As the president of the American Pediatric Society (APS) in its 118th year, Footnote 1 it is at least understandable, perhaps even forgivable, if I am relatively brief, to wax historical for part of my presidential remarks. I began my academic career at Stanford University. I had a good start in a good place. Now, nearly three decades later, I am the third holder of the Harold K. Faber Professorship in Pediatrics at Stanford, after Norman Kretchmer and Philip Sunshine. Both of the previous holders of this chair were my teachers and I honor their legacy at Stanford. Norman served as APS president in 1978 to 1979 and Phil, who served as Chief of Neonatology at Stanford for almost 20 y, received the Apgar Award from the American Academy of Pediatrics (AAP) in 2001.

However, I knew little of Harold K. Faber, whom many of my older colleagues had known personally (Fig. 1A). He came to Stanford in 1915 as head of Pediatrics, a discipline that was a subdivision of the Department of Medicine. In 1927, Pediatrics became a separate department at Stanford, and he was the first chair. He was the president of this society in 1946 to 1947 and the recipient of the Howland Award in 1956. At the 75th anniversary of the APS in May of 1963, he again addressed his colleagues. He recounted the society's genesis and adjusted history slightly, to recognize an individual whom he characterized as a “forgotten pioneer” (1), Job Lewis Smith, the second president of the APS in 1889 (Fig. 1B). As the story goes, Job Lewis Smith, who was chairman of the Pediatric Section of the 9th International Medical Congress, proposed the creation of a new, independent society on September 9, 1887. A small group of his colleagues elected Smith as the temporary chairman and selected the name “American Pediatric Society” for the new organization. One individual proposed that the new society become a section of the American Medical Association (AMA). Fortunately, Smith insisted that a new organization “be organized on the highest possible literary and scientific basis and that it must not enter into entangling alliances.” And as a result, in 1888, the APS was founded. A year later, Smith became the second president of the APS, after Abraham Jacobi, whom Smith had recommended as the first holder of the post. In Harold K. Faber's address, published in the Journal of Pediatrics in October 1963 (1), he made a strong case that, while taking nothing away from the contributions of Abraham Jacobi, “Smith was one of the two chief pioneers of American Pediatrics.” Moreover, Faber left little doubt that, in his opinion, “Job Lewis Smith was the father of the APS.” But, what was Faber suggesting when he pointed out Smith's admonition that the Society must not enter into “entangling alliances”? As a previous PAS program chair and now as this year's APS president, I have vigorously encouraged quite the contrary and witnessed an increasing number of partnerships and affiliations that have enriched our annual scientific meeting.

Figure 1
figure 1

(A) Harold K. Faber. From Nagel GW, A Stanford Heritage. Reprinted with permission from the Stanford Alumni Medical Association. (B) Job Lewis Smith. Reprinted from J Pediatr 63, Faber HK, “Job Lewis Smith, forgotten pioneer”, pp 794–802, 1963, with permission from Elsevier.

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PEDIATRIC ACADEMIC SOCIETIES' ALLIANCES

Certainly, Smith must have been referring to the importance of establishing pediatrics as a specialty—separate and distinct from adult medicine. From what I know of Faber and the institution that was his academic home (Stanford), he could hardly have wanted to discourage the collaboration of scientists from different disciplines, not only among the life sciences, but also among the physical and chemical sciences, to address the complex problems in pediatric medicine. That is certainly Stanford's legacy and its future. In fact, as the 117th president (1), I am confident of the independence of pediatrics as a specialty; nonetheless, I am challenged to ensure that more scientific alliances, not fewer, are created, not only within the academic disciplines of pediatrics (Table 1), but across the artificial boundaries of science that, at a superficial level, have distinguished our various disciplines, as well as the adult and pediatric science communities. I am challenged to ensure the assembly of scientists, whatever their ilk, with all the variety of new tools necessary to solve the “big problems” in biology, and also the translation of our scientific breakthroughs to improve the health of children, not only in our own practices, but regionally and globally.

Table 1 Pediatric Academic Societies' alliances
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WHAT IS PHYSIOLOGY?

As a physician and scientist, I have always been interested in physiology, which I consider to be a basic science. This notion that the study of function in living things is a basic science is held as well by many others among you. Yet, how is it that, at Stanford, we do not even have a Department of Physiology? Instead, we describe the kind of biologic function which is our particular interest; for example, cellular and molecular. Such designations are artificial, but probably have some usefulness.

George N. Somero at Stanford's Hopkins Marine Station in Monterey, and the late Peter W. Hochachka suggest in their text, Biochemical Adaptation (2), that there are other adjectives, which inform us about several kinds of physiology that, in my opinion, have special relevance for the physician. The adjectives they use to describe these conceptual approaches to physiology include: “mechanistic,” “comparative,” “environmental,” “ecological,” “evolutionary,” “adaptational,” and “integrative”. I would like to comment briefly about several of these “physiologies,” but not all of them, as their scope goes beyond my purpose in this talk. In particular, I will comment on mechanistic physiology, comparative physiology, and integrative physiology, without any intent to demote the other physiologies in importance or relevance to the human condition and our understanding of biochemical adaptation.

“Mechanistic physiology” is focused on discovering how living things do what they do. Since the 17th century, scientists have contributed to what has become a largely experimental tradition, underpinning and informing 20th century Western medicine. Now in the 21st century, the borrowing of concepts and tools from other fields of science continues to fuel mechanistic physiology. The new imaging technologies serve as modern examples of such synergies.

“Comparative physiology” often complements mechanistic physiology. In fact, many mechanistic physiologists are also comparative physiologists. Moreover, a variety of organisms provide unique experimental opportunities. In particular, organisms adapted to extreme environmental niches often allow fundamental principles to be deduced through comparative studies, the conservation of certain essential processes implying that discoverable structural modifications must inform such preserved function.

However, it is “integrative physiology” that seems to be most demanding for the expansion of scientific alliances. The goal of such physiology is to study function “across all levels of biologic organization, from the molecular to the ecological to the biogeographical.” Indeed, after mapping the human genome, our intensive focus is now on function. As scientists, we appreciate well that knowing all the letters of the genetic code does not give us all the texts that inform biologic functionality. Thus, the emphasis is not so much on the genetic map (certainly a fundamental structure), but on gene function and control as a way to understand normal development and health as well as abnormal development and disease. The theme is clear—structure and function go hand and hand. Their relationship is not static, but dauntingly dynamic. One cannot be fully investigated without considering the other, and the context of our interrogation is relevant to our discoveries. Our biochemical structures—our enzymes and structural proteins, nucleic acids, and lipoprotein structures—are always being tested by nature, that is, by natural stressors, such as, for example, temperature. One only has to consider life near the deep sea vents or fish in the arctic, living in slush, to appreciate that structural or physico-chemical modifications must occur to preserve function and conserve physiology at such extremes. Or just consider the fetus that must transition from the womb to extrauterine life.

As a part of my general commentary on physiologic investigations and scientific alliances, a few remarks on my own career might help to personalize the perspective on science that I am sharing with you.

SCIENTIFIC INVESTIGATIONS

My first serious investigative efforts began simply enough, under the supervision of John Johnson, a generous mentor and role model, at Stanford. Although I did some research in the beginning of my career on the ontogeny of the disaccharidases, as many others had done before me, under the direction of Norman Kretchmer and Philip Sunshine, I was guided by John in a direction slightly off the main gastrointestinal tract toward the liver and the study of heme oxygenase (HO), another enzyme, which for me, at that point in time, was simply the first and rate limiting step in the production of bilirubin, the bile pigment causing neonatal jaundice, one of the most common problems in pediatrics.

Heme oxygenase.

Only later in my career did I begin to fully appreciate that the heme catabolic pathway (Fig. 2) is a phylogenetically ancient and highly conserved system in the biology of plants and animals with many different roles in different tissues at different points in time—an essential complex of reactions supporting life on a planet rich with iron, oxygen, and light—one of innumerable biologic fulcrums or balancing points in life's biochemistry. Indeed, HO is the rate limiting enzyme that degrades heme to produce equimolar quantities of carbon monoxide (CO), iron, and biliverdin, which is immediately reduced by cytosolic biliverdin reductase to form bilirubin (3). Two primary isoforms of HO, the products of single and distinct genes, have been the most studied: the inducible (HO-1) and the constitutive (HO-2) (4,5). A third isoform, HO-3, has also been identified and reported to be a processed pseudogene derived from HO-2 transcripts and appears to have little activity (6).

Figure 2
figure 2

Heme oxygenase pathway. Carbon monoxide (CO).

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Interestingly, HO-1 is a heat shock protein (HSP32) or, more broadly, a stress responsive protein, which can be induced by many stressors, such as heavy metals, oxidants, UV radiation, lipopolysaccharides (LPS), and thermal stress, etc. (Fig. 3) (4,7). Besides its role in maintaining homeostasis through the regulation of cellular heme and hemoprotein levels, HO-1 also has antioxidant, anti-inflammatory, and anti-apoptotic roles, mediated mostly through the bioactive metabolites of heme degradation. In fact, it is known that biliverdin and bilirubin are strong antioxidants (8–10); in higher plants, biliverdin is the precursor of phytochrome, which is involved in light-induced morphogenesis; free iron is used for cell growth and hemoglobin formation; and CO, a diffusible gas molecule similar to nitric oxide (NO) (11), has the ability to relax vascular smooth muscle through activation of soluble guanylyl cyclase, to serve perhaps as a signaling molecule in the CNS, and possibly to modulate the activity of other heme-containing enzymes, of which there are plenty.

Figure 3
figure 3

HO-1 promoter and its response to stimuli. Distal enhancer-2 (DE-2); distal enhancer-1 (DE-1); proximal enhancer (PE); and promoter (P).

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Notably, there is individual variation in HO-1 gene expression in the human population, the consequences for which have not been explored fully, coming mainly from two genetic phenotypes: (1) polymorphism of (GT)n dinucleotide (microsatellite) repeats found in the human HO-1 regulatory region and (2) HO-1 mutant alleles (12,13). Length of these repeats is associated with variability in basal HO-1 gene expression levels and disease states (12,14). One example of a human HO-1 deficiency has been reported from Japan (15). The child suffered growth retardation, anemia, and developmental delay and eventually died. Thus, the biology related to HO is broad in its relevance to human well-being and ill-being is extremely complex. It is a developmentally regulated system, which is environmentally sensitive. Now older and a little wiser, with my curiosity even more piqued, I am challenged and humbled by the biology that I had embraced so naively about three decades ago. The field of HO biology has been rekindled; many secrets remain to be discovered. For me, the reaction is still fundamentally a beautiful and mysterious one, involving a variety of molecules that clearly have stood the test of time and have their unique roles to play in the lives of many different living things, including us. The physiologic process of the enzymatic degradation of heme has been conserved throughout much of nature, and I am still on a quest to understand why. And, of course, there are many “whys” that could be asked. For example, why do HO-1-deficient embryos have poorly developed placentas and rarely survive past the intrauterine stage (16,17)? Why is reduced HO-1 expression associated with pregnancy disorders, such as recurrent miscarriage, spontaneous abortions, and pre-eclampsia (14,18)? Only mechanistic and comparative physiologic experimentation is likely to provide answers to such questions.

SCIENTIFIC ALLIANCES

In the physiologic tradition, I have always been interested in studying what I have referred to as “situated biochemistry” or in vivo metabolism, to better understand “how things work.” In collaboration with chemists, engineers, and applied physicists, I have encouraged others and helped when I could to develop some of the tools that I needed for this purpose.

Hendrik J. Vreman, my long-time research associate, “right hand” in the laboratory and friend, and Ronald J. Wong, my other “right hand” in the laboratory and also a friend, have been scientific partners in these ventures, along with many others. For example, we had to invent better breath collection systems for babies and more sensitive gas detectors. These technologies allowed us to study CO production (19), as an index of bilirubin formation (20–23), in cells (24–27), tissues (24,28–31), and small and large animals (32–40), including human neonates (41–56).

With David A. Benaron, a past trainee of the National Institute of Child Health and Development (NICHD) Developmental and Neonatal Biology Training Program at Stanford, we reported the first optical time-of-flight absorbance (TOFA) imaging of biologic media in 1993 with subsequent applications to the imaging of brain function of critically ill neonates (57). Our first images were satisfying enough for our Applied Physics colleagues, as we visualized a screw inside an olive, hidden in a tube of blood (Fig. 4), but we were most excited by our images of structures inside a living mammal, using the absorption and scattering of light as our way of probing the organism (58–61). David's light-based TOFA device (Fig. 5) could be used at the bedside for assessing structure and function simultaneously, and was applied to human neonates for this purpose (60). Such technology has been developed further by David and others, and an instrument that can provide pulseless tissue oximetry is now available commercially to noninvasively detect hypoxia, ischemia, and tumors in human and animal subjects (62–64).

Figure 4
figure 4

Optical time-of flight and absorbance imaging. (A) Visualization of a screw inside an olive, hidden in a tube of blood. (B) Scan of a rat with the use of TOFA imaging. Reprinted from Science 259, Benaron DA and Stevenson DK, “Optical time-of-flight and absorbance imaging of biologic media,” pp 1463–1466, 1993, with permission from Science.

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Figure 5
figure 5

Optical imaging headband. Reprinted from Photochem Photobiol 68, Hintz SR et al., “Stationary headband for clinical time-of-flight optical imaging at the bedside,” pp 361–369, 1998, with permission from the American Society of Photobiology.

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With David Benaron, Christopher H. and Pamela R. Contag, the latter also having been National Institutes of Health–funded postdoctoral trainees at Stanford, and others, we were also the first to image gene expression in living mammals using a luciferase (luc) reporter gene system (65), and created the HO-1-luc transgenic mouse (66), validating its use for studying the transcriptional regulation of HO-1 in development (38) and under a variety of conditions relevant to the newborn infant, such as HO inhibition to modulate bilirubin production (67,68). These same in vivo imaging tools now have been applied to study infection (69), including host–pathogen interactions in living mammals (70,71), immunomodulation (72), oncogenesis (73,74), vascular and neuronal function (75), injury and repair (76), as well as stem cell trafficking and engraftment (77). But have my physiologic approaches been integrative? Should I be looking for yet other scientific alliances?

My daughter, Charlotte, has given me reason to ponder such questions. She is a marine biologist, who has been working on the eco-toxicological effects of perfluorochemicals on p-glycoprotein or (p-gp), the cellular multidrug transporter, using the marine mussel, Mytilus californianus, as a model system (78). I am familiar with p-gp because of its relevance to understanding the accumulation of bilirubin in the CNS of rodents (79,80). What Charlotte and her colleagues point out is that these perfluorochemicals are persistent, globally pervasive chemical pollutants that have been detected in water, wildlife, and humans. They are used in a variety of industrial household products, such as firefighting foams, textile and paper coatings, and insecticides. Their uncontrolled impact on p-gp in real life settings, including inhibition and induction, has not been considered by most of us in medicine, as we have studied only uncontaminated model systems, or worse yet we are still ignorant of such contamination, even in our models. What else of consequence could I be missing because my view has been too narrow or my scale too small?

I am now alerted by my daughter and other colleagues that I must pay attention not only to the microenvironments of the cell or of a tissue or organ of interest, but also to the macroenvironment in which we live to appreciate functionality. The earth is changing. As pediatricians, we must pay attention to the full range of potential influences that impact the systems that we study, remembering that we live in a world that constantly presents us with a variety of challenges, chemically and physically, even culturally and politically. The changing climate of man and our contribution to such changes cannot be ignored. Our “marginal stability” (81), the ability of our most fundamental structures to perform the functions we need in the contexts in which we reside, is at stake. And the impact of such global changes on what is more personal and intimate is likely to be profound. We need to work not only on basic problems and be narrowly focused, but also on a global scale with an expansive view. We must work together and we must embrace scientific alliances and not shun them, so that scientists from different disciplines with different tools can approach the “big problems” in biology and human health and solve them together. This is what we are doing at Stanford. This is what we all should be doing. This is not a time to ignore or dismiss science. Science should be on the edge – not the edge of funding, but the cutting edge of inquiry and the creation of new knowledge; life hangs literally in the balance.

And, as my other daughter, Terrell—a premedical student and historian studying the impact of the language, used to describe individuals with trisomy 21, on the behavior of physicians and the public over the decades—has instructed me: “Do not get trapped by the words that set the limits of the current paradigm; see beyond your words and invent the language of your future.” Science can help us see beyond our words and invent the new limits of our world.