hubbell JP, Taeusch HW, at Boston Children’s Hospital, I was set research meetings and had my first peer- Avery ME. Association between maternal diabetes mellitus and respiratory distress syndrome in the to interview there in July of 1974 for a reviewed publications in the New Eng- newborn. N Engl J Med (1976) 294:357–60. doi:10. third year of pediatric training. I was just land Journal of Medicine (2) and Jour- 1056/NEJM197602122940702 starting my second year of pediatrics in nal of Applied Physiology (3). In fact, 2. Sosenko IR, Kitzmiller JL, Loo SW, Blix P, Ruben- Los Angeles and had been focusing more when I moved on to University of Miami, stein AH, Gabbay KH. The infant of the diabetic on the mechanics of completing pediatric I continued the line of research look- mother: correlation of increased cord C-peptide levels with macrosomia and hypoglycemia. N Engl training than on choosing a fellowship. Dr. ing at lung development in the animal J Med (1979) 301:859–862. Mary Ellen Avery had just become Chil- model of the IDM, this time examining 3. Sosenko IR, Lawson EE, Demottaz V, Frantz ID. dren’s Physician-in-Chief. In fact, she was pulmonary antioxidant enzyme develop- Functional delay of lung maturation in fetuses still finding her way about the place, both ment in offspring of streptozotocin-treated of alloxan diabetic rabbits. J Appl Physiol (1980) physically and professionally. It was my sec- rats (8). 48:643–647. 4. Sosenko IR, Hartig-Beecken I, Frantz ID. Cortisol ond interview, the first resulting in less She opened her heart to me not just reversal of functional delay of lung maturation in than positive news about the possibility professionally but socially and personally fetuses of diabetic rabbits. J Appl Physiol (1980) of my obtaining a senior pediatric resi- as well. I remember a cozy Thanksgiving 49:971–974. dency for the coming year. She did not let evening when just she, my husband, and I 5. Sosenko IR, Frantz ID, Roberts RJ, Meyrick B. Mor- phologic disturbance of lung maturation in fetuses me be discouraged, made it known that sat by the fire in her Wellesley condo and of alloxan diabetic rabbits. Am Rev Respir Dis (1980) she would welcome me there, and sug- dined on delicious leftovers from the day. 122:687–696. gested I could pursue the start of a fel- She hosted the two of us to a very spe- 6. Frantz ID III, Sosenko IR. Lung maturation in an lowship before completing my full pedi- cial Boston evening: a “double date” with experimental model of diabetes in pregnancy. J Jpn atric training. What type of fellowship? Dr. Fred Rosen for dinner at the Harvard Med Soc Biol Interface (1980) 11:76–81. 7. Sosenko IR, Werthammer J, Cunningham MD, I certainly hadn’t spent much time con- Club and then to hear the Boston Sym- Frantz ID III. Surfactant in diabetic offspring not templating this. How about neonatology, phony. When I was about to have my first affected by inhibitors or lecithin fatty acids. J Appl she suggested, and immediately arranged child, she was glowing when I came to Physiol (1983) 54:1097–1100. for me to see Dr. Bill Taeusch, newly her with the news. She wanted to make 8. Sosenko IRS, Frank L. Lung development in appointed Neonatology Division Director. sure I would be nursing him which of the streptozotocin rat fetus: antioxidant enzymes and survival in high oxygen. Pediatr Res (1986)

So serendipity, and more importantly, Dr. course I was. When he was born, she pre- 20:67–70. Mel Avery are responsible for my career in sented us with a beautifully framed print 9. Avery ME, Sosenko IR. Breast feeding. Harv Med Sch neonatology: I joined the first official JPN of a mother rabbit and her pups (how Health Lett (1979) 4:3–4. fellows’ group that started training in July appropriate!) which we hung above his of 1975. changing table. And once I had success- Received: 07 March 2014; accepted: 10 March 2014; published online: 24 March 2014.

Dr. Avery was a pioneering researcher fully established nursing and returned to Citation: Sosenko IRS (2014) My personal tribute in the field of neonatology and a great work, she invited me to write an article to Dr. Mary Ellen Avery. Front. Pediatr. 2:23. doi: research motivator as well. She had over- with her on the benefits of breast feed- 10.3389/fped.2014.00023 seen a recent publication associating an ing for the Harvard Medical School Health This article was submitted to Neonatology, a section of increased risk of hyaline membrane dis- Letter (9). the journal Frontiers in Pediatrics. Copyright © 2014 Sosenko. This is an open-access arti- ease in infants of diabetic mothers (1). My respect and admiration for Dr. cle distributed under the terms of the Creative Commons She “shepherded” me into examining this Mary Ellen Avery are without bounds. Attribution License (CC BY). The use, distribution or further, thus leading me both to the deliv- There is no doubt that Mel brought me reproduction in other forums is permitted, provided the ery room to collect infants’ cord blood into neonatology, fostered my career, and original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance for C-peptide measurements (2) and into opened her intellect and heart to me with accepted academic practice. No use, distribution or the animal lab with alloxan-diabetic preg- many years ago. For this I am eternally reproduction is permitted which does not comply with nant rabbits and the lung development grateful. these terms.

www.frontiersin.org March 2014 | Volume 2 | Article 23 | 12 OPINION ARTICLE published: 07 April 2014 PEDIATRICS doi: 10.3389/fped.2014.00029

“PADding” my career with Dr. Mary Ellen Avery

Heber C. Nielsen* Department of Pediatrics, Tufts Medical Center, Boston, MA, USA *Correspondence: [email protected] Edited by: John Steven Torday, University of California Los Angeles, USA Reviewed by: Lynne Smith, Harbor-UCLA Medical Center, USA Keywords: mentoring, Mary Ellen Avery, neonatology, tribute, memorial

On Wednesdays at 2:00 p.m., faculty, fel- comment from Dr. Avery over time I real- have you made this week?” For a while this lows, and research associates in the Joint ized there was a significant learning insight seemed odd. How could she expect that Program in Neonatology (JPN) at Harvard for my career. If I cannot show that I am new discoveries would be made each week? would meet in the conference room of the intimately familiar with all the relevant lit- Obviously, research is time-intensive; new Seeley Mudd building for Research Con- erature as I present a research idea or study, discoveries don’t just pop up each day! But ference. Dr. Avery would come bustling in, then I cannot expect to get others inter- with time I saw that she was teaching us settle in a chair, and ask the group “So, ested and excited about the project. This two important attitudes. First, our research what exciting discoveries have you made truth has had a major impact on the devel- is exciting and we should always approach this week?” Those Wednesday conferences opment of my skills in presentations and it that way. Second, every finding, no mat- with Dr. Avery became one of the major writing of papers and grants. “Prepare” is ter how small, is new and unique, and mentoring environments of my neonatal a necessary component for success in our deserves to be celebrated. We don’t have fellowship training. I now group the many academic life. to wait until a research project is finished opportunities to gain mentoring from Dr. We frequently had outside speakers to derive the joy of scientific learning and Avery into three main categories, which at these Wednesday conferences, includ- discovery. Thus, “Discover” is an element I like to think of as Prepare, Ask, and ing speakers on topics far afield of the of every day in the lab. Without it we just Discover (PAD). research interests and even expertise of the aren’t approaching our work with the right Very early in my first year of training, group. Dr. Avery was always attentive. What attitude. I conceived a research question involv- impressed me was that she was always there Prepare, Ask, and Discover was central ing perinatal/neonatal hypoxia and pul- with questions. It didn’t matter if the ques- for Dr. Avery. It governed our relationships monary hypertension. I thoroughly stud- tions were clever or if they were simply with her, it stimulated her interest in fol- ied the literature to educate myself on way off the mark. She didn’t hesitate to lowing us in our careers after we left the what was known about oxygenation and state or even show that she simply was incubator, and it led to some of the most pulmonary blood pressure, and created a not informed on the topic. A few times imaginative thinking I have witnessed. For research hypothesis and approach. Soon she asked a question that caused private example, in a Wednesday conference Dr. it was my turn to present a proposed fel- smiles, because it seemed that she had over- Avery proposed the concept that male and lowship research project to the Research looked some of her basic biology in posing female cells from non-reproductive organs Conference. I discussed the background to the question. But she was never embar- have fundamental differences in their biol- my idea, the science it was based on, my rassed. As time went on I noted that by ogy. This concept has only recently become hypothesis, and my proposed approach. At asking questions, no matter how basic or a major consideration in human transla- the end there were, of course, many ques- uninformed on the subject, her personal tional biology research. In 1980, Dr. Avery tions. After all, I was just a first year fellow knowledge of that subject grew such that in told us to begin to look out for unusual and needed to learn my place. The discus- the future she was able to converse knowl- cases of neonatal respiratory distress syn- sion was capped off with Dr. Avery’s com- edgeably on the topic. This was the second drome, because we would begin to find ment “there is a huge literature in adults major learning insight for me. “Ask” ques- mutations in surfactant protein genes that on hypoxia and pulmonary hypertension; tions; no one should be embarrassed by underlie some cases. This preceded the I think you need to go back to the library a lack of even basic knowledge on a sub- identification of such mutations by some and study that to better develop your ratio- ject. Don’t worry about the possibility of 20 years. In retrospect, it was obvious, but nale, hypothesis, and study approach.” I coming across as uneducated. “Ask” is the in 1980, it was a new and far sighted knew about that literature; I had studied major way we have to learn about things. prediction. it carefully and it had definitely influenced This component of Dr. Avery’s mentoring One final tribute. As a mentor I am only the project I had so carefully designed and is one I have had to continue to work on as good as the people who mentored me. presented. I was strongly tempted to say throughout my career. Dr. Avery has had a profound impact on “yes, I know, I read all of that,” fortunately, Let me come back to Dr. Avery’s signa- my career and I hope on those who have I did not. As I thought about that humbling ture question “What exciting discoveries developed under my guidance. The impact

www.frontiersin.org April 2014 | Volume 2 | Article 29 | 13 Nielsen Mary Ellen Avery mentorship tribute

and legacy of a great physician–scientist Citation: Nielsen HC (2014) “PADding” my career Attribution License (CC BY). The use, distribution or like Dr. Avery will go on and on through with Dr. Mary Ellen Avery. Front. Pediatr. 2:29. doi: reproduction in other forums is permitted, provided the 10.3389/fped.2014.00029 original author(s) or licensor are credited and that the the generations of medical science. This article was submitted to Neonatology, a section of original publication in this journal is cited, in accordance the journal Frontiers in Pediatrics. with accepted academic practice. No use, distribution or Received: 20 March 2014; accepted: 24 March 2014; Copyright © 2014 Nielsen. This is an open-access arti- reproduction is permitted which does not comply with published online: 07 April 2014. cle distributed under the terms of the Creative Commons these terms.

Frontiers in Pediatrics | Neonatology April 2014 | Volume 2 | Article 29 | 14 OPINION ARTICLE published: 23 April 2014 PEDIATRICS doi: 10.3389/fped.2014.00031

My tribute to Mary Ellen Avery

John StevenTorday* Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA *Correspondence: [email protected] Edited by: Heber C. Nielsen, Tufts University School of Medicine, USA Reviewed by: Charles Michael Cotten, Duke University, USA Keywords: lung surfactant, soap bubbles, Boston Lying-In Hospital, joint program in neonatology, Montreal Chidren’s Hospital, Boston Children’s Hospital, Brigham and Women’s Hospital, antenatal steroids

“Life is that which can mix oil and water” Associate. During my early years at the of steroid therapy the management of – Robert Frost Boston Lying-In Hospital (BLI), where in preterm birth was essentially passive, so the 1950s Dr. Avery had previously dis- that method was adequate. But with the Mary Ellen Avery was a force of Nature. covered that Hyaline Membrane Disease onset of the use of antenatal steroids, there I first met her while I was a graduate stu- was due to surfactant deficiency in preterm was a sea change in Neonatology, the fetus dent at McGill University in the early 70’s. newborns, I conducted studies on the phys- becoming a patient treated in the womb. She and her colleagues had been studying iologic role of hormones in fetal lung devel- To improve on the antenatal testing for the effects of glucocorticoids on fetal lung opment in support of the clinical use of lung maturation, I developed the Saturated maturation and surfactant production,and antenatal steroids to accelerate the produc- Phosphatidylcholine Assay, which was far had stumbled onto a curious “neighbor tion of surfactant. Antenatal steroid treat- superior to the L/S Ratio, being more than effect” – when they treated one of the fetal ment dramatically improved the survival 90% accurate in predicting the risk of Res- rabbits in the womb by direct injection, of preterm infants. It is considered one piratory Distress Syndrome. So here was an they found an effect on the maturation of the major breakthroughs of twentieth example of how the burgeoning discipline of the lungs in the collateral pups. I was century medicine, saving the lives of hun- of Neonatology was able to use experimen- studying fetal endocrinology at the time dreds of thousands of newborns. During tal methods to optimize the well-being of in Claude Giroud’s Laboratory at Mon- the course of the first clinical trials of ante- preterm newborns. treal Children’s Hospital, and had access natal steroids for the prevention of Respira- During that era, we used to have 4th to radiolabeled cortisol, so I could deter- tory Distress Syndrome, it was found that of July picnics for the Joint Program in mine if the hormone was passing from males were much less responsive to such Neonatology. We’d inevitably have to play one fetus to the other. Having demon- treatment than females, reprising my inter- softball because it was Dr. Avery’s passion. strated this effect, Dr. Avery named me as est in the sexual dimorphism of fetal devel- She loved to pitch. I was sitting on the side- a co-author on their paper describing this opment, the subject of my Masters’ thesis lines with my then 2-year old daughter,who phenomenon, which was quite generous of in graduate school at McGill. As always, turned to me at one point and said loud her – but that was in her nature, as I was Dr. Avery was open to whatever we wanted enough so all could hear,“Dr. Avery doesn’t to discover in a 20-year journey with her as to study, so one of her Neonatal Fellows, do that very well.” It was then and there my mentor. Heber Nielsen, and I began a 20-year inves- that I knew I would not live out my days at In the spring of 1974, while on an ele- tigation of this mechanism in trying to Harvard. vator at Montreal Children’s Hospital, Dr. maximize the benefit of antenatal steroid Meanwhile, our basic research effort Avery invited me to join her research group therapy. to understand why males were refractory at Harvard Medical School. She said that During that era, the Director of the to antenatal glucocorticoid treatment was it was important to maintain the highest Joint Program in Neonatology, H. William advancing. We were able to determine that scientific standards in developing the bur- Taeusch, asked me to start a clinical labo- this was due to a physiologic mechanism by geoning discipline of Neonatology because ratory for the measurement of lung surfac- which androgens delayed the maturation she was concerned about doing harm in the tant at the BLI. Since this was a direct exten- of the fetal lung, allowing for persistence name of doing good. I had already commit- sion of my basic scientific work, I accepted of the growth phase of lung development. ted to a post-doctoral position with Jack the challenge. The laboratory began pro- This was due to androgen perpetuating the Gorski and N.L. First in the NIH Repro- cessing amniotic fluid samples in the spring production of Transforming Growth Fac- ductive Endocrine Program at the Uni- of 1977 in parallel with the advent of tor Beta in the connective tissue cells sur- versity of Wisconsin-Madison, so I had to the clinical implementation of antenatal rounding the alveoli, promoting more, but decline the invitation,with the understand- steroids. At that time, the standard method immature alveoli. ing that I would come to Boston after my for measuring surfactant was the L/S ratio, I left Boston in 1991, joining the Neona- Fellowship. I joined the Joint Program in which was known to lack sensitivity and tal Division at the University of Maryland. Neonatology in July, 1976 as a Research specificity, but prior to the implementation It was there that I discovered the Neutral

www.frontiersin.org April 2014 | Volume 2 | Article 31 | 15 Torday My tribute to Mel

Lipid Trafficking phenomenon – the active her own way to keep it simple (KISS). Conflict of Interest Statement: The author declares movement of lipid substrate between con- In fact her perennial question to her stu- that the research was conducted in the absence of any commercial or financial relationships that could be nective tissue and epithelial cells mediated dents regarding whether something was construed as a potential conflict of interest. by specific signaling mechanisms stimu- worth studying was “can you live with- lated by both hormones and mechanical out it?” Received: 21 March 2014; accepted: 28 March 2014; stretch. Dr. Avery had kept in touch with Further study of the cellular–molecular published online: 23 April 2014. me, and knew of my interest in the role signaling mechanisms for alveolar surfac- Citation: Torday JS (2014) My tribute to of “stretch” in lung development, send- tant homeostasis have led to a fundamen- Mary Ellen Avery. Front. Pediatr. 2:31. doi: ing me scientific papers to keep me on- tal understanding of how physiology has 10.3389/fped.2014.00031 track. The annual meeting of the Society evolved. Now there is a way of under- This article was submitted to Neonatology, a section of the journal Frontiers in Pediatrics. for Pediatric Research was held in Balti- standing the how and why of physiol- Copyright © 2014 Torday. This is an open-access arti- more in 1992, so while attending the meet- ogy from its origins in unicellular organ- cle distributed under the terms of the Creative Commons ing Dr. Avery paid me a visit in my new isms, providing a “logic” that simplifies Attribution License (CC BY). The use, distribution or laboratory. She handed me a book, enti- what had become artificially complicated. reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the tled Soap Bubbles: Their Colors and Forces I am indebted to Mary Ellen Avery for original publication in this journal is cited, in accordance

Which Mold Them, by C.V. Boys, saying giving me the opportunity to pursue new with accepted academic practice. No use, distribution or that everything she knew about lung sur- knowledge. reproduction is permitted which does not comply with factant was in that book! Telling me in She is missed. these terms.

Frontiers in Pediatrics | Neonatology April 2014 | Volume 2 | Article 31 | 16 OPINION ARTICLE published: 24 April 2014 PEDIATRICS doi: 10.3389/fped.2014.00020 How Mary Ellen Avery influenced my career as an investigator

Cynthia Frances Bearer*

Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA *Correspondence: [email protected] Edited and reviewed by: John Steven Torday, University of California Los Angeles, USA

Keywords: Mary Ellen Avery, tribute, career influences, simple observations, mentor

I arrived in Boston during the summer of development of surfactant therapies (4), N-cadherin do not, then ethanol may tar- 1984, having been coaxed there by F. Ses- development of pharmacotherapies (pre- get the L1–lipid raft interaction (14). These sions Cole, III. The carrot was the shorten- natal steroids) for the preventions of RDS observations lead to the next series of sim- ing of residency to 2 years,and thus a return (5), etc. For my own work, I have tried to ple questions, such as, if ethanol has an to the lab all the quicker. Dr. Avery was make simple observations. My first sim- effect on lipid raft trafficking, do other the chair of the department at that time, ple observation was that the then recently solvents? (Answer – yes). If the lipid raft and so supported my bid to enter the Spe- described non-oxidative metabolites of is the target for ethanol, are there unique cial Alternative Pathway. While that may ethanol, fatty acid ethyl esters (FAEE), and novel interventions for the impact sound easy, I had unintentionally made it accumulate in adipose tissue, so they might of ethanol on the developing central ner- more difficult by doing my internship as accumulate in meconium. Meconium is the vous system? (Answer – yes). So, after sev- my fourth year of medical school. To the accumulated gastrointestinal contents dur- eral grants and many publications, we are American Board of Pediatrics, on paper, ing gestation which is passed soon after poised to begin the next series of simple I had done only a year of residency, and birth and is presumed to be metabolically observations that will hopefully improve would not be board eligible if I left my inert. Thus, meconium could be a dosime- neurodevelopmental outcomes following residency program. After much negotia- ter for prenatal ethanol exposure. I devel- neurotoxicant exposure, including ethanol, tion, the Johns Hopkins University School oped a simple method of extracting FAEE toluene, bilirubin, volatile anesthetics, and of Medicine recalled my diploma, and re- from meconium (6), and then was able chlorhexidine. issued it with a graduating date of 1982 to validate that they were associated with One more simple observation occurred rather than 1983. And thus I started my maternal self-reported drinking during to me early in my career. The observation fellowship after 2 years of official residency! pregnancy in several different populations was that we use adult blood to transfuse And did get back to the lab a year sooner (7–9), and that they indicated children into our very low birth weight (VLBW) than otherwise. at risk for poor neurodevelopmental out- babies. Adults are known to be exposed The next issue to be solved was one of comes (10). I was even able to demonstrate to lead, mercury, and other heavy metals, housing. In order to access the Harvard that they accumulate in sheep meconium some at occupational levels of exposure University housing office, I needed a note (11)! For these experiments, I received NIH that would be inappropriate and danger- from the chair. I believe this is the only per- funding, several publications, and a patent! ous for children.Adults who work with lead sonal note I have signed by Dr. Avery, but The next simple observation was actu- are monitored for their blood lead level it guaranteed me a place to live while get- ally made by someone else – that patients which can be as high as 45 mg/dL before ting to work on my clinical and research with fetal alcohol syndrome and patients being removed from the position that is training. with a mutation in the gene for L1 cell causing the exposure. Yet, donated blood More importantly, her own research adhesion molecule (L1) had very similar is not screened for potentially high levels work was inspirational for me in my neuropathologies (12). This observation of heavy metals. We have shown that the research career. Namely, the ability to see led to the hypothesis that L1 is a target blood lead concentration increases follow- the importance in common observations for ethanol developmental neurotoxicity. I ing transfusions in VLBW, and that about that others did not recognize. Her obser- was able to build on this observation that 25% of donor blood has concerning lev- vation that babies who died of respiratory the neurite outgrowth promoted by L1 was els of lead (15, 16). We are now engaged distress syndrome (RDS) had no bubbles exquisitely sensitive to ethanol, whereas in research to determine if the cumulative in their airways, whereas babies who died that promoted by laminin or N-cadherin dose of lead or mercury is a risk factor of other causes had these bubbles (1). This was not (13). This lead to my own simple for poorer neurodevelopmental outcome seemingly simple observation lead to the observation that, since L1 promotes neu- of our most vulnerable patients. gastric aspirate shake test (2), the identi- rite outgrowth via trafficking through a Thank you Dr. Avery for your gift of fication of lack of surfactant in RDS (3), lipid raft compartment, and laminin and simple observations!

www.frontiersin.org April 2014 | Volume 2 | Article 20 | 17 Bearer A gift of simple observations

REFERENCES 9. Bearer CF, Santiago LM, O’Riordan MA, Buck K, lead exposure. Lancet (2003) 362:332. doi:10.1016/ 1. Avery ME. Surfactant deficiency in hyaline mem- Lee SC, Singer LT. Fatty acid ethyl esters: quanti- S0140-6736(03)13989-X brane disease: the story of discovery. Am J Respir tative biomarkers for maternal alcohol consump- 16. Bearer CF, O’Riordan MA, Powers R. Lead expo- Crit Care Med (2000) 161:1074–5. doi:10.1164/ tion. J Pediatr (2005) 146:824–30. doi:10.1016/j. sure from blood transfusion to premature infants. ajrccm.161.4.16142 jpeds.2005.01.048 J Pediatr (2000) 137:549–54. doi:10.1067/mpd. 2. Farrell PM, Avery ME. Hyaline membrane disease. 10. Peterson J, Kirchner HL, Xue W, Minnes S, Singer 2000.108273 Am Rev Respir Dis (1975) 111:657–88. LT, Bearer CF. Fatty acid ethyl esters in meconium 3. Avery ME, Mead J. Surface properties in relation are associated with poorer neurodevelopmental to atelectasis and hyaline membrane disease. AMA outcomes to two years of age. J Pediatr (2008) Conflict of Interest Statement: The author declares J Dis Child (1959) 97:517–23. 152:788–92. doi:10.1016/j.jpeds.2007.11.009 that the research was conducted in the absence of any 4. Taeusch HW, Keough KM, Williams M, Slavin 11. Littner Y,Cudd TA, O’Riordan MA, Cwik A, Bearer commercial or financial relationships that could be R, Steele E, Lee AS, et al. Characterization CF. Elevated fatty acid ethyl esters in meconium construed as a potential conflict of interest. of bovine surfactant for infants with respira- of sheep fetuses exposed in utero to ethanol – a tory distress syndrome. Pediatrics (1986) 77: new animal model. Pediatr Res (2008) 63:164–8. 572–81. doi:10.1203/PDR.0b013e31815f651e Received: 18 February 2014; accepted: 08 March 2014; 5. Rokos J, Vaeusorn O, Nachman R, Avery ME. Hya- 12. Charness ME, Safran RM, Perides G. Ethanol published online: 24 April 2014. line membrane disease in twins. Pediatrics (1968) inhibits neural cell-cell adhesion. J Biol Chem Citation: Bearer CF (2014) How Mary Ellen Avery influ- 42:204–5. (1994) 269:9304–9. enced my career as an investigator. Front. Pediatr. 2:20. 6. Bearer CF. Detection of Teratogen Exposure. US 13. Bearer CF, Swick AR, O’Riordan MA, Cheng G. doi: 10.3389/fped.2014.00020 patent no. 5,952,235 (1999). Ethanol inhibits L1-mediated neurite outgrowth This article was submitted to Neonatology, a section of 7. Bearer CF, Jacobson JL, Jacobson SW, Barr D, in postnatal rat cerebellar granule cells. J Biol the journal Frontiers in Pediatrics. Croxford J, Molteno CD, et al. Validation of a Chem (1999) 274:13264–70. doi:10.1074/jbc.274. Copyright © 2014 Bearer. This is an open-access article new biomarker of fetal exposure to alcohol. 19.13264 distributed under the terms of the Creative Commons J Pediatr (2003) 143:463–9. doi:10.1067/S0022- 14. Tang N, Farah B, He M, Fox S, Malouf A, Littner Attribution License (CC BY). The use, distribution or 3476(03)00442-6 Y, et al. Ethanol causes the redistribution of L1 reproduction in other forums is permitted, provided the 8. Bearer CF, Lee S, Salvator AE, Minnes S, Swick cell adhesion molecule in lipid rafts. J Neurochem original author(s) or licensor are credited and that the A, Yamashita T, et al. Ethyl linoleate in meco- (2011) 119:859–67. doi:10.1111/j.1471-4159.2011. original publication in this journal is cited, in accordance nium: a biomarker for prenatal ethanol exposure. 07467.x with accepted academic practice. No use, distribution or Alcohol Clin Exp Res (1999) 23:487–93. doi:10. 15. Bearer CF, Linsalata N, Yomtovian R, Walsh M, reproduction is permitted which does not comply with 1097/00000374-199903000-00016 Singer L. Blood transfusions: a hidden source of these terms.

Frontiers in Pediatrics | Neonatology April 2014 | Volume 2 | Article 20 | 18 OPINION ARTICLE published: 31 March 2014 PEDIATRICS doi: 10.3389/fped.2014.00018

Mel Avery: mentor, role model, friend, mother of us all

Mary E. Sunday* Pathology, Pediatrics, Medicine, and Cell Biology, Duke University Medical Center, Durham, NC, USA *Correspondence: [email protected] Edited and reviewed by: John Steven Torday, University of California Los Angeles, USA Keywords: twentieth century, historical perspective, neonatology, translational medical research, basic science research, mentoring

Dr. Mary Ellen Avery, affectionately known We’re going out to lunch!” Thus began a success could save lives. Another day, Mel as “Mel,” was a woman of courage, with a great friendship. whisked me to lunch with another pedia- sense of humor and deep humanity. She When I first presented at an American trician who was returning to clinical work was an intellectual powerhouse, highly cre- Thoracic Society meeting, Mel sat beside after years of disability. By dessert, we were ative, and productive, similar to many lead- me,commenting,“Interesting data,but you energized, embracing the future with Mel. ers. Yet she became the most beloved men- have to change your slides from black- When someone asked Mel how she tor for many. Here, I share some personal on-white, which doesn’t project well. Use felt about not having any children, Mel memories hoping to inspire others juggling yellow-on-blue.” Very constructive – very smiled,“What do you mean? I’ve had thou- life and career responsibilities. Mel! Writing a grant with Jackie Coal- sands of them!” There were no problems, I first met Mel in 1977 when she son about bronchopulmonary dysplasia only challenges; no regrets, only oppor- taught our Harvard Medical School (HMS) (BPD), I called Mel. At lunch, she pat- tunities. Working with UNICEF deepened class about respiratory distress syndrome ted my arm, “Mary, BPD isn’t a problem her awareness of global health needs, often (RDS). She held a critical audience entirely anymore.” By the 1990s, with surfactant simple yet unattainable. In India, she saw captive, listening with rapt attention. In therapy for RDS, BPD had become milder three babies in one NICU incubator and 1979, while I was doing a medical school than originally described (3). Regardless, asked if they were triplets. No, they said, rotation in obstetrics at St. Thomas’s Hos- Mel knew BPD remained a challenge, and it was their only incubator. There weren’t pital in London, Mel visited as Grand even collaborated with Jackie herself (4). sufficient resources to save all babies. She Rounds speaker. A gracious guest, she cited Mel encouraged countless young pro- spread the word. recent work by St. Thomas’s faculty. Always fessionals, especially women, but also men. Mel rejoiced when her trainees had chil- do your homework! she later said. She Her magic stemmed from unconditional dren. When I was 8 months pregnant with was also hospitable. Mel hosted Mother faith in others. Lewis First, then Assis- my third child, I invited Mel for dinner Teresa when the sister received an hon- tant Professor and previously Mel’s intern, at our home. She brought Maine blue- orary degree at Harvard in 1982. Later, at was asked by Mel to co-edit a new berry jam, happy to meet my family. My Children’s Hospital (CHMC), she hosted Pediatrics textbook with her (5). Lewis 2-year-old son delighted her by ooh-ing Mildred Stahlman,who was the first to ven- is now a Pediatrics Chairman (6). Mel and ahh-ing over the dessert, hoping to tilate a baby. Originally competitors, Mel thought highly of Mary Williams from skip dinner. She later sent a warm thank and Millie had become good friends. Boston University, who had done a sab- you note, including 20 unusual baby names In 1980, Mel spoke to the women MD- batical in CHMC Neonatology, and often she’d collected from the NICU. PhD students at HMS, recalling her father’s sought Mary’s valuable critique. When In 1994, Mel was elected into the loving support. She shared some personal Stella Kourembanas became a Neonatology National Academy of Sciences for her dis- challenges, especially convalescing from TB SCCOR Program Director at CHMC, Mel covery that newborns require surfactant during internship. “I had a lot of time to was delighted and attended monthly meet- to breathe (7, 8). Her comment? “Imagine think about the lung – and I did!” she ings, closely following our progress with that! I never even published in that jour- laughed, closing with:“don’t simply do well interest. During those years, it seemed that nal!” Later she ran for AAAS President (9) in your field. Create a new field. For exam- Mel was passing the baton to Stella, one of opposite an engineer whose essay detailed ple, we could really use a field of Informa- her closest protegés. Now, Stella is Director his leadership experience. Mel’s essay sim- tion Technology!”Mel often had innovative of Newborn Medicine at CHMC. ply addressed many challenges facing sci- ideas (1). Mel’s enthusiasm was infectious. Once ence: needs for improved rice production, Starting my laboratory at Brigham and she asked me to tour the new Beth Israel vaccinations, clean water, recognizing chil- Women’s Hospital (BWH), seeking to learn NICU with her. The facilities and care were dren as our most precious resource. Mel methods of studying lung development, impressive, yet the highlight was one infant won the election. I collaborated with John Torday, whom who would only drink mother’s milk, but Mel was nobody’s fool. She would tell Mel had brought from McGill to Harvard. not from a bottle – so they tried feeding her her new ideas to over 14 people so every- When I asked for Mel’s feedback on our milk from a cup. Breakthrough! Mel was one knew the ideas were hers; then she first manuscript (2), suggesting a meeting excited because many developing coun- would publish quickly. She was neither in her office, she replied, “Absolutely not! tries have insufficient bottles. This simple offensive nor defensive. In Japan (10), Mel

www.frontiersin.org March 2014 | Volume 2 | Article 18 | 19 Sunday Mel Avery as mentor

Returning home from Mel’s funeral, I gazed out at our brown December garden and a rose bush that had been dead for over a year, surprised to discover – a piece of paper? No, it was a perfect full-blown pink rose (Figure 1). “Mel did it!” I thought. She could move mountains – of course it was Mel! That single rose lasted over 3 weeks in winter weather. Mel, you were right: we only have to do one thing well. Love is the key: love of scientific discovery and human- ity. Giving everything to help children, Mel transcended departmental expectations by founding neonatology. She transcended academics by making the world her insti- tution through UNICEF. Ultimately, she transcended time by living on in the hearts of all. Mel’s greatest legacy was her inspi- ration of so many to believe in themselves FIGURE 1 |The Rose sent by Mel: the Redouté Rose was named after Joseph-Pierre Redouté, a Belgian and what they can do to make the world a artist who painted roses for Marie Antoinette, then for Josephine Bonaparte, “the rarest and most beautiful plants obtainable.” He was immortalized through his timeless inspiration of others. better place, symbolized by a perfect rose. Just like Mel. REFERENCES 1. Greenes RA, Shortliffe EH. Medical informatics. An emerging academic discipline and institutional said: “I close with a quotation attributed Then, Mel became increasingly forgetful priority. JAMA (1990) 263:1114–20. doi:10.1001/ to a famous German pathologist in the last and stopped coming to CHMC. She had jama.1990.03440080092030 century (Virchow): all new knowledge goes live-in nursing care, thanks to her family: 2. Sunday ME, Hua J, Dai HB, Nusrat A, Torday JS. through three phases: (1) it is ignored; (2) it Sue, Bill, Jennifer, and Carl Smith. At home, Bombesin increases fetal lung growth and matura- evokes hostility; (3) haven’t we known this Mel held tightly to her biography, written tion in utero and in organ culture. Am J Respir Cell Mol Biol (1990) 3:199–205. doi:10.1165/ajrcmb/3. all along?” by Bojan Jennings, her chemistry professor 3.199 Mel lived a full life. She often traveled from Wheaton College (11). She was cling- 3. Northway WH. Bronchopulmonary dyspla- with a companion. Her niece, Sue, wrote: ing to memories, precious jewels slipping sia: twenty-five years later. Pediatrics (1992) “everyone in our family had trips with Mel away. 89:969–73. including my folks. Moreover, she often The last time I saw Mel was 5 days 4. Berger TM, Frei B, Rifai N, Avery ME, Suh J, Yoder BA, et al. Early high dose antioxidant vitamins took friends/colleagues with her on trips before she died, at a nursing home near do not prevent bronchopulmonary dysplasia in to various parts of the world.” CHMC her childhood home. Sue and Bill had premature baboons exposed to prolonged hyper- Neonatology held a surprise 70th birth- filled her room with her awards, nametags, oxia: a pilot study. Pediatr Res (1998) 43:719–26. day party for her, with ~30 people telling and family photographs: a lifetime of love doi:10.1203/00006450-199806000-00002 5. Avery ME, First LR. Pediatric Medicine. Baltimore: Mel stories. When she received the How- and accomplishment. At that moment, Williams & Wilkins (1989). land Award, Pediatric’s greatest award, her all I did was sit beside her, holding her 6. Hostetter MK. Introduction of the Ameri- previous intern, Margaret Hostetter pre- hand. She was awake and comfortable, gaz- can pediatric society’s 2005 John Howland sented it (6). Her post-award celebration ing into the distance and speaking in an award recipient, Mary Ellen Avery, M.D. Pedi- included Lewis First’s musical rendition of unknown language to someone only she atr Res (2005) 58:1311–6. doi:10.1203/01.pdr. 0000189312.67186.d8 “Mel,” which she enjoyed singing at home. could see. 7. Avery ME, Mead J. Surface properties in rela- She was delighted to stop and smell the On December 4, 2011, with Sue and Bill tion to atelectasis and hyaline membrane disease. roses. beside her, Mel became a free spirit. Her AMA J Dis Child (1959) 97:517–23. After moving to Duke in 2004, I vis- funeral was at the church she’d attended 8. Avery ME. Surfactant deficiency in hyaline mem- ited Mel every year around Thanksgiving. as a child. Like Mel, it was unpretentious brane disease: the story of discovery. Am J Respir Crit Care Med (2000) 161:1074–5. doi:10.1164/ Once, I drove her to pick up a complete and heartfelt, with family and a few friends ajrccm.161.4.16142 turkey dinner for her family. Mel had never Linda van Marter and I went together. Fred 9. Avery ME. Presidential address. What is good for learned to cook, but that never stopped her Lovejoy extolled her influence at CHMC. children is good for mankind: the role of imag- from having a party. Another time at her Sue spoke a universe of love. Bill intro- ination in discovery. Science (2004) 306:2212–3. home, Mel showed me her nametag collec- duced Mel as The Personal Physician for doi:10.1126/science.306.5705.2212 10. Philip AG. Historical perspectives the underpin- tion from the meetings she had attended. the Smith Family: “take 2 aspirins and call nings of neonatal/perinatal medicine: surfactant In 2007, Mel was animated about the BBC me in the morning.” How marvelous that deficiency to surfactant use. Neoreviews (2002) coming to interview her. Mel’s family has the same sense of humor! 3:e239–42. doi:10.1542/neo.3-11-e227

Frontiers in Pediatrics | Neonatology March 2014 | Volume 2 | Article 18 | 20 Sunday Mel Avery as mentor

11. Jennings BH. Mel: A Biography of Dr. Mary Citation: Sunday ME (2014) Mel Avery: mentor, role Attribution License (CC BY). The use, distribution or Ellen Avery. North Charleston, SC: CreateSpace model, friend, mother of us all. Front. Pediatr. 2:18. doi: reproduction in other forums is permitted, provided the (2009). 10.3389/fped.2014.00018 original author(s) or licensor are credited and that the

This article was submitted to Neonatology, a section of original publication in this journal is cited, in accordance the journal Frontiers in Pediatrics. with accepted academic practice. No use, distribution or Received: 05 March 2014; accepted: 06 March 2014; Copyright © 2014 Sunday. This is an open-access arti- reproduction is permitted which does not comply with published online: 31 March 2014. cle distributed under the terms of the Creative Commons these terms.

www.frontiersin.org March 2014 | Volume 2 | Article 18 | 21 OPINION ARTICLE published: 21 March 2014 PEDIATRICS doi: 10.3389/fped.2014.00021

In remembrance of Dr. Mary Ellen Avery

Joanna Floros* The Pennsylvania State University College of Medicine, Hershey, PA, USA *Correspondence: jfl[email protected] Edited and reviewed by: John Steven Torday, University of California Los Angeles, USA Keywords: remembrance, Mary Ellen Avery, Floros, Neonatology, Echo Lake

Dear Mel, The trips to “Echo” Lake – what unfor- to hear the calling of the loons and to see gettable memories these were for the the Aurora Borealis. People the world over know about your entire family. The fish experiment you Traveling with you whether in Nigeria, academic and medical accomplishments. I had planned so carefully. The hypothesis Greece, or USA was always a lot of laughs. I would like to share with your colleagues, you wanted to test was that application miss that! In the midst of laughing and joy the Mel that in the 1980s I got to know of surfactant (TA surfactant) between the you coached me to go where I belonged – to and spend time with outside the laboratory gills of freshly caught and still jumping a basic science department. In the ever can- (although science and how science can ben- fish will allow them to breath and sur- did Mel way, you said, “If you stay, we will efit “your” babies was just a breath away in vive longer out of the water than their take advantage of you.”I did move to a basic anything we did). untreated counterparts. Andreas and Nikos science department, but now I am back in The time I really got to talk with Mel (the youngest science helpers you proba- the Department of Pediatrics. There was outside the Harvard confines was when I bly ever had) kept track of the timing until something about that early “imprinting” first roomed with you in DC, USA. It was the fish stopped kicking. You had them being in Peds. But guess what? It “ain’t” the a last minute decision to attend the meet- also participate in the actual experiment, same without Mel. ing and you so graciously offered to let me holding the fish and opening the gills to Thanks for all you did. You are never far room with you. That was a great experi- apply surfactant while we kept timing. As from our thoughts! ence for a young academician to have the a good scientist you collected the data. Yana exclusive attention of a“giant”like you. The You wrote the manuscript, naming my two most memorable incident was when you young sons, then 8 and 4 years old, as coau- Received: 17 February 2014; accepted: 09 March 2014; published online: 21 March 2014. locked me out one evening. What a sur- thors. The experiment was fun, the hypoth- Citation: Floros J (2014) In remembrance of prise when the door did not open. Do I risk esis did not prove correct (if I recall cor- Dr. Mary Ellen Avery. Front. Pediatr. 2:21. doi: waking up the“giant”or do I make alternate rectly). Unfortunately, this valuable manu- 10.3389/fped.2014.00021 plans – of course if I didn’t show up all night script got lost somewhere between a move This article was submitted to Neonatology, a section of what would you have thought? You were to Pennsylvania and a house flood a few the journal Frontiers in Pediatrics. Copyright © 2014 Floros. This is an open-access article very kind and apologetic for not thinking years ago. distributed under the terms of the Creative Commons when you pulled the lock on. The subse- Not to mention the lobster dinners and Attribution License (CC BY). The use, distribution or quent evenings I made sure to be the first the boat rides on Echo Lake with the best reproduction in other forums is permitted, provided the in the room. Also not to be forgotten on captain I ever had who knew all the nesting original author(s) or licensor are credited and that the trees for the ospreys and the best fishing original publication in this journal is cited, in accordance that trip was when you suggested we all stop with accepted academic practice. No use, distribution or and play pinball, much to the amusement spots. Echo Lake getaways with Mel and reproduction is permitted which does not comply with of some teenagers on a nearby machine. family were amazing. It was the first for me these terms.

www.frontiersin.org March 2014 | Volume 2 | Article 21 | 22 OPINION ARTICLE published: 22 April 2014 PEDIATRICS doi: 10.3389/fped.2014.00019 A remembrance of Mary Ellen Avery, M.D.

Julie R. Ingelfinger 1,2*

1 Pediatric Nephrology, MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, MA, USA 2 Department of Pediatrics, Harvard Medical School, Boston, MA, USA *Correspondence: jingelfi[email protected] Edited and reviewed by: John Steven Torday, University of California Los Angeles, USA

Keywords: mentors, mentoring, pediatrics, leadership, commentary

I was a recently hired member of the I feel it is important while thinking In some published interviews, Mel newly established Division of Pediatric about Mel Avery to remember that at the acknowledged those things in which she Nephrology and an Instructor in Pedi- time she went to medical school at Johns was and was not comfortable. She was most atrics at Harvard Medical School when Mel Hopkins, few women were entering the at home with younger, not older children, Avery became the Chief of the Depart- field medicine – not all schools accepted and she always wanted to do her best. She ment of Medicine and Physician-in-Chief women, and those that did still, accepted noted that cutting corners made her tense. at Children’s in 1974. There was excite- few per class. There were 4 in her class Mel appeared to be somewhat uncomfort- ment, as Dr. Avery’s appointment was a (of 90). An extraordinary student, she had able in many situations, and she was not a “first” unfolding right in front of those been encouraged by a next-door neigh- natural politician – probably not surpris- of us who, as young women physicians, bor who was a physician, the pediatri- ing given the era and her wish to complete hoped to have careers in academic pedi- cian Dr. Emily Bacon. Mel’s trajectory was all charges and tasks to perfection. atrics, and anticipatory talk filled the cor- admirable, in that she made her seminal I thought she was also, in a certain way, ridors of Children’s. On her arrival, Mel discovery at a relatively young age. The shy. What I perceived as Mel Avery’s shyness Avery was an automatic role model for the number of women in most classes had and reticence to speak of her accomplish- women among the faculty. She had made more than doubled by the time I went to ments was, in my view, a mixed blessing. a major scientific discovery that a lack of medical school, but it was still pitifully low. It was refreshing to have a chief who did surfactant caused respiratory distress syn- And Dr. Avery predicted that before long at not seem to have a big ego, as many do. She drome in neonates, and she was still young least a third of most medical school classes clearly had vision,but it was hard to ferret it (in her mid-forties), with abundance of would be women – a prediction that antic- out on a daily basis. But vision,she had,and energy. I was delighted and proud to have a ipated an increase but falls short of current it was something I particularly appreciated. woman, and one so accomplished, become statistics. One of her lasting accomplishments the Physician-in-Chief at Children’s. Her I do not think Mel fully understood how while at Children’s was the establishment of hiring and her achievements allowed us important a mentor she was for those of the Joint Program in Neonatology at Chil- to see that a woman could have a promi- us who were house officers and junior fac- dren’s and the other nearby Harvard Hos- nent role in academic medicine. The sense ulty, even those of us with whom she did pitals. It strengthened the residency pro- I had as a young faculty member was that not work closely as individuals. What she gram and was an improvement for all the Dr. Avery expected hard work and dedica- shared in formal interviews, for example, programs concerned. Under Mel’s hand, tion, which was a self-selected trait among with Georgia Litwack, with whom she sub- neonatology became a major strength in those women in the Department of Pedi- sequently wrote a book, would have had an Boston Pediatrics. atrics at Children’s. So, the fit for us was a extremely empowering effect had she been After her years as Physician-in-Chief good one. able to share it more directly with those of at Children’s, Mel turned her attention to It was a boost in the arm to see that Dr. us who were coming along in the depart- global health, and was particularly con- Avery supported women in medicine, and ment at that time. However, a number of cerned about human rights and socioeco- she was instrumental in asking Dr. Mary people became closer to her over time, with nomic disparities. She worked hard with Ellen Wohl, who had come to Children’s in excellent effect. UNICEF as a health ambassador, advocat- 1969, to become the chief of the Division of Dr. Avery realized that the expectations ing world wide to encourage polio vaccina- Pediatric Respiratory Diseases, and in the of patients and the public were changing, tion and oral rehydration therapy. ensuing years Dr. Wohl became a pioneer and she made efforts that Children’s would While thinking about Mel Avery, I feel in her own right. And in 1975, Dr. Lynne pay attention to this trend, which proved that her contributions were both focused Reid, a pulmonary pathologist became the prescient. I think she helped Children’s get and broad. I feel fortunate to have had her Chief of Pathology at Children’s. ready for these changes. as my chief.

www.frontiersin.org April 2014 | Volume 2 | Article 19 | 23 Ingelfinger Mary Ellen Avery, MD remembrance

Conflict of Interest Statement: The author declares Citation: Ingelfinger JR (2014) A remembrance of Mary Attribution License (CC BY). The use, distribution or that the research was conducted in the absence of any Ellen Avery, M.D. Front. Pediatr. 2:19. doi:10.3389/fped. reproduction in other forums is permitted, provided the commercial or financial relationships that could be 2014.00019 original author(s) or licensor are credited and that the construed as a potential conflict of interest. This article was submitted to Neonatology, a section of original publication in this journal is cited, in accordance the journal Frontiers in Pediatrics. with accepted academic practice. No use, distribution or Received: 16 February 2014; accepted: 07 March 2014; Copyright © 2014 Ingelfinger. This is an open-access arti- reproduction is permitted which does not comply with published online: 22 April 2014. cle distributed under the terms of the Creative Commons these terms.

Frontiers in Pediatrics | Neonatology April 2014 | Volume 2 | Article 19 | 24