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Perspectives in Physiology

Lawrence D. Longo

The Rise of Fetal

and Neonatal
Physiology
Basic Science to Clinical Care
Second Edition
Perspectives in Physiology

Published on behalf of The American Physiological Society

by Springer
Perspectives in Physiology
This fascinating series seeks to place biomedical science inside a greater historical
framework, describing the main pathways of development and highlighting the
contributions of prominent investigators.

This book series is published on behalf of the American Physiological Society

(APS) by Springer. Access to APS books published with Springer is free to APS
members.

More information about this series at http://www.springer.com/series/11779

APS publishes three book series in partnership with Springer: Physiology in Health
and Disease (formerly Clinical Physiology), Methods in Physiology, and Perspec-
tives in Physiology (formerly People and Ideas), as well as general titles.
Lawrence D. Longo
This work was completed by Steven M. Yellon,
Ravi Goyal, Ciprian P. Gheorghe, Justo Alonso,
and Michael A. Kirby

The Rise of Fetal and

Neonatal Physiology
Basic Science to Clinical Care

Second Edition

Foreword by Kent L.R. Thornburg

Lawrence D. Longo (deceased)
Formerly at:
Longo Center for Perinatal Biology,
Loma Linda University School of Medicine
Loma Linda, CA, USA

This work was completed by

Steven M. Yellon Ravi Goyal

Professor of Physiology Associate Professor of Physiology
Departments of Basic Sciences and Pediatrics Department of Basic Sciences
Lawrence D. Longo Center for Perinatal Lawrence D. Longo Center for Perinatal
Biology Biology
Loma Linda University, School of Medicine Loma Linda University, School of
Loma Linda, CA, USA Medicine
Loma Linda, CA, USA
Ciprian P. Gheorghe
Assistant Professor of Neonatology Justo Alonso
Department of Obstetrics and Gynecology, Professor and Chairman Department of
Loma Linda University, School of Medicine Obstetrics and Gynecology
Loma Linda, CA, USA Department of Obstetrics and Gynecology
University of Uruguay, Montevideo
Michael A. Kirby School of Medicine
Professor of Anatomy Montevideo, Uruguay
Departments of Pathology and Human
Anatomy and Pediatrics
Lawrence D. Longo Center for Perinatal Biology
and
Associate Vice-President Research Affairs
Loma Linda University, School of Medicine
Loma Linda, CA, USA

Perspectives in Physiology
ISBN 978-1-4939-7482-5 ISBN 978-1-4939-7483-2 (eBook)
https://doi.org/10.1007/978-1-4939-7483-2

Library of Congress Control Number: 2017955620

© The American Physiological Society 2013, 2018

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Foreword to the Second Edition

When you ask a successful scientist about their training, he or she will inevitably
refer to one or more heroes who have changed the course of their careers. In every
case, the hero being revered will have been a brilliant scientist and marvelous
mentor. In addition, he or she will have had a gift for writing, caring, nurturing, and
teaching academic survival skills. Thus, for those of us who are among the
privileged who pursue the secrets of the natural world, we have our heroes to
thank. Hero reproduction, it appears, is the mechanism by which cutting-edge
science is passed from one generation to the next.
In my case, I was molded by professors who encouraged me, beginning as an
undergraduate. Those who influenced me most included Drs. Elver Voth, Howard
Hilleman, Job Faber, and James Metcalfe. However, not all of my heroes were
overseeing my education. I came to know and appreciate others at national scien-
tific meetings and at different universities during my travels. These included
Geoffrey Dawes, Robert Boyd, and David Barker. In addition, there were scientific
contemporaries from universities around the world with whom I “grew up” in the
field and for whom I have great admiration to this day.
I am particularly pleased to honor one of my heroes in this foreword, the late
Lawrence D. Longo (1926–2016). Dr. Longo had the personal appearance, not so
far from the Albert Einstein look, and the intense personality of a natural born
leader. Not only have I admired him for decades because he paid so much attention
to me when I was a junior faculty member, but more because I discovered that he
was a source of encouragement to a host of people in the field of human develop-
ment both on a personal level and as a cheerleader for the Society for Reproductive
Investigation.
Over the course of Dr. Longo’s long career, he saw dramatic changes in the field
he loved most—pregnancy and fetal development. As for all scientists in this highly
important field, his lineage began decades ago with greats such as Joseph Barcroft
(1872–1947) at Cambridge University, Donald Barron (1905–1993) at Yale Uni-
versity, Geoffrey Dawes (1918–1996) at Oxford University, Geoffrey Thorburn
(1930–1996) at Monash University in Melbourne Australia, Elizabeth Ramsey

v
vi Foreword to the Second Edition

(1906–1993) at the Carnegie Institution in Washington, and Jeffrey Robinson

(professor emeritus) at the University of Adelaide, Australia. It was the powerful
contributions to the field of pregnancy and fetal development of these leaders and
their colleagues that led Dr. Longo to enshrine a few of them in this volume and by
so doing remind young scientists of their roots.
By the mid-twentieth century, the field of fetal development was warming
up. The pioneering work of these aforementioned forefathers and mothers set the
field aflame and the fire spread across the globe, especially across North America,
Australia, and New Zealand. Longo himself was swept up in the quest to understand
the mysteries of the invisible, and mostly inaccessible, fetus. Once it was discov-
ered in the 1960s that the sheep fetus could be studied chronically in its natural
habitat, it became the model of choice for dozens of groups worldwide. The
resulting information rush brought a thorough description of fetal hemodynamics
and metabolism, placental blood flow, brain development, endocrine regulation,
and pulmonary maturation. We now take for granted our understanding that the
hemoglobin of the fetus binds oxygen more tightly than does its mother’s, that
blood flows through the heart muscle of the fetus at twice the rate found in the adult
heart, and that the fetus must drink its amniotic fluid and practice breathing before it
is born. From all these marvelous discoveries, modern obstetrical medicine owes a
great debt to fetal physiologists who discovered the intricacies of development and
which now provide the foundation for the practice of clinical fetal medicine.
New technologies appeared during the 1970s and 1980s that allowed fetal
measurements that were not previously thought possible. These included measure-
ment of fetal blood flow with radiolabeled microspheres, miniature Doppler flow
sensors, Doppler ultrasound, and electromagnetic and transit time flow sensors in
addition to implantable electrodes to measure electrical activity in the brain and
striated and smooth muscle. Many discoveries in the fetus, like surfactant therapy
from Dr. Mont Liggins’ laboratory in Auckland, changed clinical practice for
women and their fetuses forever. Toward the end of the 1980s, after hundreds of
papers had been written demonstrating the homeostatic mechanisms ensuring fetal
survival in the womb, scientists began to wonder what new frontiers would be
needed to provide better clinical applications of the knowledge gained over the
previous 30 years. Then, without warning, the landscape changed dramatically.
In 1989, Professor David J.P. Barker from the University of Southampton
published data showing an inverse relationship between mortality from ischemic
heart disease and birthweight among 15,000 men and women in Hertfordshire,
UK. Many fetal scientists, including me, were skeptical, lacking an obvious bio-
logical explanation. However, Barker was undeterred. He embraced the world of
basic science and sought out fetal physiologists to find answers. Soon, a new field of
so-called fetal programming, now officially called the developmental origins of
health and disease (DOHaD), was born. Suddenly, experts on pregnancy and fetal
development were uncovering mechanisms explaining the very core of human
existence, the early life origins of chronic disease. To this day, fetal biologists
and pregnancy experts sprinkled across the Western world are making headway in
Foreword to the Second Edition vii

understanding how developmental plasticity in early life leads to vulnerability for

disease in adulthood. Until their deaths, Drs. Longo and Barker were among them.
With a sudden link to human disease, no longer would fetal biologists be content
to describe obscure facts regarding physiological development. The quest had
changed. Now the question for all developmental biologists became: what are the
mechanisms though which environmental stressors influence reproduction and
postnatal development and lead to vulnerability for adult-onset disease? This
change in mind-set came at a time when the prevalences of obesity, diabetes, and
uncontrolled hypertension were increasing year after year as they are today. The
rapid epidemic of chronic disease in the USA over the past 20 years cannot be
explained by changes in DNA sequence. Rather, based on recent evidence from
fetal biologists, one can fairly argue that the recent unprecedented increases in
chronic diseases are rooted in responses to environmental challenges during early
development. Thus, current students of development have a new mandate linked
directly to human health.
Dr. Longo was clever of mind; he intuitively understood the importance of the
developmental origins of disease as a game changer for the field of fetal physiology.
Over his career, he gained expertise on one topic after the next as he followed his
interests. His focus moved from pregnancy to placental function to fetal cardiovas-
cular function and finally to fetal brain development. In every case, he and his
colleagues made highly significant discoveries.
After becoming the director of the Center for Perinatal Biology (1973–2012), he
recruited a strong team of young scientists who carried the field forward with
enthusiasm. Dr. Longo and collaborators began to study the adaptations made by
the vasculature of the fetal brain under conditions of hypobaric hypoxia when
pregnant ewes were housed at 12,000 feet at the White Mountain Research Station
in California. Their findings led to concerns about how fetuses deprived of oxygen
might suffer later as adults, a field of study for which the Loma Linda team is
deservedly held in high esteem to this day.
During his long tenure at Loma Linda University, Dr. Longo became an impor-
tant leader for the entire field because somehow he was able to “adopt” scientists
from around the country as part of the Loma Linda family. An invitation to visit the
Loma Linda laboratories meant an invitation to join a new family of investigators.
Thus, scientists, invited from around the world, came to Loma Linda to join in the
quest for answers to the most difficult problems in human pregnancy and late life
diseases of offspring. While the contributions made by Dr. Longo and colleagues
will be long remembered through their hundreds of significant contributions to the
literature, Dr. Longo himself has contributed much more to science than an
impressive list of published papers. He modeled for young men and women how
to become a scientist of stature and integrity. It is that very contribution to the lives
of others that will continue, like heritable DNA replication, to be passed on from
this generation to the next.
What makes a person a highly effective mentor? Reliving Dr. Longo’s success
may go some way toward giving an answer.
viii Foreword to the Second Edition

Dr. Longo had vision. Visionary people often have trouble keeping their feet on
the ground. They sometimes become hopeless utopians. However, Dr. Larry
Longo’s vision was practical. He envisioned building a world-class group of fetal
investigators and along with his talented colleague, Gordon Power, he saw his
vision come to fruition.
Dr. Longo had courage. Young people may not know that a great deal of courage
is required to build an organization from scratch. Why, because if talent and
resources are not forthcoming, the enterprise fails. Overcoming the risk of failure
with courage is key to success. Dr. Longo charged into an area of biology, the
developing brain, in which he had not previously worked. His early discoveries
were highly complex and difficult to explain. Nevertheless, those novel findings
now shed new light on the regulation of the vascular elements in the brain in
response to hypoxia and apply to millions of people who were deprived of oxygen
before birth.
Dr. Longo had a warm sense of humor. No one who knew him will forget his
hearty laugh. One time when I visited Loma Linda, I showed our new function
curves from the right and left ventricles of the fetal heart. I remarked that Ray
Gilbert, one of Dr. Longo’s esteemed colleagues, was indeed the father of the fetal
function curve. Larry Longo was tickled by the comment and he asked, if Ray was
the father, who was the mother. I said I guessed I was. He could hardly stop
laughing. In spite of the fact that he was not above being angry over an inept
comment by a grant reviewer, or worse, a grant application rejection, he was always
able to cool down and resume his true nature as a kind and gentle person who cared
about Loma Linda University, his scientific colleagues, and a host of people across
the country who knew him as a friend.
When you read this volume, I suggest that you see it through the eyes of
Lawrence Longo who was fascinated by history and who knew more about the
historical roots of fetal biology than any other person alive today.

Center for Developmental Health Kent L.R. Thornburg

Knight Cardiovascular Institute
Portland, OR, USA

Moore Institute for Nutrition and

Wellness, Oregon Health & Science
University, Portland, OR, USA
Foreword to the First Edition

The 1960s and 1970s were wonderful times to be doing research in fetal
physiology. To be in Oxford during that period was to be in one of the great centers
of research activity. I had the good fortune to be at the right place at the right
time. Oxford was our Camelot. Colleagues from around the world spoke
enviously of one having a “Been to Oxford” (BtO) degree. Geoffrey S. Dawes
(1918–1996), Director of the Nuffield Institute for Medical Research in Oxford,
was undoubtedly the father figure (some said godfather figure) of fetal physiology
in his day. His contributions were of such significance that his position as a giant in
the field was unassailable. He had built upon the foundations laid by Barcroft,
Eastman, Barron, and those others who had preceded him to define a new field
of investigation.
Why was Oxford so special? Partly, it was the lure of that venerable city, and the
Oxford “way” of doing things. Partly, it was the coming together of a remarkable
group of outstanding and enthusiastic young physiologists working with some
extraordinary senior leaders and visitors. There was a critical mass of colleagues
and supportive technical staff, and a buzz around Geoffrey’s Nuffield Institute.
Time was immaterial, there always was someone working at a new problem or
ready to share a new finding. Crucial was the realization that the fetus as not just a
little adult, but was a distinct, viable entity, with a separate and often quite different
physiology. It was clear that everything that we knew about adult physiology did
not necessarily apply to the fetus, and needed to be rediscovered or at least
reexamined. Every day seemingly brought another discovery, another surprise.
The institute was adjacent to the University of Oxford’s John Radcliffe Hospital
and its Nuffield Departments of Obstetrics and Gynecology and of Pediatrics. The
leaders of those departments were sympathetic towards research, and it was quickly
clear that this new science had immediate application to clinical practice in
obstetrics and pediatrics. The proximity of the institute to the clinical wards, to
enthusiastic young physicians, and our attendance at clinical rounds facilitated this
process. We were doing translational research and knowledge exchange before it
became fashionable, without even the need to give it a fancy name.

ix
x Foreword to the First Edition

Without question, the simultaneous and coincidental development of an array of

new techniques was crucial to the opening of this new field. There was a rapid
advance from the study of the sheep fetus in short-term acute experiments, ex
utero, to extraordinary studies with the in vivo chronically catheterized fetal lamb.
In 1969, Geoffrey Thorburn had published with John Bassett the rise in plasma
cortisol concentrations that preceded the onset of birth in chronically catheterized
fetal sheep, and later had helped establish that procedure in Oxford. I shall always
remember that great physiologist and chronicler of the placenta, Emmanuel
Ciprian Amoroso, returning to the ARC Institute of Animal Physiology at
Babraham, Cambridge, from a trip to Australia. I was a graduate student at that
time, and Amo lost no chance to sing the praises of Geoff Thorburn and this
remarkable advance. Little did I know that in 4 years I would be working with him
and I could not have guessed at the influence that he would have on my own career.
But, let us get back to Oxford. Mention also must be made of Derek Wyatt, an
outstanding physicist and member of the institute, who was crucial in developing
many of the flow probes that would be used in these new “fetal” preparations. The
new technique of radioimmunoassay had just been developed to the point that we
could measure multiple hormones in very small samples of fetal blood. We had
techniques for recording electrical signals from the fetal brain in utero, we could
measure blood flows and distribution, and we could ask the “undisturbed fetus”
questions of critical clinical importance: “how are you? how are your blood gases?
what are your glucose levels?” We could measure fetal responses to perturbations,
infusions of hormones and drugs, follow physiologic changes through the birth
process and into the newborn period. I remember well the time that we were
making the first measurements of the rise in Prostaglandin E2 in the fetal circula-
tion before birth. I proudly showed the print out from the scintillation counter to
Geoffrey Dawes. He was unimpressed. I had not explained that as the counts went
down, the concentration was going up. But then he asked whether this might have
anything to do with the decline in fetal breathing movements that occurs at that
time, and suddenly I had his full attention, and a year’s worth of suggested
experiments!
Our scientific advances were helped by good-natured fellowship and by com-
petition. There was great collegiality and daily debate at morning coffee and
afternoon tea held around the round table in the lobby of the institute (see my
letter to LDL in Chap. 20). Here Geoffrey Dawes was masterful and a wonderful
stimulator of new ideas. There was also great debate at the White Hart Pub at lunch
time and after work in the evening. It is strange that today we have to force these
interactions with scheduled meetings. But, there was also competition. In the early
1970s there were three related Medical Research Council (MRC) program grants at
Oxford, led by Geoffrey Dawes (GSD), Geoffrey Thorburn (the big G) and
Alexander Cuthbert Turnbull (later Sir Alexander; 1925–1990), respectively, deal-
ing with parturition and fetal physiologic changes near birth. The competition in
research was and is healthy. It helps to drive us forward. It also infuses an
Foreword to the First Edition xi

environment with measureable energy that leads to pride and excitement, and
eventually to a legacy of accomplishment. It helps create leadership and lifelong
friendships and networks. It was an environment that brought Oxford together at
international meetings, particularly in exchanges with other major centers that
were emerging at that time. Importantly locally amongst these was the excellent
group in Cambridge of Robert Comline, Marion Sliver, successors of Sir Joseph
Barcroft in the perinatal research field, with the young Peter Nathanielsz and
Abigail Fowden (although, as a Cambridge graduate, I was just a little uneasy
with the light blue–dark blue conflict). The University of Oxford Nuffield Depart-
ment of Obstetrics and Gynaecology photographs from 1974 to 1975 are so
revealing of the environment at that time. Virtually every one of the junior staff
members and trainees in those pictures went on to hold a major chair or a
directorship later in their career, but as colleagues they have remained in touch
with each other, bonded by the Oxford experience.
The public environment was also “right” for doing fetal research. In the United
Kingdom, the MRC was enthusiastically supportive through staff appointments and
research grants; in the USA, fetal physiology was gaining momentum at the
National Institutes of Health. The media, the general public, and some key politi-
cians wanted to know about life and development in the womb. Preterm birth
occurred in one in ten pregnancies. At a time when we were just starting to learn
about the regulation of lung surfactant, the public wanted to know how to prevent
preterm birth and how to look after the premature baby. The landmark study of
“Mont” Liggins and Ross Howie on the use of glucocorticoids to prevent respira-
tory distress syndrome was published in 1971. It resulted directly from studies of
cortisol infusion into fetal sheep, the perceptive insight of Mont Liggins, and
minimal bureaucracy in moving basic research into a clinical trial. Mothers wanted
to know how the environment might affect their baby. Research offered answers.
The magic and mystique of the environment inside the womb became mainstream
reading. A black box was opening quickly with new information based on excellent
science. Politicians and funding agencies listened carefully and were extremely
supportive.
But research happens in cycles. Often these last only 5–10 years. An area
becomes topical, a new approach offers a major advance and folk jump onto the
bandwagon, until the research becomes routine. For a short time, grant funding
committees and study sections look favorably on something that is cutting edge.
It may be a new field of research (such as fetal physiology) a new topic
(prostaglandins, insulin-like growth factors), a fascinating and important discov-
ery (surfactant), or the emergence of a new technique (the chronic fetal sheep
preparation and assay of hormone receptors). Fetal physiology seemed to happen
in a way and at a time that allowed a convergence of these different factors and
approaches. The field opened up technically, the translation (such as in fetal
xii Foreword to the First Edition

monitoring, stimulation of lung surfactant, or surfactant therapy), was obvious in

obstetric and neonatal practice, and that fuelled public interest and media support.
Because there was a whole field of fetal physiology to be discovered, the wave
lasted a bit longer than many. In many ways this was good. But I also believe that
fetal physiologists lost the game or only recognized it when it was too late for
them, to the developmental biologists, initially, and then to mice. We missed the
fiscal reality of switching from sheep to mice and we were slow to appreciate the
power of mutating a gene and the ability to knock in and knockout genes. Of
course, we soon became useful in helping to interpret phenotypes (and there was
some very naı̈ve phenotypic interpretation of some early mouse knockouts), but
the agenda had changed, and a new generation of investigator was driving it.
The field of fetal physiology continues today, of course; that is the nature of
scientific waves. But, I think this is what Geoffrey Dawes meant by his oft (mis)
quoted comment about the major questions in fetal physiology being answered by
the time of his retirement. Most major questions had been addressed at a physio-
logic level, and needed new genetic approaches to achieve further mechanistic
advance. Geoffrey also saw the emerging importance of understanding the fetal
origins of adult disease, and championed the meeting in Italy in 1989 where David
J.P. Barker presented his very early information to a group of fetal physiologists. If
there was an obvious way forward for fetal physiology, it was through understand-
ing the developmental origins of disease. This needed a physiologic approach but
had to be coupled with application of different ’omic techniques and epigenetics.
But, many Ob-Gyn departments had missed an opportunity to emerge as the
hotbeds of university and hospital research, as departments of developmental
reproductive biology, combining integrative physiology with cellular and molecu-
lar mechanisms of development.
Interestingly, the antivivisection movement was also a factor in the decline of
fetal physiology as we knew it. It easily generated more adverse press against
research with sheep and subhuman primates, than it did against research on mice.
New rules for the conduct of research, new animal requirements, and spiraling costs
have driven many classic fetal physiologists out of the animal house. Ironically, the
antivivisection movement and fiscal reality actually forced some sheep fetal phys-
iologists toward developmental biology, to develop new models and gain familiar-
ity with new molecular approaches. The new models of translational research that
link basic science to population biology and the health care systems will allow fetal
physiologists to flourish, and I am optimistic that we are still training a cadre of
needed and worthy successors.
Geoffrey Dawes became Director of the Nuffield Institute at age 30 in 1948;
5 years before Watson and Crick published the structure of DNA. At the time, he
had only eight publications to his name. This volume portrays him accurately. He
was an astute and critical investigator, maintaining the highest standards of
scholarship and expecting others to reach those same values. He was sometimes
Foreword to the First Edition xiii

antagonistic. He was harshly critical when he felt it justified, and he could be

polarizing. But if one matched his standard, worked hard and thoughtfully, one
gained his respect. You had won a friend, not just in science but for life. But if
you had come up through one of the other “schools,” it would always be that
much harder, and to my mind Geoffrey never accepted you in quite the same way.
Over the years he developed a special affinity with Canada, and it has saddened
me that our great Canadian Universities did not recognize Geoffrey appropriately
for that.
There was also a very compassionate side to Geoffrey Dawes that often went
unrecognized. I saw him go to extraordinary lengths to help a colleague with a
medical problem, or to assist a student in financial difficulty. He was kind and
thoughtful towards the institute staff, knew their names, and quietly would offer
his advice or assistance if he thought that it would be helpful. His trainees became
his extended family. He followed their progress with great interest and enthusi-
asm. He shared in the excitement of their discoveries and would enjoy the
intellectual discourse with them, clearly proud as they established their indepen-
dence and faculty appointments. He was, of course devoted to his wife, Margaret.
In this book Christopher Redman describes Geoffrey coming into his office,
discussing a new finding, and leaving with the comment, “Isn’t this fun.” That
vignette captures the essential Geoffrey Dawes, enthused about good science, just
like a small boy.
Finally, I must say a brief word about the author of this book, Lawrence
D. Longo. Larry is one of my heroes. He was there, seemingly at the beginning
and is still going strong! This volume chronicles the foundations built by the
great historic leaders, it tells how they laid the building blocks, and with Dawes
and others created a new field of investigation. It tells of the science and of the
scientific societies that underpin the discipline. Geoffrey was not there at the
beginning of the Society for Gynecologic Investigation in 1953, but he was
clearly aware of the advances being made by colleagues across the Atlantic.
This volume is a scholarly account of the development of the new field of fetal
physiology and the translation of its research to help mothers and babies. It is
also a story of relationships, sometimes fuelled by competitiveness, often fuelled
by collegiality. It is a story with many subtexts driven by the desire to acquire
new knowledge. There was healthy competition, between Cambridge, Oxford,
San Francisco, New Haven, Boston, and others as they emerged as leaders and
were then linked by new partnerships and the next generation of scientists.
There may be other descriptions of the growth of this field, but it is unlikely
that there will be any that captures the spirit, the excitement, and the hope for
mothers and their children as effectively as Longo has given here. In this
volume he has ensured his place as the great chronicler of a generation of
investigators, and of a new approach to science. We are fortunate to have a
colleague of his intellect and modesty, of such insight into the accomplishment
of others. This is the story about how a field of research unfolds. But any new
xiv Foreword to the First Edition

field needs its champion. For many, Geoffrey S. Dawes was that champion; a
man of formidable intellect, a great experimentalist, commanding yet compas-
sionate, the leader of his time.

Department of Physiology John R.G. Challis

University of Toronto, Ontario, BC
Canada

Department of Obstetrics and

Gynecology, University of Toronto
Ontario, BC, Canada

Simon Fraser University

Burnaby, BC, Canada

University of British Columbia

Vancouver, BC, Canada

University of Western Australia

Crawley, WA, Australia
Preface to the Second Edition

Dr. Longo had sent copies of the first edition of his book on the history of fetal
physiology to friends, former postdoctoral fellows, and colleagues around the
world. From my conversation with Jimin Suh, the Center’s Program Manager
who worked closely with Dr. Longo on the first edition, many who read his book,
based upon their expertise and insights from research activities, sent thank you
notes with praise and comments. Some sent personal recollections of a notable
historical figure featured in the book. In addition to comments, other perspectives
were provided and wishes that expressed more information would have
complemented certain topics. The accumulation of feedback from respected
sources and the recognition that important advances in the field had been made
since the first edition was published, based upon his proclivity for nocturnal
readings, motivated Dr. Longo to make plans for a 2nd edition. Esteemed col-
leagues with unique expertise were invited to make contributions to this volume
with a goal of providing an even more “comprehensive” review of the history and
future of the fields of fetal and neonatal physiology. This project added to his many
other responsibilities, foremost as principal investigator for an NIH Program
Project grant for over 20 years, and an R01 that was approaching 45 years of
continuous funding. Though shy of attention, he personally knew almost all of the
pioneering modern contributors to development of this field of study during the last
half of the twentieth century. His personal contributions were the writing of more
than 350 papers, actually with a mechanical pencil; most were peer reviewed, with
dozens of chapters and over 20 books. The impact of his efforts on society was
enhanced by his writing several United States Surgeon Generals’ Reports to
Congress (1979–1981) about the Health Effects of Smoking on Pregnancy and
Infants, his membership on many NIH Center for Scientific Research grant review
panels, and international recognition for publications on the history of medicine.
His illustrious career came as a true Clinician scientist based upon a balance of
responsibilities for patient care, call schedules, surgery as a practicing Obstetrician,
many academic responsibilities with scientific societies, and multiple research
grants to support laboratory operations and trainees, often at the sacrifice of

xv
xvi Preface to the Second Edition

personal time with family. Despite his seniority, he worked at a seemingly indefat-
igable pace to build a world-class perinatal research center in the School of
Medicine at Loma Linda University, as well as helped to create other centers of
research excellence as part of promoted infrastructure improvements that are
regarded by peer reviewers as outstanding. Amidst all these efforts, no one knew
that his work to revise this book would be the last major project of his career. Even
when hospitalized in intensive care, revisions were provided and sections of text
edited. His efforts are well represented by Lord Byron (1788–1824) in the quote
from Childe Harold’s Pilgrimage, Canto 4 [5 issues, page. 71] (1818), “But I have
lived, and not lived in vain. My mind may lose its force, my blood its fire and my
frame perish even in conquering pain, but there is that within me which shall tire
torture and time, and breathe when I expire.” These words and the desire to honor
Dr. Longo inspired several past trainees to help complete his final opus. Contrib-
utors to this volume were, for Chaps. 12 and 15, Dr. Ravi Goyal, M.D., Ph.D.
(Associate Professor, Basic Sciences, LLUSM; postdoctoral fellow with Dr. Longo
2007–2009 and successor principal investigator of several projects); for Chap. 14,
Professor Justo Alonso, M.D. (Professor and Chairman, Department of Obstetrics
and Gynecology, University of Uruguay (Montevideo) School of Medicine,
Fogarty fellow with Dr. Longo 1988); and for Chaps. 11 and 12, Ciprian Gheorghe,
M.D., Ph.D. (doctoral student with Dr. Longo 2000–2006). Dr. Michael A. Kirby,
Ph.D. (member of the Center since 1986 and Professor of Human Anatomy and
Pediatrics, LLUSM) contributed, as Editor, an inestimable time to proof- and fact-
check the entire document. My contribution to this book was to serve as Senior
Editor, tasked to oversee interactions with the publisher (Spinger) and the American
Physiological Society, to maintain a uniformity of voice in writing style, as well as
organize and complete unfinished chapters to as close as possible to Dr. Longo’s
standards. This impossible task was made easier by what seemed like near daily
interactions with him from my first day at Loma Linda University, May 1, 1985, for
my first and only academic job. This opportunity was, in a large part, due to his
efforts. Over many years, our common interests in science and life, intense profes-
sional collaborations in research projects and grants, as well as a personal friend-
ship stood the test of time. I am especially grateful for the help of Jimin Suh upon
whom Dr. Longo relied during his work to prepare this revised edition. I also wish
to acknowledge the exceptional competencies of Charlotte Marshall, who stepped
into this role as Editor’s assistant to locate sources and references and follow
through with due diligence for preparation of this manuscript.
Accordingly, this revision and expansion is dedicated to the memory of Law-
rence D. Longo, M.D. (1926–2016). Collectively, our efforts honor his memory as
an inspirational and exemplary leader (Director of the Center for Perinatal Biology
1972–2012), mentor, inquisitive polymath, and at times quixotic motivator to push
boundaries of understanding. His efforts provided a sustaining contribution to the
development of each of our professional perspectives and those of many more
trainees and colleagues to pursue important clinically relevant questions. His
values, sense of wonder, persistent questions, and thoughtfulness, which encour-
aged critical thinking and problem solving in a supportive environment, were to the
Preface to the Second Edition xvii

professional and personal benefit of all who knew him and for a greater good. For
Dr. Longo his lifelong quest, included in the Epilogue to the first edition of this
book (p. 487), could be summarized as to advance in practical and theoretical ways
the understanding of fetal and neonatal physiology so as to lessen the gap between
fundamental and clinical sciences and reduce perinatal morbidity and mortality. He
appreciated that a vast terra incognito of unknowingness remains, as evidenced by
the recalcitrance of current preterm birth rates and the epigenetics of fetal origins of
adult diseases. Clearly, the task of basic and clinician scientists is to stand on the
shoulders of pioneers in this field, brought to current attention by this treatise, to
generate replicable data that promotes useful knowledge of the mechanism through
which species reproduce with successful pregnancy and the natural process of birth.
The critical value of this understanding must be widely communicated as having
enormous benefit to confront challenges to the health and well-being of present and
future generations, as well as surmount the impact of hypercompetition for dwin-
dling resources that creates risk for academic life as we know it. As Dr. Longo so
often said, “Our task therefore is clear: it is to Persevere!”

August 2017 Steven M. Yellon

Preface to the First Edition

History is always best written generations after the event, when cloud, fact and memory
have all fused into what can be accepted as truth, whether it be so or not” (Theodore Harold
White 1961, p. 188)

It was in the autumn of 2008 that Charles Evans Wood, of the University of
Florida, Gainesville, chairman of the program committee of the Fetal and
Neonatal Physiological Society, invited me to present the Geoffrey S. Dawes
Memorial Lecture at the 2009 meeting of that society. This lecture, initiated in
1998 to honor Geoffrey Sharman Dawes (1918–1996), traditionally has been
presented by an established investigator who reviews some aspect of his or her
studies during the previous several decades. Rather than follow that formula,
however, I developed a different plan. As one interested in the history of ideas
and the evolution of medicine, for some time I had thought that it would be of
value to document some of the major issues and events associated with the
genesis and development of the rather specialized field of fetal and neonatal
physiology. This was, in part, because of its relatively brief history of less than a
century, but also because of its enormous contributions to understanding func-
tional physiologic principles, and because of its concentration on a vital and yet
often overlooked aspect of biomedical science that has made a profound impact
on clinical medicine.
Among the seminal figures and major forces in developing the field of fetal and
neonatal physiology was Geoffrey S. Dawes of the Nuffield Institute for Medical
Research, University of Oxford. Trained as a physician, he dedicated his career to
understanding the physiologic and pharmacologic basis of important clinical prob-
lems relating to the developing organism. In a sense, this monograph could be
viewed as a case study of the role of an individual scientist, and many of the
individuals he trained, in fostering, advancing, and shaping a given field of
research. Dawes’ scientific career covered a period of 55 years (1941–1996), during
which time he published over 220 papers. Included among these were a number of
highly cited scientific contributions, major reviews, introductions to symposia, and
chapters in books. As noted in the Foreword by John Richard George Challis,

xix
xx Preface to the First Edition

critically, Oxford’s Nuffield Institute served as a seedbed and salutary environment

for the education and training of a generation of bright young scientists.
Several individuals have asked why I would undertake such a formidable
endeavor. Actually, about a decade ago I had commenced working on an article
reviewing some of Geoffrey Dawes’ many contributions to life. We had been good
friends, meeting once or twice a year in Oxford, at international meetings, or my
home base in Loma Linda, and I had high regard for his work. Within several years
the project had expanded beyond a mere review. Then, following the 2009 Dawes
Lecture I realized that to place it all into perspective the enterprise would require at
least a small monograph. Several other reasons are relevant.
I probably am one of the last people alive who knew most of the leading figures
(with the exception of Huggett and Sir Joseph Barcroft) and lesser lights who
contributed to the evolution of ideas, methodologies, and the synthesis of the
problems and issues of developmental physiology. In addition, I have participated
with many of these notables in relatively small seminars, large conferences,
National Institutes of Health (NIH)-supported study sections, and various brain-
storming sessions to identify some of the vital issues and challenges that lie ahead.
Also over the years, I have conducted active correspondence with these individ-
uals on a regular basis, and have had the pleasure of having a large number serve as
visiting scientists and seminar speakers at our Center for Perinatal Biology. Almost
without exception, these discussions have been an enriching experience. Remem-
brance of many of their comments, experiences, frustrations, and insights, can
perhaps provide a thoughtful background for the vicissitudes in science, and the
life of the mind.
In addition, I elected to survey this field in an effort to assist young investigators,
both basic scientists in physiology as well as clinical researchers in perinatology—
fetal and neonatal clinical medicine—to gain an appreciation of their heritage and
what has gone before. With today’s World Wide Web, information technology, and
nanosecond communication, it is sobering to acknowledge that for many young
investigators, that which is more than a few years old is terra incognito. In general,
we live in an ahistorical age. Life is for Now—the Present. For most of the
biomedical literature, reference citations in MEDLINE and PubMed go back only
to the late 1940s. Thus for practical purposes, contributions before that time simply
do not exist. Our perpetual, annihilating present tends to sever our kinship with the
past. A sense of our history and tradition, however, argues for the continuity of
thought, experience, and feeling that accompanies the journey across the gulf of
time. Without our hieroglyphic scribbling, we lose not only the heritage of the past
but also our perspective and outlook, and our sense of who and where we are. With
the arrangement as presented, readers will have the ability to review quickly the
background of a given problem in a single chapter or subchapter. In addition to the
story itself, perhaps of greatest value will be the accompanying references (each of
which I have perused myself, many in great detail), which they may read and
evaluate for themselves. In the present essay, I have attempted to present some of
the epistemology of the threads of scientific thought in the context of their times.
Nonetheless, we cannot ignore the words of Theodore Harold White (1915–1986)
Preface to the First Edition xxi

that opened this Preface, and found in his Making of the President (White 1961). As
the Harvard pediatrician Clement Andrew Smith (1901–1988) observed regarding
this aspect of developmental physiology, growth in knowledge increases desire to
understand its special fields, and “this is particularly true of those periods during
which life is more dynamic. In no other brief span of existence can such profound
alterations and adjustments be studied . . .” (Smith 1945, p. 3).
Nonetheless, several caveats are in order. Although I have attempted to be
reasonably complete in considering the experimental studies of various investiga-
tors, rather than exhaustive detail, my goal has been to stress the significance of
their contributions. Because of the many subjects encompassed by this field of
research, and its complexity and progress, the present essay makes no attempt to
survey the topic either in extenso or to the present day. Rather, it focuses on the role
of some individual scientists and those in their circle. Also because of the extent and
vastness to which this field has expanded, I have limited the review chiefly to the
second half of the twentieth century, considering issues that came to the fore during
that time. One might ask, where does history end, and contemporary physiology
commence. As can be appreciated, no history of a given field of discipline can be
completely current and up-to-date. With each new day and passing week and
month, the advances move the frontiers and expand the horizons. With that in
mind, for the most part the present survey concludes about the time of Geoffrey
Dawes’ death in the mid-1990s.
As a corollary, so that this synthesis may be of value to investigators and others
with interest in this facet of science, the general bibliography is rather extensive,
and that for Dawes includes every paper of which I am aware he wrote (abstracts are
not included). The bibliography also includes a number of review articles and
volumes that the interested reader may consult to pursue a given topic in depth.
Although the over 2,000 references given may appear somewhat exhaustive, it
constitutes only a tithe of those papers published in the field during the period of
this survey. As such, I trust that these may be of value as a “taking-off” point for one
who wishes to explore the topic in greater depth. Importantly, rather than being
viewed as an encyclopedic list of names, dates, and isolated facts, I trust that these
would help to place the rise of fetal and neonatal physiology in its proper context. In
the paragraph that contains the opening quotation of Theodore H. White, he notes,
“What can be reconstructed now out of the contemporary recall of those present
must be seen as a fog-shrouded range of facts in which occasionally one peak or
another appears at a given hour of the day, but whose connection to the next peak of
facts is obscured by the clouds in between” (White 1961, p. 188). Or as Napoleon
Bonaparte (1769–1821) is alleged to have stated, “What then is ... the truth of
history? A fable agreed upon.” A work in progress, history is best served by
constant reanalysis and rewriting, as opposed to a museum-quality sculpture in
resplendent marble.
An additional caveat is in order. For the most part, investigators in this field
worked in what Thomas Samuel Kuhn (1922–1996) referred to as canonical
“normal science,” or “current paradigm.” That is, their studies were conducted
within a relatively restricted “model” or “system” with an accepted body of
xxii Preface to the First Edition

concepts, techniques, and methodologies that guided their thinking and worked to
determine the problems to be explored (Kuhn 1962). Several discoveries of what
might be regarded as “revolutionary science” or “paradigm shifts” occurred during
this period, such as that of the role of the fetal hypothalamic-pituitary-adrenal axis
in the initiation of labor, and the role of pulmonary surfactant in respiration.
However, despite a number of breakthrough advances, these were not typical of
the period as a whole.
That being said, a number of exclusions and gaps will be evident to the reader
versed in this discipline. From the standpoint of contemporary biomedical science,
for the most part, much of what is reviewed is general organ physiology, with little
consideration of advances in cellular and molecular biology. In fact, some would
regard this era as “nineteenth-century” descriptive science, phenomenology, or
worse. Nonetheless, it is important to recall that our present understanding is
based on previous description of fundamental facts and advances. In the words of
Sir Isaac Newton (1642–1727) and those before, “If I have been able to see farther
than others, it was because I stood on the shoulders of giants” (Merton 1965).
As is well known, “Clio’s many mansions” of history may be considered from a
number of standpoints: macro-, micro-, global, national, regional, local, social,
cultural, political, economic, biographical, and others. For the most part, the present
essay is a combination of technological science and internal history. It also includes
a fair bit of biography. I would like to think that not inappropriate, for as Ralph
Waldo Emerson, (1803–1881) observed, “All history becomes subjective . . . there
is properly no History, only Biography” (Emerson 1883, p. 5). As one who has
spent almost five decades as a laborer in this field, as noted an advantage in this
approach is that with the exception of the very earliest workers, I knew each of the
contributors and many were dear friends. Thus, without sounding self-serving, I
would like to think that I have more than superficial insight into the developments
and issues involved. A limitation, of course, is that in this presentation only a
cursory attempt is made to include a number of related social, cultural, political, and
economic aspects. In part, the constraints of scholarly research, but also the
limitations in publication, require focus of narrative. Although considering chiefly
internal events and the “foreground,” I have attempted to place the work within the
context of its times. In this regard, I deliberately reject the concept of “continuity”
in the development of this field of research. Also, the present essay makes no
attempt to resolve certain battles of priority of particular innovation, or to impose
“progressive” or teleological schemes on this record. A “Whig” view of historical
progressivism (Butterfield 1965), this is not.
In preparing this work it has been inspiring to recall the fine, dedicated individ-
uals and the accomplishments of those who have labored so diligently to develop
this field of research—to glimpse the greatness of some of the early achievements
that we now take for granted. Rather than being the definitive history, however, I
trust that it will be viewed as one perspective of fetal and neonatal physiology,
albeit one that is rather personal.
In closing, I am particularly grateful to a number of colleagues, many of whom
worked at Oxford’s Nuffield Institute, who shared stories, anecdotes, and
Preface to the First Edition xxiii

impressions of their work and interactions with other colleagues. Importantly, I am

in great debt to Jimin Suh who worked indefatigably in helping to locate obscure
references and other sources, and to prepare this manuscript in its present form. She
is absolutely the finest associate for whom one could wish.

Loma Linda, CA, USA Lawrence D. Longo

References

Butterfield H (1965) The Whig interpretation of history. W.W. Norton, New York
Emerson RW (1883) Essays.... First and Second Series. A.L. Burt Co., New York
Kuhn TS (1962) The structure of scientific revolutions. University of Chicago
Press, Chicago, IL Merton RK (1965) On the shoulders of giants. A Shandean
Postscript. With a Foreword by C.D. Bowen. The Free Press, New York
Smith CA (1945) The physiology of the newborn infant. C.C. Thomas, Springfield,
IL. 2nd edn, 1951; 3rd edn, 1959
White TH (1961) The making of the President, 1960. Atheneum Publishers,
New York
Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2 A Scientific Genealogy: Early Development of Fetal-Neonatal
Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.1 The Beginnings and Some Definitions . . . . . . . . . . . . . . . . . 9
2.2 Arthur St. George Huggett and Early Studies of Fetal
Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.3 Late Nineteenth- and Early Twentieth-Century Contributions
by German Physiologists and Others . . . . . . . . . . . . . . . . . . 13
2.4 Nicholson J. Eastman, Huggett, and Others of the 1930s
to 1950s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.5 Joseph Barcroft and a Widening of Interest in Physiology
of the Fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3 Oxford and the Development of Physiology, with Notes on the
Nuffield Institute for Medical Research . . . . . . . . . . . . . . . . . . . . . 47
3.1 William Harvey and the Seventeenth-Century Physiology . . . 47
3.2 Other Early Oxford Physiologists . . . . . . . . . . . . . . . . . . . . . 51
3.3 Founding of the Royal Society . . . . . . . . . . . . . . . . . . . . . . . 54
3.4 The Oxford Medical School and Further Developments in
Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
3.5 The Nuffield Institute for Medical Research . . . . . . . . . . . . . 61
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4 Geoffrey S. Dawes: A Life in Science . . . . . . . . . . . . . . . . . . . . . . . 69
4.1 Early Life and Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
4.2 Dawes and the Fetal Cardiovascular System: The 1950s
and 1960s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

xxv
xxvi Contents

5 Fetal Asphyxia and the Primate Colony in Puerto Rico . . . . . . . . . 85

5.1 Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
5.2 Eastman and “Mt. Everest in Utero” . . . . . . . . . . . . . . . . . . . 88
5.3 William F. Windle and the Primate Colony at
Cayo Santiago . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
5.4 The Puerto Rico Studies of Asphyxia . . . . . . . . . . . . . . . . . . 91
5.5 Virginia Apgar and Evaluation of the Newborn Infant . . . . . . 95
5.6 In Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
6 The Pulmonary Vasculature and Dawes’ Foetal and Neonatal
Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
6.1 The Pulmonary Vasculature of the Fetus and Newborn . . . . . 103
6.2 Dawes’ Foetal and Neonatal Physiology . . . . . . . . . . . . . . . . 112
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
7 Embryology and Early Developmental Physiology . . . . . . . . . . . . 119
7.1 Origins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
7.2 Stazione Zoologica di Napoli . . . . . . . . . . . . . . . . . . . . . . . . 129
7.3 Embryology Becomes a Science . . . . . . . . . . . . . . . . . . . . . . 134
7.4 Franklin Paine Mall and the Carnegie Institution
Department of Embryology . . . . . . . . . . . . . . . . . . . . . . . . . 136
7.5 Other Early Twentieth-Century Developments
in Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
8 Some Aspects of the Physiology of the Placenta . . . . . . . . . . . . . . . 153
8.1 Late-Nineteenth and Early-Twentieth Centuries . . . . . . . . . . 153
8.2 Mid-Twentieth Century to the Present: Placental Fine
Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
8.3 Some Aspects of the Uteroplacental Circulation and
Transplacental Exchange . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
8.4 Pathology of the Placenta . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
8.5 The Human Placental Project . . . . . . . . . . . . . . . . . . . . . . . . 179
8.6 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . 179
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
9 Some Aspects of Endocrinology of the Placenta . . . . . . . . . . . . . . . 195
9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
9.2 Steroid Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
9.3 Polypeptide Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
9.4 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . 207
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
10 Maternal Physiology of Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . 217
10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
10.2 Frank E. Hytten and Early Studies on Maternal Physiology . . . 218
Contents xxvii

10.3 The Reproductive Tract in Pregnancy . . . . . . . . . . . . . . . . . . 224

10.4 Maternal Metabolic Changes in Pregnancy . . . . . . . . . . . . . . 227
10.5 Pregnancy-Associated Changes in the Endocrine System . . . . 228
10.6 Cardiovascular System: Blood Volume . . . . . . . . . . . . . . . . . 235
10.7 Maternal Cardiac Output . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
10.8 Arterial Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
10.9 Cardiovascular Hemodynamics of Pregnancy . . . . . . . . . . . . 240
10.10 Uteroplacental Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . 241
10.11 The Respiratory System in Pregnancy . . . . . . . . . . . . . . . . . . 245
10.12 The Kidneys and Urinary Tract in Pregnancy . . . . . . . . . . . . 246
10.13 The Gastrointestinal Tract in Pregnancy . . . . . . . . . . . . . . . . 248
10.14 Amniotic Fluid and Its Dynamics . . . . . . . . . . . . . . . . . . . . . 248
10.15 Uterine Contractions of Labor . . . . . . . . . . . . . . . . . . . . . . . 251
10.16 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
11 Maternal Complications of Pregnancy that Affect Fetal
Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
11.1 Premature Onset of Labor and Delivery . . . . . . . . . . . . . . . . 281
11.2 Chorioamnionitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
11.3 Obesity in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
11.4 Diabetes in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
11.5 Hypertension in Pregnancy: Preeclampsia/Eclampsia . . . . . . . 314
11.6 HELLP Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
11.7 Mental Health and Neuropsychiatric Issues . . . . . . . . . . . . . . 335
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
12 Fetal Growth and Its Restriction . . . . . . . . . . . . . . . . . . . . . . . . . . 365
12.1 Early Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
12.2 Neonatal Birthweights, Fetal Growth Restriction, and the
Small for Gestational Age Infant . . . . . . . . . . . . . . . . . . . . . 371
12.3 Further Perspectives on Fetal Growth Restriction . . . . . . . . . 378
12.4 Fetal Growth Restriction in Laboratory Animals . . . . . . . . . . 381
12.5 Cardiovascular Function with Fetal Growth Restriction . . . . . 382
12.6 Fetal Growth Restriction and Neuropsychological Correlates . 385
12.7 Fetal Growth Restriction and the Placenta . . . . . . . . . . . . . . . 386
12.8 Fetal Growth Restriction and the Developmental Origins
of Adult Health and Disease . . . . . . . . . . . . . . . . . . . . . . . . . 390
12.9 Conclusions with Perspective . . . . . . . . . . . . . . . . . . . . . . . . 394
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
13 Fetal-Neonatal Growth and Metabolism . . . . . . . . . . . . . . . . . . . . 413
13.1 Robert A. McCance, Elsie May Widdowson, and Continued
Studies of Growth and Metabolism . . . . . . . . . . . . . . . . . . . . 413
13.2 Metabolic Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
xxviii Contents

14 Fetal Growth Restriction at High Altitude: Clinical

Observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
14.1 High-Altitude Long-Term Hypoxia and the Human
Condition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
14.2 The Colorado and Mountain States Studies . . . . . . . . . . . . . . 424
14.3 Clinical Studies from the altiplano of South America . . . . . . 426
14.4 The Relation of Birthweight to Gestational Age . . . . . . . . . . 428
14.5 Translational Studies of Pregnancy at High Altitude . . . . . . . 429
14.6 High Altitude and the Placenta . . . . . . . . . . . . . . . . . . . . . . . 430
14.7 Conclusions with Perspectives . . . . . . . . . . . . . . . . . . . . . . . 431
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
15 Fetal Growth Restriction at High Altitude: Basic Cellular and
Subcellular Physiologic Considerations . . . . . . . . . . . . . . . . . . . . . 435
15.1 Pregnancy and High-Altitude, Long-Term Hypoxia . . . . . . . . 435
15.2 Interrelations of Fetal Blood O2 Affinity and Capacity
with that of the Mother . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
15.3 Initial High-Altitude Studies on the Peruvian Altiplano . . . . . 445
15.4 Studies in Sheep Subjected to Hypobaric Hypoxia . . . . . . . . . 451
15.5 Cardiovascular Studies in the Chick Embryo . . . . . . . . . . . . . 453
15.6 Studies of Prolonged Hypoxia in Rodents . . . . . . . . . . . . . . . 454
15.7 Studies in Sheep Acclimatized to High Altitude at the
White Mountain Research Station . . . . . . . . . . . . . . . . . . . . 455
15.8 Further Sheep Studies on the Altiplano . . . . . . . . . . . . . . . . . 457
15.9 Fetal Cardiovascular Responses to Long-Term Hypoxia . . . . 458
15.10 Fetal Coronary Vascular Responses . . . . . . . . . . . . . . . . . . . 461
15.11 Fetal Cerebrovascular Responses to Long-Term Hypoxia . . . 462
15.12 Some Aspects of Cardiovascular Function in the Llama
Fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
15.13 Long-Term Hypoxia and the Fetal Hypothalamic-Pituitary-
Adrenal Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
15.14 Fetal Metabolic Responses to LTH . . . . . . . . . . . . . . . . . . . . 473
15.15 Hypoxia-Mediated FGR and Neuropsychological Correlates . . . 475
15.16 High Altitude and the Placenta . . . . . . . . . . . . . . . . . . . . . . . 476
15.17 Conclusions with Perspectives . . . . . . . . . . . . . . . . . . . . . . . 480
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
16 Epigenetics and the Fetal Origins of Adult Health and Disease . . . 501
16.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
16.2 A Brief Introduction to Epigenetics and Development . . . . . . 502
16.3 The Dutch “Hunger Winter” of 1944–1945: A Case Study . . . 506
16.3.1 Maternal and Infant Characteristics . . . . . . . . . . . . . 506
16.3.2 Metabolic Sequelae . . . . . . . . . . . . . . . . . . . . . . . . . 508
16.3.3 Cardiovascular Sequelae . . . . . . . . . . . . . . . . . . . . . 509
16.3.4 Related Sequelae . . . . . . . . . . . . . . . . . . . . . . . . . . 510
16.3.5 Neuropsychological Sequelae . . . . . . . . . . . . . . . . . 511
Contents xxix

16.4 Other Antenatal Maternal Starvation Studies . . . . . . . . . . . . . 513

16.5 A Perspective on the Fetal Origins of Adult Health and
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
16.6 Critiques of the “Fetal Origin” Hypothesis . . . . . . . . . . . . . . 519
16.7 Malnutrition During Pregnancy as a Global Health Problem . . 521
16.8 Further Questions to Consider . . . . . . . . . . . . . . . . . . . . . . . 522
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
17 Some Aspects of the Developing Brain and Nervous System . . . . . 535
17.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
17.2 Developmental Neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . 538
17.3 Cognitive Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
17.4 Cerebral Blood Flow in the Fetus and Newborn . . . . . . . . . . 545
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
18 Related Developments in Fetal and Neonatal Endocrinology . . . . . 557
18.1 The Beginnings of Reproductive Endocrinology and
Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558
18.2 Fetal-Neonatal Endocrinology . . . . . . . . . . . . . . . . . . . . . . . 559
18.3 Developmental Neuroendocrinology . . . . . . . . . . . . . . . . . . . 563
18.4 Hormonal Regulation of the Timing of Birth . . . . . . . . . . . . . 567
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
19 Further Developments in Fetal and Neonatal Physiology . . . . . . . 581
19.1 Pulmonary Physiology and Respiratory Distress Syndrome . . 581
19.2 Corticosteroids and Maturation of the Fetal Lung . . . . . . . . . 593
19.3 A Tribute to “Mont” Liggins . . . . . . . . . . . . . . . . . . . . . . . . 598
19.4 Blood and Hematology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
19.5 Hyperbilirubinemia and Kernicterus in the Fetus and
Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
19.6 Immunology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
19.7 Chronic Catheterization of the Fetus . . . . . . . . . . . . . . . . . . . 609
19.8 Cardiovascular Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . 612
19.9 Related Fields of Research . . . . . . . . . . . . . . . . . . . . . . . . . . 614
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
20 Additional Clinical Aspects of Developmental Physiology
and Clinical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
20.1 Neonatal Intensive Care in Preterm Birth . . . . . . . . . . . . . . . 631
20.2 Retinopathy of Prematurity . . . . . . . . . . . . . . . . . . . . . . . . . 643
20.3 Transcutaneous O2 Measurements . . . . . . . . . . . . . . . . . . . . 647
20.4 Thermoregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
20.5 Some Aspects of the Development of Maternal-Fetal
Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
20.6 Some Aspects of Newborn and Child Care . . . . . . . . . . . . . . 656
20.7 Pathology of the Fetus and Newborn . . . . . . . . . . . . . . . . . . 658
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
xxx Contents

21 Governmental Support of Research in Fetal and Newborn

Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
21.1 The Medical Research Council of Great Britain . . . . . . . . . . 673
21.2 The Medical Research Councils of Canada and Australia . . . . 677
21.3 The US National Institutes of Health . . . . . . . . . . . . . . . . . . 678
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
22 Bioethical Issues in Research on the Fetus and Newborn Infant . . . 691
22.1 An Awakening of Responsibility . . . . . . . . . . . . . . . . . . . . . 691
22.2 The Emergence of Bioethics . . . . . . . . . . . . . . . . . . . . . . . . 693
22.3 The Massachusetts Experience . . . . . . . . . . . . . . . . . . . . . . . 694
22.4 Later Developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
23 Textbooks, Monographs, and Other Volumes on Fetal and
Newborn Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
23.1 Volumes on Physiology of the Fetus and Newborn Infant . . . 703
23.2 The Josiah Macy, Jr. Foundation Conferences on Gestation . . 708
23.3 New York Academy of Sciences Conferences on Fetal
Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
23.4 Essays in Perinatal Medicine . . . . . . . . . . . . . . . . . . . . . . . . 711
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
24 Fetal “Breathing” in the 1970s and Fetal Heart Rate Analysis
in the 1980s and Early 1990s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
24.1 Early Studies of Fetal Breathing Movements . . . . . . . . . . . . . 715
24.2 Fetal Breathing in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . 722
24.3 Early History of Fetal Heart Rate Monitoring . . . . . . . . . . . . 724
24.4 Subsequent Studies on Electronic Fetal Heart Rate
Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
24.5 Some Contemporary Developments . . . . . . . . . . . . . . . . . . . 731
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
25 Dawes’ Contributions to Symposia and a Summing Up . . . . . . . . . 745
25.1 Ciba Foundation Symposia . . . . . . . . . . . . . . . . . . . . . . . . . 746
25.2 The Barcroft Centenary Symposium . . . . . . . . . . . . . . . . . . . 749
25.3 The “Dawes Symposium” and Others . . . . . . . . . . . . . . . . . . 750
25.4 A Summing Up by Dawes . . . . . . . . . . . . . . . . . . . . . . . . . . 752
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754
26 Dawes as a Mentor: Reminisces of Former Graduate Students,
Postdoctoral Fellows, and Associates . . . . . . . . . . . . . . . . . . . . . . . 757
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
Another random document with
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 Soitto kaikuu ulkoravintoloista ja torvet kimaltelevat auringossa.
Pikkulapset juoksentelevat punaisina, valkoisina taikka sinisinä ja
leikkivät hiekkaläjissä tynnyrinvanteilla, palloilla taikka
ilmarakkuloilla. Ne nauravat ja lörpöttelevät, taikka itkevät
hillittömästi, kun ilmarakkula on karannut ja josta pian näkyy
ainoastaan pieni pilkku kaukana, kaukana — lähellä aurinkoa.

Naiset pukeutuvat vaaleihin pukuihin, kalossit sysätään syrjään, ja

herrat etsivät kävelykeppejään ja kiiltäviä silinterihattujaan. Valkoisia
lakkeja, kultalyyryjä ja nuorisoa vilisee odottaen saada näyttää
maailmalle ylioppilaiden kaunista voitonmerkkiä.

Ruohokentät rupeavat kimaltelemaan hennossa vihreydessään,

esplanaadien penkereillä aukeavat kukat auringonpaisteessa,
pensaihin ilmestyy pieniä lehtiä ja vesikioskien portit aukaistaan.

Mutta kun illalla lapset ovat viedyt huoneisiin, soitto tauvonnut ja

yö tullut, vallitsee kaduilla hiljainen ja omituinen tunnelma. On yö,
mutta ilma on kuitenkin valoisa, läpikuultava, luonto uinuu, mutta
valvoo maatessaankin, kaikki lepää, mutta elää kuitenkin; kaikkialla
on hiljaista ja kuitenkin on kaikkialla sointua ja säveltä. Ei ole
ainoatakaan ikkunaa, jonka uutimien takana ei uneksittaisi uusia
unelmia, ei ole muuria, jonka sisäpuolella olisi ihminen, jota ei
kevään kaikkivalta olisi koskettanut. Haaveillaan töistä ja
laakeriseppeleistä, rakkaudesta ja valoisista kesäpäivistä,
säihkyvistä silmistä, joihin on katsottu, puolittain tehdyistä
lemmentunnustuksista ja lupauksista, kaikesta, joka ei vielä ole
tapahtunut, mutta joka voi tapahtua, kaikellaisesta, josta ei oikein
itsekään olla selvillä mitä se on… Seisoissamme ajatuksiimme
vaipuneina näemme kulkijan jossain kaukana, kuulemme hänen
askeleittensa heikon kaiun haihtuvan pois, hän katoo itsekin kuin
usvahaamu, kaukaa kuuluu serenaadi, ja milloin tahansa voi toinen
kuulua aivan läheltä. Ei valoa, ei varjoa, ainoastaan yksi ainoa, suuri
unelma.

Kuka meistä ei joskus elämässään olisi seisonut uudenaikaisessa

kaupungissa, ilman sukuperää ja muistoja, hurmautuneena ja
tuntenut puolivaloisan toukokuun yön tuhatäänistä, melkein
kuulumatonta elegiiaa!

3.

Taistelu talven jälkijoukon ja eteenpäin kiirehtivän kevään välillä on

vetäytynyt pohjoiseenpäin, jonnepäin talvi on peräytynyt
luoksepääsemättömään napalinnoitukseensa. Lumiräntä, joka
toisinaan vielä on näyttäytynyt, on muuttunut lämpimäksi sateeksi,
tuulten voima on laimentunut, pilvet hajautuvat ja aurinko levittää
voittavan loisteensa, elähyttävän paisteensa, lemmekkään lämpönsä
luonnon yli, joka hurmaantuneena nauttien, muistuttaa nuoren
morsiamen kaihoa, autuuden ilme kuvastin kirkkaiden sisäjärvien ja
lahtien sinisessä katseessa.

Koivulehdot, jotka ovat olleet punertavia ja pronssinkarvaisia,

rupeavat nyt muuttumaan viheriäisiksi, leppien tahmeat umput
paisuvat ja pihlajien pitkät lehtien suojukset puhkeavat ja antavat
tilaa monihaaraisille untuvaisille lehdille kehittymiseen. Lehmus,
vaahtera ja haapa, kaikki saavat elon, mahla pulppuaa niissä, kaikki
kiirehtivät elämään, kukkimaan ja kantamaan hedelmää lyhyessä
kesässä.
 Oi, kuinka tuolla metsän poluilla lemuaa, siellä tuntuu kuivuneiden
lehtien, sammalen ja itse maankin lemu, jota tallaamme, ja loistavien
valkovuokkojen, jotka ovat tulleet esiin leppämullasta! Oi, mikä
elämä ja liverrys puiden oksissa, mikä kiire pehmeitä pesiä
valmistuissa, ja mitä lemmenkiistaa sitten vähä väliä! Käellä yksin ei
ole aikaa pesimiseen ja rakentamiseen, hän ei voi ajatella
tulevaisuutta ja vastuksia pienien poikasten kanssa. Käkipariskunta
lentää vaan läpi lehtojen koko kevään, yhdessä ainoassa
lemmenhuumauksessa ja ehtii tuskin hakea ruokaansa.

Eläimet viedään taas laitumelle ja pelloilla kynnetään ja kylvetään

ja ahdistetaan tunkeilevia variksia, jotka tulevat syömään siementä.
Päivät kestävät melkein kauvemmin, kuin voimat riittävät, ja työ
sujuu hyvin. Miesten huudot kuuluvat vainioilta, naisten laulu kaikuu
tuvista, joiden ovet ovat auki, ja illalla tulevat lehmät hitaasti käyden
kotiinpäin polkuja pitkin kilisevin kelloin ja kärsimättömästi ja iloisesti
mylvähdellen.

Saaristoissa on vielä jäätiköltä jälellä jossain varjoisalla rannalla ja

puut ja vihreys ovat myöhästyneet. Mutta siellä on sentään
sykkäilevää eloa. Kun jäälohkareet vielä uiskentelivat ympäri, tulivat
haahkat suurissa parvissa, näyttäen pilvenhattaroilta ja telkät,
koskelot, mustasorsat ja allit — kaikki ovat saapuneet. Haahkat ovat
hajautuneet ja lepäävät parittain kallioilla ja leikkivät
lemmenleikkiään tyyninä aamuina kimaltelevien vesipatsaiden
keskellä, haahkatelkkä viheriänä ja mustana ja komeana
koreudessaan ja haahka ruskeana, niin että sitä tuskin näkyy luodon
ollessa takalistona.

Usva lepää hienona ja valkoisena aamulla, mutta kun

ensimmäinen heikko itätuulahdus on herännyt poistuu sumu suurien,
kevyiden pumpulipilvien kaltaisina, joiden lomista loistaa sininen
taivas. Silloin parveilevat muuttavat allit ympäri pienissä joukkioissa
hajautuneina koko rannikolle tuhansittain ja tuhansittain, silloin
laulavat ne avaruuden täyttävää lauluaan, niin että se kuuluu kuin
kaukainen torventoitotus. Ilma suhisee lintujen lennosta, vesiryöpyt
kimaltelevat niiden heittäytyessä mereen, kaikkialla kuuluu laulua ja
vihellystä ja laukauksia pamahtaa näkymättömistä pyssyistä, jotka
ovat piilossa kallioiden vedenpuoleisilla reunoilla, höyrylaivojen ja
purjealusten risteillessä kulkuväylien tuhansissa mutkissa.

Niin, kevät on voittanut, kaikkialla on eloa, elämää ja väriä,

höyryävässä maassa siitiniloa, kaikkein katseissa herännyttä riemua
ja nautintoa koko luonnossa.

Niin, nauttikaamme siis me kaupunkilaisihmisetkin valosta ja

lämmöstä, sulkekaamme koulut ja tukahuttavat vuokrakasarmit ja
etsikäämme kaikkein meidän äitiämme, luontoa, joka odottaa meitä
valkovuokko-, kielo- ja tuomenkukkakinoksineen ja koivunlemuineen
ja antaa terveyttä ruumiillemme ja virkistystä kaupungin
ahdasmielisyydessä ja melussa väsyneille aivoillemme.

Helsingissä 1900.

Äiti

Siis olet sinä tullut, rakas poikani — kiitos, kiitos, että tahdoit
vaivata itseäsi pitkällä matkalla. Varmaankaan ei ollut niin hauska
jättää elämää siellä, opinnoita, suuria kaupunkia, rikasta luontoa ja
mahtavia vuoria, tullaksesi tänne vähävaraiseen kotiisi näkemään
vanhan äitisi kuolevan pois luotasi ja isäsi luota — kiitos tulemastasi
— nyt olette te minulla molemmat vieressäni — elä itke, katsos, ei
koko maailman tiede voi pelastaa minua, sillä ääni sydämmessäni
puhuu tyynesti ja varmasti, että kuolema lähenee — —

Mutta kerro minulle enemmän alpeille nousuistasi, enemmän niistä

jyrkistä huipuista, jotka ikuisen lumen peittäminä, kylpien
auringonvalossa, kuten rohkeat aatteet ja ajatukset kokoutuvat ylös
avaruuteen. Se ei väsytä minua ja minä kuuntelen niin mielelläni.
Tiedätkö, minä tunnen itseni niin ihmeelliseksi, ei tunnu ollenkaan
siltä, kuin olisin lähellä pimeää hautaa, missä maallinen majani
muuttuu jälleen maaksi, vaan minä tunnen päinvastoin täydellistä
sopusointua, tunnen itseni terveeksi sairaudessanikin.

*****

Sinä kysyt minulta katseellasi — et tahdo tehdä sitä suullisesti —

pelkäät, että puhun itseni väsyksiin. Minä vastaan sinulle, poikani,
minä ymmärrän sanattomat kysymyksesi. Isä ei koskaan osaa
selittää sinulle sitä — sinä olet liian vaitelias isä, sinä — —

Niin, katsos, minä kasvoin kaukana maalla, kodissa, jota suuri

puisto ympäröi, jossa kävelin ympäri haaveillen nuoruuden unelmia.
Lukemiseni, jonka vanha isäni minulle valitsi, johti unelmieni tiet
turhamaisuuden kujilta suurten vainajien seuraan, henkieni, jotka
olivat olleet ihmiskunnan hyväntekijöitä ja luonnonkuvaukset
herättivät mielikuvitukseni rikkaaseen elämään. Ajattelepas, minä,
lapsi, minä istuin puutarhassa ja luin ja minä näin ihania maisemia
avautuvan eteeni, kukkivat omenapuut veivät minut seutuihin, jotka
keväisin ovat kukkien lumesta valkeita, suuret puut muuttuivat
mahtaviksi seeteripuiksi, ja iltasin menin minä usein näköalavuorelle,
nähdäkseni yhä laajemmalle. Silloin muodostui kaikki mitä näin,
sisäisten toivomusteni mukaan. Näin välkkyviä meriä, joilla suuret
höyrylaivat liikkuivat, tehden kultaisia vakoja, kylät tulivat suuriksi
kaupungeiksi loistavan valkoisine rakennuksineen, ja pilvijoukkiot
jotka ukkosilmoilla kokoutuivat yhteen, olivat alppia, joiden huiput
kimaltelivat punaisina ilta-auringon valossa.

Katsokaas, vanha äiti on vielä hieman runollinen. Nyt lepään

hetkisen.

*****

Niin, ja sitten kasvoi minussa vähitellen suuri halu nähdä kaiken

tämän todellisuudessa, mitä olin haaveillut, saada ottaa tehokasta
osaa vilkkaaseen elämään, nähdä meriä ja avaruuksia, ja mahtavia
alppia — päästä pois tasaiselta maalta, niin, minun mielestäni rupesi
melkein elämä kotona tuntumaan yksitoikkoiselta ja jokapäiväiseltä
ja että kaunis puutarha oli huonosti hoidettu ja ruma.

Sitten tuli kevät, maa rupesi viheriöitsemään ja koivujen ja

haapojen latvat saivat pitkiä ripsuja, jotka loistivat, kuin pronssi.
Vuokot puhkesivat, muuttolinnut palasivat ja illat tulivat lämpöisiksi.
Silloin tuli isä — niin, hän oli nuori ja keikarimainen silloin — ja sitten
rupesi hän katselemaan minua ja minä häntä, vaikka en
tahtonutkaan. Ei, minä en tahtonut, usein istuin minä ylhäällä
näköalavuorella vain herättääkseni eloon vanhoja unelmia alpeista ja
avaruuksista ja niiden avulla syrjäyttääkseni kaiken uuden. Mutta se
ei auttanut. Tuo uusi tunkeutui ylitseni vastustamattomalla
hurmauksella, samalla kun surukseni näin vanhan, vanhat tunteeni
— ei kuolevan — vaan syrjäytyvän. Ja niin laskin minä käteni isän
käteen eräänä iltana kukkivan tuomen alla. Missä on kätesi nyt isä,
ojenna se minulle taas — näin.
 *****

Nyt loppuivat pian unelmat korkeuksista ja avaruuksista — ne

muodostuivat toisenlaisiksi nyt. Laaksoon jäisin minä ja asuisin
siellä, ja sinne minä jäin ja siellä asuin — mutta se oli kukoistava ja
tuoksuava laakso, siellä kasvoi ruusuja ja kieloja ja linneat
puhkesivat metsän hämäryydessä. Punaposkinen pienokainen
kasvoi vieressämme laaksossa, samalla kun isä ja äiti näkivät
vuosien hiljaa vierivän yksitellen, ja riemuiten huomasivat tunteitten
ja ajatuksien heräävän pienokaisessa ja kuinka ne yhä enemmän ja
enemmän kehittyivät. Pienokainen olit sinä, rakas poikani. Niin,
laaksossa asui ihmeellinen onni kukkien joukossa, onni, jota ei nuori
tyttö milloinkaan täydellisesti voinut aavistaa maatessaan vanhan
kotinsa puutarhasohvalla ja katsellessaan pilvenhuippujen loistoa.
Niin, kiitos isä, että veit haaveilevan tytön elämän elävään
todellisuuteen — kiitos!

*****

Ei, antakaa minun vaan puhua nyt, kun kerran olen alkanut. Niin,
minä kiitän molempia sydämellisesti kaikesta siitä onnesta, mikä on
tullut osakseni, kaikesta mitä olette antaneet minulle. Olen
tyytyväinen ja onnellinen vielä kuollessanikin — joka ei ollenkaan
tunnu minusta vaikealta. Kuoleman kauhun asemasta, josta olen
lukenut ja kuullut puhuttavan, on, kuten jo sanoin ihmeellinen
sopusointu sydämessäni — ei mitään tuskia enää, ainoastaan
väsymystä — ja sitten nuo ihmeen ihanat soinnut — joiden syytä ja
alkua en täydellisesti voi selvittää. — Mutta ehkä sentään voinkin —
se johtui juuri mieleeni, kun kohtasin katseesi, rakas poikani. Mutta
minä kokoan vähän voimia.

*****
 Niin, se oli sinun kotiintulosi, joka saatti sopusointuisuuden
sydämessäni ylimmilleen — se herätti täyteläisempään eloon
tunteen, joka aikaisemmin piili siellä pohjalla — nyt on se paisunut
ilahuttamaan viimeisiä hetkiäni. Se on päässyt valtaan aina, kun olen
lukenut rakkaita kirjeitäsi, poikani katsos, se on nuoruuden runous,
joka on herännyt täyteen kukoistukseen, se on kaikkein
näköalavuorella haaveilemieni unelmain täyttymys, joka vaikuttaa
tämän onnellisen tunteen kuoleman läheisyydessä. Katsos, lapseni,
— niin, sinähän olet kaikessa tapauksessa minun lapseni, niin vanha
kuin oletkin — katsos, sinä olet saavuttanut sen, josta minä
haaveilin, sinä olet nähnyt välkkyvät meret, suuret kaupungit ja
pulppuavan elämän, sinä olet tutkinut tieteitten pesäpaikoissa, sinä
olet katsellut äärettömiä avaruuksia ja kiivennyt korkeille alpeille,
jotka lumikoristuksessaan loistavat punaisina ilta-auringossa ja
ikäänkuin mahtavat aatteet ja ajatukset pyrkivät avaruutta kohti —
sinä olet nähnyt kaiken tämän ja saavuttanut. Ja sittenhän on, kuin
jos minä itse olisin tehnyt sen — nähkääs, tämä mahtoi sentään olla
kaikkein nuoruuden unelmaini sisältö. — Niin poikani, vanha äitisi on
elänyt useamman elämän, isän ja sinun ja hän on ollut onnellinen
teidän menestyksistänne, hänellä on mielestään ollut osansa
kaikesta, mitä te olette toimittaneet — ja tämä tietoisuus, joka nyt on
selvinnyt varmuudeksi, mahtaa olla se, joka hymnin lailla kaikuu
minulle ja täyttää sydämeni elämän täyteläisyydellä ja taittaa
kuolemalta kärjen.

*****
 Päiväkirjasta.

Toukokuun 3 päivä.

Siitä on kulunut vuosi, ei kauvempaa. Kuinka tämä vuosi on

tuntunut pitkältä, ja kuinka paljon se on opettanut minulle!

Kuinka vanha hän nyt olisikaan? kun lasken. Niin, hän olisi nyt
kolmenkymmenen vuotias, koska Signe on kuuden.

Me olemme olleet tänään haudalla, Signe ja minä ja koristaneet

sen kukilla. Kuinka onnellista, että lapsen suru sentään niin helposti
haihtuu! Signen mielestä ei elämä enää ole niin surullista ja
erinomaista senvuoksi että hänen äitinsä on kuollut. Onnellinen ikä!

Joskus vaan enää tapahtuu, että äidin muisto jälleen herää, ja

silloin voi Signen pienessä sydämessä syttyä kiihkeä kaiho sen
perään, joka oli hänen paras apunsa ja hellä ystävänsä.

Kuluneena vuotena olen minä koettanut johonkin määrin korvata

vainajaa. Kuinka naurettavasti ja tuhmasti käyttäydyinkään ensi
alussa! Oli tuhansia asioita, joita en osannut, joita minun täytyi
vähitellen oppia ja joita Signen täytyi minulle opettaa. Minä tunsin
itseni ensin melkein yhtä avuttomaksi, kun Robinson saarellaan,
kaikkien noiden pienien vaatteiden, kaikkien noiden ajatusten ja
kaikkien lapsellisien kysymysten kanssa, joihin on niin vaikea
vastata.

Minä muistan esim. vielä aivan hyvin, kuinka minä muutama päivä
jälkeen kuolemantapauksen osottauduin taitamattomaksi ja
tuhmaksi. Minun oli onnistunut pukea Signen päälle noin jotensakin
ilman muistutuksia hänen puoleltaan, ja kun hän oli valmis, oli hän
mielestäni erinomaisen hyvin puettu. Sitten menimme me
kahvipöytään.

"Saanko kaataa kahvin, isä, kyllä minä osaan?"

Toden totta ei minulla ollut sydäntä kieltää, pidin kuitenkin käteni

läheisyydessä sillä varalta, että apua olisi tarvittu. Pienet sormet
tarttuivat toimekkaasti kahvikannun kädensijaan ja kuppi täyttyi
vähitellen. Lopuksi rupesi pikku käsi vapisemaan ja kannu asetettiin
alas pienellä läjähdyksellä.

"Se painoi, mutta kuppi täyttyi kuitenkin," sanoi Signe, kasvot

punaisina ja riemuiten.

"Nyt kaadan minä sen sijaan sinulle."

"Mutta eihän Signellä ole tapana saada kahvia!"

Salatakseni nolouttani sanoin minä silloin, että hän sentään

tänään saisi puoli kuppia.

"Senkö vuoksi, että äiti on kuollut?"

"Niin, sen vuoksi."

"Saanko minä aina tästedes kahvia?"

"Et, ainoastaan joskus."

"Niin, eihän äiti sentään olekkaan kuollut hänhän on taivaassa.

Voiko hän sieltä nähdä, kuinka me juomme kahvia?"
 "Ehkä" — enhän tietänyt mitä minun piti vastata.

"Mutta kattohan on edessä."

"No sitten ei hän ehkä näekkään meitä."

"Jos hän näkisi, niin kyllä kai Signe hänen mielestään olisi oikein
taitava, kun voi kaataa kahvia isälle."

"Kyllä varmaan."

"Isä, ei Signe oikein ymmärrä tuota, että äiti on haudattu maahan

ja sentään on taivaassa?"

"Niin, tänään saa Signe myöskin leivoksen, ja sitten menemme me

ulos kävelemään."

"Mihin, torilleko?"

"Niin, torille."

Kaikeksi onneksi sain nuo pikku aivot työskentelemään toiseen

suuntaan.

Sellaisia keskusteluja on meillä ollut usein, ja tavallisesti olen minä

joutunut ymmälle. En käsitä, kuinka äidit selviytyvät sellaisesta.

Vuoden kuluessa olen minä kuitenkin tullut vähän enemmän

huomaamaan, kuinka on meneteltävä, kun on kuusivuotias tytär
hoidettavana ja kasvatettavana, taikka kenties on parempi sanoa,
että Signe on tullut huomaamaan, kuinka kuuden vuotiaan tytön
tulee kasvattaa isäänsä.
 Kaikessa tapauksessa on hän avuttomuudessaan kiintynyt minuun
pienen sydämensä koko lämmöllä ja hellyydellä ja me kasvatamme
yhä edelleen toinen toistamme.

Minkälaisia muutoksia yhdessä vuodessa!

Toukokuun 10 päivä.

Kuinka kauniita nämä kevätaamut ovat! Kevät onkin tullut aikaisin

tänä vuonna lämpimineen ja saattanut maan viheriöitsemään. Kun
aukaisen verannan oven, virtaa koko maailman auringonpaiste
minua vastaan ja höyryävä maanhaju tuntuu. Koivujen kaikkein
pienimmät hiirenkorvat kimaltelevat kuin kulta ja hamppuvarpunen
laulaa. Vanhassa lepässä viheltelee rastas laulua
lemmenonnestaan. Minä otan työni ulos verannalle ja kirjoitan
hetkisen pöytäkirjoihini, Signe makaa vielä. Mutta työstä ei tahdo
tulla mitään. Suloiset kevät-aamut ja pöytäkirjat eivät varmaankaan
kuulu yhteen.

Minä menen Signen huoneeseen ja vedän uutimet syrjään ja

annan auringon paistaa sisään ja istun hänen vuoteensa viereen.

Kuinka lämpimänä ja pehmeänä hän lepää pikku vuoteessaan

valkoisena ja hienona kuin joutsenenuntuvat! Kuinka kauniina
ruusuinen pää lepää tyynyllä, keltaisten hiusten ympäröimänä. En
tiedä, tekeekö sen kevät, taikka mistä se tulee, mutta minä tunnen
itseni melkein onnelliseksi, istuissani tuon makaavan pienokaisen
käsi omassani, onnelliseksi, muistojen kaihon sekaantuessa
onneeni.
 Signe ei herää enkä minä herätä häntä. Minä nautin istuissani
täten hänen vuoteensa vieressä, vasta heräävä kevät ulkopuolella,
linnunlauluineen, joka kaikuu sisään ikkunasta ja loistavine
auringonpaisteineen yli maailman.

Enhän koskaan ole ollut runoilija, mutta minun mielestäni pitäisi

sitä, mitä tunnen, voida pukea runomuotoon. Jos voisin runoilla,
kirjoittaisin nyt runon, joka sisältäisi melkein seuraavaa:

"Herää pienokaiseni, herää, nouse vuoteen pehmeästä suojasta,

lämpöisenä kuin linnunpoika ja valkoisena ja hienona kuin joutsenen
untuva."

"Herää pienokaiseni, herää, huuhtele valkeaa ruumistasi ja

punaista poskeasi lähteen kirkkaalla vedellä."

"Pue itsesi valkeihin vaatteihin, niin kävelemme pitkin

auringonpaisteista polkua tuoksuavan tuomen ja koivun alla,
leivosten liverrellessä."

"Tahdon viedä sinut viheriälle niitylle, missä kielot kukkivat."

"Herää pienokaiseni, herää, sano hyvää huomenta visertelevän

iloisesti, niin iloisesti, kuin hamppuvarpunen laulaa ikkunan
ulkopuolella."

"Herää pienokaiseni, lämpöisenä ja hienona, niin menemme ulos

kielojen keskelle!"

Ja sitten herää Signe, aukaisee silmänsä ja luo silmäripsiensä

välistä minuun loistavan katseen.
 Toukokuun 15 päivä.

Vuosi sitten luulin minä, että olisi aivan mahdotonta meille

kahdelle, Signelle ja minulle, päästä läpi elämän yhdessä. Näytti,
kuin olisi päälleni sälytetty vastuunalaisuus, jota en koskaan voisi
täyttää.

Nyt se on joka tapauksessa muodostunut toisellaiseksi, ei siten,

kuin olisi vastuunalaisuudentunne heikontunut, ei, päinvastoin, mutta
minä olen rohkaissut luontoni ja uskon itse, että se onnistuu meille.
Asia on vaan se, että minä ennen ajattelin aivan liian paljon
päiväkirjojani ja liian vähän sitä, että elämä itse asiassa vaatii
muutakin minulta. Ennen olivat nuo kirjoituspuuhat mielestäni
elämäni varsinaisena tarkoituksena, s.o. tuo tunne oli juurtunut
minuun, vaikka en tietänyt siitä, minä en ollut koskaan ajatellutkaan
asiaa. Signe on opettanut minulle toista, Signe on opettanut minulle,
että pöytäkirjat ovat vaan elämisen välikappaleita, sivuasioita, jota
vastoin elämä itse, eläminen, on pääasia.

Kun olen nyt tullut huomaamaan tämän ja ajattelen, minkälainen

minä ennen olen ollut, huomaan minä, että useat elinvuosistani ovat
hutiloimalla kuluneet. Täällä olen minä istunut ja lukenut
paperikimppuja ja kirjoittanut paperikimppuja ja koonnut rahoja,
viettääkseni komeaa elämää, voidakseni elää mukana, kuten
sanotaan, vaikkei vaimovainajani ollenkaan pitänyt sellaisesta
suuresta seuraelämästä, eikä ottanut mielellään siihen osaa.

Pyörre oli tarttunut minuun ja minä olin alkanut pyöriä sen

mukaan.
 Nyt näen minä selvään kuinka vähän todellista riemua sellainen
elämä sisältää, kuinka tyhjää tämä kaupungin remuava ilo on.
Kaiken täytyy tulla sisältäpäin, onnen, ilon, elämisen taidon.

Sen olet sinä opettanut minulle, Signe! Kuinka iloinen olenkaan,

siitä surusta huolimatta, joka ei koskaan haihdu, kuinka onnellisia
olemmekaan toistemme kanssa, ja kuinka vähän me todellisuudessa
tarvitsemme tämän maailman hyvyydestä! Me iloitsemme
voikukkasista tien vieressä, tuomenkukkien tuoksusta, lintujen
laulusta ja auringon loisteesta järvellä, me iloitsemme ystävällisten
ihmisten katseista ja naurusta ja pienistä lavertelevista lapsista, joita
tapaamme kävelyillämme puistoissa.

Niin vähästä olemme me onnellisia, Signe sen vuoksi, että se

kuuluu hänen ikäänsä ja minä sen vuoksi, että olen oppinut, kuinka
paljo tässä vähässä on.

Minä olen onnellinen ja iloinen Signen itsensä tähden. Kuinka

paljon hän minulle onkaan, lapsellisuudessaan ja pienuudessaan.
Mitä kaikkea onkaan hänessä ja mitä voi tulla tuosta pienestä
siemenestä, kunhan se saa kehittyä oikein sinisen taivaan ja
auringon alla.

Niin, minä luotan itseeni, minä uskon, että minä voin johtaa hänen
mahdollisuutensa kehitykseen, minä ainakin teen mitä voin, se on
oleva elämäni tarkoitus ja päämäärä — pöytäkirjain tästedes vaan
ollessa sivuseikkana, välikappaleena.

Toukokuun 20 päivä.
 Tänne tulee tätejä sekä isän että äidin puolelta puhumaan Signen
tulevaisuudesta, hänen koulunkäynnistään — vaikka se onkin liian
aikaista vielä, voi ja tuleekin joka tapauksessa sitä ajatella, eihän
keskusteleminen vahingoita asiaa.

No niin, minä annan tätien keskustella. Itse olen enimmäkseen

vaiti, kunnes suvaitsen ilmoittaa heille, että aion itse pitää koulua
Signelle.

"Sinä koulua! Onpa nekin tuumia!"

"Minä rupean pitämään ulkoilmakoulua."

"Mitä se on? Tuleeko hänen oppia lukemaan ulkona, tai mitä sinä
tarkoitat?"

"Lukemaan? Sitä ehtii myöhemminkin."

"Mutta siitä kai on alotettava! Niinhän on ollut kaikkina aikoina, niin

kauvan kun muistamme."

"Ulkoilmakoulussa me enimmäkseen kävelemme, katselemme

kasvia, kiviä ja eläimiä, soutelemme järvellä, kaivamme maassa,
tutkimme tähtitaivasta, katselemme talonpoikain työtä ja niin
edespäin."

"Siitä mahtaa tulla ihmeellinen koulu."

"Niin, ainakin huvittava. On aika kaivaa esiin unohtuneet tietoni,

opiskella ja istuttaa Signeen rakkautta luontoon, vielä hänen
ollessaan pieni. Sitten kun aika tulee, annan minä jonkun teistä
opettaa hänet lukemaan."
 "Sinä näyt aikovan kasvattaa häntä jonkinlaiseksi ihmeeksi!"

"Minä tahdon vaan välttää tavallisen koulun tasoittavaista

vaikutusta, tahdon välttää sen kasvatusta."

"Sinä näyt olevan kehittymäisilläsi runoilijaksi."

"Ehkä."

Itse asiassa olen minä kyllä paljonkin ajatellut tuota kouluasiaa, ja

päättänyt tehdä niinkuin ylläoleva keskustelu osoittaa. Minkätähden
en tekisi niin? Voin niin hyvin ajatella, että lapsiin voi istuttaa — ei, se
ei ole oikea sana — että lapsissa voi herättää rakkauden luontoon ja
elämään antamalla heidän vähitellen nähdä yhtä toisen perään,
puhua siitä, mitä on nähty, esittää erilaisia ominaisuuksia, puhutella
maalaisia heidän töissään, katsella kyntämistä, kylvämistä ja
elonkorjuuta, työkaluja ja kotiteollisuutta, kalastusta y.m. Täytyyhän
täten yksinkertaisesti ja helposti voida opettaa lapsille kasvioppia,
eläintiedettä, uskontoa, matematiikkaa, vieläpä kieliäkin —
edellyttäen, että itse osataan kaikkia noita aineita ja omataan
opettamiskyky ja kyky johtaa keskustelua siten, että lapsen aivot sen
käsittävät ja valita oikea ikä yhdelle niinkuin toisellekin.

Kuusi, seitsemän vuotta! Siinä ijässähän se yleensä on liian

varhaista. Enkä minäkään ehkä olisi puhunut aikomuksistani, elleivät
tädit olisi kiusanneet minua.

Kuuden seitsemän vuoden ijässä voi sentään joka tapauksessa

sirottaa ruokaa pikkulinnuille, katsella kuinka kukat kehittyvät ja
opetella katselemaan, kuinka kaunista luonto on.
 Mutta mitä hyödyttää puhua koulusta. Opetushan seuraa kaikkea
muuta, sehän on vaan osa kasvatuksesta, eikä se riipu niin paljon
siitä, tiedämmekö sen tai sen, pääasia on saada tunne kehittymään
ja sydän lämpenemään.

Kuitenkin matkustamme me vielä tänään maalle ja katsomme,

mitä voimme tehdä puutarhalle. Signe saa oman maapalasensa,
jonka hän saa muokata ja kylvää. Kun puhun tästä hänelle, tulee
hänen katseensa kuin auringonpaisteeksi, pieniä pyyleviä käsiä
taputetaan riemusta, ja me menemme ulos käsi kädessä.

Ulkona laulaa linnut ja maa on täynnä elävää elämää. Miksi emme

me kaksikin voisi elää, tarvitsematta silti olla runolijoita taikka
ihmeitä.

"Mitä sinä arvelet, Signe?"

Toukokuun 25 päivä.

Tänään on palvelustyttö ollut kaupungissa asialla ja Signe on

mennyt mukana.

Kun he palaavat, tulee Signe minun luokseni, sinne missä istun

papereineni.

"Isä, Fiina sanoo, että jos Signellä ei olisi sinua, niin ei Signellä
olisi ketään, jonka luona olla, sitten kun äiti on mennyt taivaaseen."

"No niin, mutta onhan Signellä tätejä."

 "Signellä ei olisi kotia, missä asuisi, ei vuodetta missä makaisi, ei
ruokaa, eikä mitään."

"Onhan sinulla tätejä, jotka antaisivat sinulle kaiken tuon."

"Mistä sinä sitten saat kaikki sellaiset, isä?"

"Minä ansaitsen työlläni."

"Eikö Signekin voi ansaita?"

"Eikö sinulla ole kaikki hyvin nyt sitte?"

"On, mutta jos isä menisi taivaaseen."

"Ei isä kuole, ennenkun Signe tulee suureksi."

"Menihän äitikin pois Signen luota."

"Äidin täytyi mennä, mutta isän ei täydy, isän täytyy olla täällä —
miten on sinun uuden nukenvaunusi laita, sopiiko se hyvin nukelle?"

Mielessäni olen raivoissani koko palvelusväelle. He eivät näy

olevan kasvattajia. Puhua sellaista lapsille!

Signe menee hakemaan nukenvaunuaan ja tulee vetäen sitä

perässään. Äkkiä jättää hän sen ja juoksee minun luokseni, kiipee
syliini ja painaa koko pikku olentonsa minua vasten.

"Kuinka hyvä sinä olet, isä, annat Signelle uusia vaatteita, uudet
kengät ja leikit kanssani kaikenmoista."

"No, nyt katselemme nukenvaunua."

 Jos minä kuolisin — mitä tulisi silloin Signestä? Luontoni vastustaa
tuota ajatusta. Minä en voi enää ajatella, että hän voisi elää ilman
minua, yhtä vähän kuin minä ilman häntä.

Köyhä ja surullinen olen minä, lohduttomana seisoin minä

hautakummulla ja itkin, mutta sinä, sinä pikkuruinen asetit pehmeän
kätesi käteeni.

Sinä katsoit silmiini kuin lapsi katsoo, viattomuudella ja

luottamuksella, ja sinä annoit minulle uuden onnen.

Minä tahdon tehdä elämäsi iloiseksi ja valoisaksi kuin

auringonpaisteinen sunnuntaiaamu, kun laineet loiskivat.

Köyhä ja surullinen olin minä, mutta sinä asetit lapsenkätesi minun

käteeni ja annoit minulle uuden onnen.

Toukokuun 27 päivä.

Pikku Signe ei voi hyvin tänään. Näen, että hän on kalpea ja

toisinaan häntä viluttaa. Hän ei mene ulos, vaan istuu sisällä
värilaatikoineen ja nukkineen. Iltapäivällä saa hän pään kipua ja
tahtoo itse mennä vuoteesen. Parin tunnin kuluttua herää hän taas ja
on kuumeessa. Hän sanoo voivansa paremmin, mutta lääkäriä on jo
haettu. Hän tulee, antaa jotain pieniä määräyksiä yöksi, sanoo,
rauhoittaakseen minua, että se on vaan vähäpätöinen vilustuminen,
joka pian menee ohi.

Me juomme teetä illalliseksi ja minä istun Signen vuoteen vieressä

pidellen kuppia ja tukien hänen lämmintä päätään. Huomaan, että