Career perspective: Peter D Wagner
© Wagner; licensee BioMed Central Ltd. 2013
Received: 1 October 2013
Accepted: 8 October 2013
Published: 8 November 2013
This perspective focuses on key career decisions, explaining the basis of those decisions. In so doing, it exemplifies the unexpected influences of serendipity and the interaction between serendipity and planned events in shaping the career of one individual.
KeywordsCareer choices Serendipity Physiology Mathematics Ventilation/perfusion inequality Exercise Altitude O2 transport VEGF
On reading the four preceding Career Perspectives in this Journal [1–4], one thing becomes clear—styles vary greatly and, more importantly, focus also varies. Author instructions encourage reflection on the facts of one's own contributions to science and on what the future holds for the author. What is not stressed in the instructions are what might be the two most useful aspects (for any young investigators reading this) of the author's scientific research career: First, what career decisions/choices had to be made, and when and how were those decisions reached? And second, which contributions to the scientific journey were more important: (a) simple, logical, linear thought progression or creativity; (b) hard, sometimes boring, obsessive/compulsive work behavior or having others do it for you?; and (c) serendipity or planned ventures?
It is in these two areas—career choices and contributing factors to research outcomes—that my essay will concentrate. By using the major research topics of my past as 'coat hangers,’ I believe I can achieve the objectives for this perspective as envisioned by the Editors and at the same time show how and why my path went in certain directions, and not just of what it was built.
Early career choices and decisions
It is relevant that I grew up in Australia in the middle of the twentieth century. The custom then was to graduate from high school at age 17 and immediately enter a university program (such as a medical school or PhD program)! Let me stress—for those headed into major programs like this, the decision of one's life had to be made in the last year of high school, usually as a 16-year-old, well under the legal age for drinking, voting, or driving. All I knew at that age was that I wanted to be a researcher, although my skills to that point were evident only in the physical and mathematical sciences because back then, biology was not even an optional part of the high school curriculum. Hence, I was leaning towards a research career in physics or mathematics. Foreign languages, English, and History were areas of forced hard labor where I skated by with little enthusiasm but when presented with equations, I was happy. As the choice deadline approached, I started to fear a possible sterility inherent in maths and physics research and wondered about the challenges I might encounter in biology. Biophysics was in its relative infancy, and it struck me that there may be great opportunities to use maths and physics in biology. For a scholastic prize in high school, I chose two of the three Otto Glasser volumes titled 'Medical Physics’ [5, 6] and pored through them. I still possess those books, half a century later. This was it. Or so I thought.
It was soon brought to my attention that there was another large question to be answered even if I was heading towards a math/biology research career (despite absolutely no exposure to biology): Should I do a PhD in math/physics and try afterwards to pick up some biology? Or should I go to medical school and continue my math/physics education on the side, giving up formal PhD research training in exchange for gaining clinical insights and skills as an investment for the future of this integrated pathway? I chose the latter, and it was the best career decision I ever made. Yes, it gave me a surefire plan B if I flunked research, but I would have made an impossible family doc, I knew it then, and I had no desire to pursue that. What medical school gave me was the ability to greatly expand my research horizons by understanding the human body in health and disease, both biologically and in terms of human experimentation opportunities as a trained physician. It has been very empowering to initiate and control human investigation and to be able to perform procedures such as muscle biopsy and catheter placement—on my own terms and schedules—and to really understand the relevance of the physiology I was studying. I had also gained that hard-to-define element of being a doctor: to see a patient and recognize something amiss from the body language, no matter how subtle. Observing the details (in the presentation of a patient) was inherent to—and critical for—good medical practice, and, being clearly even more important in biological research, has served me well.
But I was lacking formal research training, and to remedy that, I interrupted the 6-year medical school curriculum after 4 years to do a 1-year research stint, much like a modern-day master's. It was then the only realistic opportunity for a medical student to learn his way around the research laboratory. Serendipity stepped in when at a social event I met Jim McRae, a faculty member in my medical school interested in radioactive tracer techniques, which were then (1960s) in their infancy. After a short discussion, I helped, during vacation, with his research . He introduced me to his fellow faculty member John Read, a noted and brilliant respiratory physician and researcher who put me onto exploration of serial blood flow heterogeneity in the rat lung  for my 1-year research effort. That worked well, I completed my medical degree in Sydney (1968), started clinical internship in Sydney (1969), and then faced the next big decision: (A) Hang up the stethoscope (shouldn't it be stethophone?) after the intern year and seek overseas postdoctoral research training or (B) complete my clinical training in internal medicine (2–3 years more for board certification) and then see what research job might be out there in Australia. The decision was made easy by more serendipity: Neil Armstrong's walk on the moon in mid-1969 during my internship, which created untold enthusiasm for space biophysics/physiology research.
Postdoctoral fellowship: MIGET
John Read advised me well and I ended up making my giant leap (for myself, not for mankind) to the University of California, San Diego (UCSD) to do postdoctoral work with John West who had just arrived there funded by NASA to investigate the effects of gravity on the lung in astronauts during orbital spaceflight. What better chance to apply maths and physics than to an organ whose primary function is fully governed by simple convective and diffusive transport processes and the principle of conservation of mass and at the same time is heavily influenced by gravity—and which reflected a very trendy new area: gravitational physiology? Sadly, soon after arrival, I was told that space research would be a transient ticket at best and to look for something more enduring.
Operation Everest II
Serendipity surfaced when I looked at some ancillary data needed for MIGET: the Po2 in the pulmonary arterial blood. I looked at this variable because a then-unanswered question was whether the Po2 in the muscle venous blood had some lower limit (below which it could not fall) and still get O2 to the mitochondria. I realized we had a completely unique data set for this question: pulmonary arterial blood gas values at (essentially) maximal exercise not just at sea level but at simulated altitudes of about 20,000, 25,000, and 29,000 ft. Although not a sample of muscle venous blood, such data must be dominated by, and thus reflect, Po2 exiting the muscle in the venous blood (Pvo2) when at peak exercise. Surely at these altitude extremes, we would readily be able to see if there was some lower limit to venous Po2.
It was no longer heresy to claim that within-muscle diffusion was a factor in as Figure 6 allowed Barclay and Stainsby to still be correct in saying that blood flow was important. Figure 6 expanded the understanding of limits to . as being due to the behavior of the entire O2 transport chain as a system, and not due to just one component of that system. was the result of how the lungs, heart, and muscles worked as an integrated O2 transport system, with each component able to affect the final result.
From a 30,000-ft viewpoint (actually 29,000 ft), it became evident that a completely serendipitous observation about venous Po2 during Operation Everest II led to an entirely new area of investigation and way of thinking about how is limited.
Enter molecular biology
Much of my effort the past several years has focused on trying to understand how and why VEGF is so important, and it may all come down to one elegant, unifying effect of exercise: intracellular hypoxia in the myocyte. As reported elsewhere , resting myocyte Po2 is quite high—perhaps 30 mm Hg. However, within seconds of starting exercise, Po2 falls dramatically: to about 3–4 mm Hg . This may do many things that all benefit exercise simultaneously:
Leave enough of a Po2 to adequately drive oxidative phosphorylation 
Maximize the capillary-mitochondrion O2 diffusion gradient to enhance O2 availability
Cause local vasodilatation to increase blood flow, matching it, and thus also O2 delivery, to local metabolic rate
Stimulate adaptive gene transcription to provide a mechanism for training
It is well known  that many of the genes involved in muscle function are hypoxically stimulated via HIF, and VEGF is one of them. This attractive, holistic theory needs to be better evaluated but is very promising.
With that I will close this short story—since it brings me to the present—with answers to the initial questions I posed:
'First, what career decisions/choices had to be made, and when, and how were those decisions reached?’ These have been answered above and bear no repetition here.
'And second, which contributions to the scientific journey were more important? a) simple, logical, linear, thought progression or creativity? b) hard, sometimes boring, obsessive/compulsive work behavior or having others do it for you? and c) serendipity or planned ventures?’
The answers, simply, are 'yes, yes, and yes.’
PDW is a distinguished professor of Medicine and Bioengineering at the University of California, San Diego.
arterial O2 concentration
- Cre Recombinase:
An enzyme that recognizes and splits upon the 34-bp nonmammalian DNA sequence known as LoxP
venous O2 concentration
Diffusion coefficient for O2 between muscle capillaries and mitochondria
Ratio of mixed expired to mixed venous inert gas concentrations (also used in MIGET)
- LOG SD Q:
Dispersion of the distribution (the second moment of the perfusion distribution about its mean calculated on a logarithmic scale)
A 34-bp DNA sequence that is digested by the enzyme Cre Recombinase
Multiple inert gas elimination technique (in which the fractional retention of six inert gases (infused intravenously) in arterial blood is measured and used to compute the distribution of ventilation/perfusion ratios in the lung)
Oxygen partial pressure
Ratio of arterial to mixed venous inert gas concentrations (the primary data used in MIGET)
University of California, San Diego
United States Army Research Institute for Environmental Medicine
Vascular endothelial growth factor
Having worked with dozens of fellow UCSD faculty, many colleagues from other universities, and hundreds of trainees, there are too many to thank individually. However, to those who set me on my academic path—Jim McRae, John Read, John West, Herbert Saltzman, and John Evans—I am especially grateful.
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