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Advances in Experimental Medicine and Biology

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Personal Reflections of Our Perinatal Research Group in the Early YearsrnrnLubo has asked me to share some of my memories about the early days of the Center. As more formal reports of the Center’s work will be provided in the following chapters, I have decided to write a few of my remembrances related only to the early days of our group. In hopes of conveying a more humanistic aspect of our beginnings, I have included mention of some of the foibles of which we were part of.rnThe idea for a perinatal group at Loma Linda grew slowly. It was conceived by Larry D. Longo and the dean at that time, David Hinshaw, who convinced Larry to come west in 1968. Larry had trained at the University of Pennsylvania with Robert E. Forster, II, a noted respiratory physiologist. He came to Loma Linda to find very modest circumstances: one lab with one technician. He had high hopes to give a serious push to research at LLU, previously known mostly for its training of medical missionaries.rnAbout a year later Larry recruited me as I was finishing a 3-year tour of duty in the Army Medical Corps, Natick, MA. The Vietnam War was at its peak. I turned down faculty appointments at Harvard and UCLA to come here to LLU. My wife approved of the location because the palm trees reminded her of growing up in Cuba. As a member of the Society of Friends (Quaker), I openly communicated that some aspects of my life did not fit the mold of an ideal Adventist faculty member. The Board of Trustees accepted me as I was.rnFor financial support, I applied for a Research Career Development Award from the NIH and Donald H. Barron came to site-visit the lab and me. Barron was a pioneer in the field of developmental physiology, having developed the chronic sheep preparation enabling fetal sheep to be studied unanaesthetized in utero. Barron landed at a small airport in San Bernardino on a hot, dry, windy day. Larry and I went to meet him. Dr. Barron got off the plane, sniffed the dry desert air, and looked at the mountains. He sniffed again, took a deep breath and said, “This is where young investigators come to die” (sniff-sniff). I didn’t get the award at that time. I did later, however. Larry later dedicated a book he had co-edited to Dr. Barron.rnThe first project I undertook after arriving at Loma Linda was to test the belief that maternal blood pressure in the placenta squeezed on fetal vessels. I had the idea that near term, when a pregnant woman lay down on her back, the gravid uterus would flop back and partially occlude the inferior vena cava,rnvrn rnrnrndam up her blood into the placenta, thus increasing the pressure in the fetal vessels to inhibit umbilical blood flow, compromising oxygen delivery to the fetus. Larry and I did some experiments with sheep that supported this “sluice” flow concept. There was considerable ado and national recognition of this concept, not surprising since there were implications that women should deliver squatting, rather than delivering in the supine position flat on her back. However two other labs did not find evidence of a sluice or waterfall flow (although their experiments were done in circumstances that gave the least chance of seeing such flow), and the idea gradually died. To this day I firmly believe, especially in humans where the placenta has a lake of maternal blood that surrounds fetal capillaries, that the concept holds true. After all, what could prevent the fetal capillaries from collapsing? We needed someone clever enough to do these studies in humans.rnAbout 3 years later, in the early 1970s we recruited Ray Gilbert. He came from Johns Hopkins and had earlier obtained his Ph.D. with Sid Cassin in Florida. Ray worked on control of fetal cardiac output, and showed there was a plateau in heart function that could not be exceeded. He had magnificent surgical skills, if you can imagine placing a catheter in a beating left atrium of a fetal sheep. A reviewer looking over one of Ray’s grant applications said, “Ray, what you propose is impossible” and turned the proposal down. In fact, Ray had already done the “impossible” and received the award at the next review cycle. I mention this because it cautions us against a tendency to become all knowing, once granted the title of reviewer.rnLarry, Ray, and I had common interests in pursing whole-animal fetal physi- ology. Surgeries were performed in lab B (the surgical lights are still there), and the schedule was quite busy with two surgeries in parallel, and sometimes sev- eral surgeries each week. We freely shared money, lab space, equipment, and supplies. I doubt NIH would have approved of this enlightened communism had they known, but it worked well for us with our common interests.rnLarry had a particular weakness for spending more money than the School had allocated for the year’s work, to help us support our research, which chiefly was supported by the NIH. The reputation of our perinatal group became progressively worse each year, and one year things were especially bad. The Dean (Gordon G. Hadley, at the time) called us into the conference room and we knew we were on the carpet and would have to account for every penny. The dean greeted us with tears welling up in his eyes. He said, “How bad is it this time? Larry, don’t tell me the details, just tell me how bad it is, and the School will pay whatever it is.” Talk about unwavering support.rnBob A. Brace brought a bioengineering approach to the group after train- ing with Arthur Guyton. He studied fetal body fluids—blood, lymph, amni- otic fluid—with great energy and purpose. In one of our faculty meetings Bob asked Larry for $2,000 so that he could complete an ongoing study. Larry went to the Dean’s office to see if he could obtain the funding and he was successful. Several weeks later, Bob ran into the Dean’s Financial Officer, Ida Winzel, in the hallway. She asked Bob what he did with the $10,000 that the Dean provided. Gulp. Bob quickly replied that he had finished the study and was preparing it for publication! Years later after Bob had left Loma Linda, he became one of the best-funded perinatal investigators in the country.rn rnrnrnOur work took on a mathematical approach in the 1970s. This included, for example, Esther Hill’s mathematical modeling of the kinetics of respira- tory gas transfer in the placenta and the lungs. Another is the work of John Wilbur, who I mention because of his distinguished career after leaving LLU. John obtained a Ph.D. in pure mathematics from the University of California at Davis and then came to Loma Linda. As a medical student he worked mostly with me to set up a mathematical model of placental water and solute flow between the blood of mother and a fetus. This involved solving a set of more than 70 coupled differential equations on a new fast computer system to which the lab had access. I think it was among the best theoretical descrip- tions of a biologic process ever written. Later in his career as an NIH scientist, John developed the PubMed algorithms that produce search results and allow “fuzzy phrase” matching. These PubMed searches are now used thousands of times a day by investigators all over the world.rnAs the years passed the theoretical phase of our group slowed down and some people thought it was about time. Nicholas Assali at UCLA said to me “So much for that theoretical crap, Gordon. You’ve got to stop all that non- sense and get back to some real experiments.”rnAbout this time a stroke of good luck came to us. Everett Koop was Surgeon General and wanted to show the dangers of a mother’s smoking on the fetus and newborns. He contacted officials at the Child Health Institute, and they in turn asked Larry for help, knowing he had written about carbon monoxide effects during pregnancy. (In fact, Larry and my first collaboration used carbon monoxide to study placental function.) In response, Larry then largely wrote the section in the Surgeon General’s report about smoking and pregnancy that led to cigarette package labeling, and so forth. The officials at NICHD were deeply grateful to Larry for his help. Thereafter, Larry’s grant applications had a way of sliding through a bit more smoothly than they might have otherwise. The NIH largess extended for decades after that.rnOne year I met Geoffrey Thorburn of Australia at a meeting. He was in failing health. I said, “Geoff, how are you enjoying the meeting?” He said, “Well, you know these meetings are a drag.” I said, “Yeah, I understand.” He said “But, you know, the reason I come to the meetings is to talk about ideas, ideas about how the body works.” That piece of wisdom has stuck with me.rnIn the early 1970s Howard Hughes was making war-related electronics for the Vietnam War effort. As many of you know he had established the Howard Hughes Research Foundation that funded biomedical investigators around the country. Larry had a brainstorm—why not get Hughes to establish the Howard Hughes Perinatal Biology Center at LLU? We thought this was rea- sonable because the Foundation’s funding decisions were made by three trustees, one of whom drove hundreds of miles to have her teeth fixed at the Loma Linda School of Dentistry. We thought she would be very partial to LLU. So, after her dental visit, Larry arranged for her to come over and talk with us. Of course, we didn’t know quite what to expect, we did know trust- ees operated with CIA-like secrecy, had complete autonomy, sought to pro- tect Hughes’ reputation, and that if she were favorably disposed millions of dollars might be provided. She arrived, a buxom, middle-aged woman accom- panied by two bodyguards. They wore dark suits and had suspicious bulgesrn rnrnrnin their left armpits. Larry and I waxed eloquent about how reproductive biology would add new dimensions to Hughes’ reputation. She seemed responsive and said she wanted to help Loma Linda. Then I said, “Well, would you like to see our lab, see where we work?” The entourage came into the lab; there on the wall was a giant poster saying, “Make love, not war” and there were other anti-Vietnam war posters around the lab too. A certain iciness descended on the room. The trustee and her bodyguards backed slowly out the door and we never heard further from the Hughes foundation.rnI’d like to say something about Steve Dale as a remembrance. Steve had been working as a manager in a Radio Shack before Ray Gilbert recruited him to our perinatal group. His first task was to set up the computer networks and data collection systems for our new group. He single-handedly wrote a spread- sheet application and data analysis program that rivaled Excel. He was an amazing self-taught programmer who wrote in C and Fortran. He worked with Tim McNaughton trying to figure out the source of the maternal fetal electrical potential difference. He was a brilliant statistician and mathematician.rnIn September 1988, Steve and Tim attempted to ascend Lone Pine Peak in the high Sierras. The ascent was more difficult than they had expected, and they turned back late in the day. A Sierra storm rolled in and their descent was cold, dark, wet, and extremely difficult. They were exposed along the ridge line. In a tragic irony, Steve, who studied the physiology of hypoxia, developed hypo- thermia and acute mountain sickness, beginning with headache and vomiting and progressing to mental changes and ataxia as the hypothermia progressed. He died just as the sun was rising and he had nearly reached base camp. His loss was a huge blow to the perinatal group, both in morale because Steve was so much admired, and because of the loss of such a brilliant mind.rnOne year Larry was driving back from a meeting in San Francisco and while passing the Sierras looked up at the mountains. He thought the high altitude would provide a natural hypoxic chamber to study the effects of low oxygen tension on fetal sheep. Thus the White Mountain project was born. A Program Project Grant application was submitted, approved, and has now continued forrn26 years. It has provided cohesion and funding for the perinatal group.rnPhysically, the Research Wing of Loma Linda University looks and feels now very much as it did 40 years ago, aside from increased bureaucracy and the fact that surgeries have moved down to the basement or to a neighboring farm due to a rampant fear of Q-fever.rnThe perinatal group itself has grown and changed. New investigators joined the group with energy and divergent interests. Like most of the field of physiological research, the interests have shifted particularly toward cell and molecular biology. Some loss in focus of the Center’s work has occurred. There has been a growing disconnect between molecular biology and clinical medicine within the Center and nationally. The emphasis on whole animal physiology has diminished while its importance has remained central to an integrated understanding of medicine. Thus there remains a need for a recon- nection between molecular biology and clinical medicine. I firmly believe whole animal physiology is desperately needed to bring about this reconnection and the Center is uniquely positioned to fulfill this role.rn rnrnrnThe free sharing of money and resources that we supported has been largely lost, and replaced with rugged individualism. This is not surprising given the low approval rates of NIH grant applications, and the need for young faculty to be funded to survive. Through it all, the good will among the faculty has been largely preserved and we have usually been able to ignore the more irritating quirks and idiosyncrasies of each other.rnPostdoctoral Fellows have come from around the world for training and returned to their native countries to have enhanced academic careers. Medical students have come, done a summer project, and gone on to residencies at big name institutions on the East Coast. The group has been promoted to a “Division” and then to a “Center,” becoming a centerpiece of research at LLU. Something over 4,000 sheep have been studied. The support of the administration has never wavered; although officials have not always under- stood what those “sheep doctors” were doing down in the basement.rnIt is my wish that those of you who are reading this will find an institution that lets you pursue your interests with the freedom that I have been granted for the past 45 years.rnrnLoma Linda, CA, USA Gordon G. Power, M.D.

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: MAHAKARYA CITRA UTAMA GROUP., 2014

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978-1-4939-1030-4

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