A Legacy of Discovery
Honoring Dr. Lawrence D. Longo ’54
By Emily Star (Wilkens) Poole
Originally published in the May-August 2013 issue of the Alumni JOURNAL.
In the late 1980s, a collection of rare and scientific books climbed to kiss the ceiling of an office belonging to Dr. Lawrence D. Longo ’54, director and lead researcher at the Center for Perinatal Biology. For hours every day, the books towered above him as he sat at his desk metabolizing the results from his latest laboratory research. Some of the staff began to worry that even the slightest shift of the San Andreas Fault, which runs directly through the Loma Linda University (LLU) medical campus, would be enough to physically bury the investigator under his subject. As a precautionary measure, the books were eventually moved. And while the threat of being buried by his subject is no more, the irony of the image remains. Dr. Longo says, “I think what makes a good researcher is what makes a good clinician, a good entrepreneur, a good athlete, a good musician; you have to have a passion for what you are doing. You have to hardly be able to think about anything else.”
For the last 40 years, Dr. Longo has worked with enduring passion as director at the Center for Perinatal Biology. Each morning, the 87-year-old scientist arrives early at the lab where a strikingly cohesive group of faculty, basic scientists, fellows, and post-graduates are daily “re-searching” a discovery that has drastically shaped our approach to medicine today. Over the last several decades, research has revealed that humans really do “cut their coat according to their cloth” as the saying goes, and that many adult diseases have an origin during fetal development. Dr. Longo says, “Much of our work relates to epigenetics—not only how prenatal influences affect the size and weight of the baby, but how they affect long-term sequelae for health and disease.”
Even as a boy, Dr. Longo was fascinated with discovery. During high school, he got his hands on a book about mathematics. “It was a big, fat book,” Longo says. “I was crazy about that book.” At night, with his sheets tented up over his head, Dr. Longo read the book on math, as well as “Robinson Crusoe,” “Gulliver’s Travels,” and other tales by flashlight until late.
After graduating from Pacific Union College with degrees in both chemistry and mathematics, Dr. Longo applied to the College of Medical Evangelists (CME), now Loma Linda University, but was denied acceptance. He applied a second time. But again he was denied. With sheer perseverance, a word Dr. Longo now signs at the bottom of most correspondences, he applied a third time and was finally accepted. “To persevere means we’ve got to pick ourselves up off the floor when we get knocked down and not complain, but just move on and do the best we can.”
In 1954, after graduating from CME, Dr. Longo went on to do a residency in obstetrics and gynecology at the University of Southern California-Los Angeles County Hospital. During that time he took an interest in brain damage in children. “It was a time in history when obstetricians were being sued if anything related to the child’s performance or development was amiss (as they are to the present day).”
Early in his career, while serving on the faculty at UCLA, Dr. Longo attended a lecture by a famous pulmonary physiologist named Dr. Robert E. Forster II. After the lecture, Dr. Longo went up to ask Dr. Forster a few questions and by the end of the conversation he asked him if there might be a position open in his lab at University of Pennsylvania. Slightly puzzled, Dr. Forster asked, “Are you an internist?” When Dr. Longo answered, “No, I am an obstetrician-gynecologist,” Dr. Forster exclaimed, “What! Can you read and write?” When Dr. Longo arrived in Philadelphia, ready to begin at his new job in the lab, Dr. Forster called him into his office to inform him that he would be heading to his family home in Cape Cod for two months and that Dr. Longo would need something to do to get started. Dr. Forster stated, “I want you to build a gas chromatograph.”
Dr. Longo hardly knew what a gas chromatograph was, much less how to construct such a complicated instrument. Dr. Forster simply gave him a few details about what the machine should be able to do. Dr. Longo then contacted the departmental machinist who would work with him on the project. When reflecting on Dr. Forster’s leadership style Dr. Longo notes, “His idea was to throw you in the pool, and you’d either sink or swim. It wasn’t authoritarian. As postdoctoral fellows, we were just supposed to think and do the best work possible. We were just curious young doctors from all over the U.S. and several foreign countries. It was an exciting place to be.” During those years in the lab, Dr. Longo says it was imprinted on his genes that that was the way scientists worked best.
In 1968, Dr. Longo received a call from Dr. David B. Hinshaw ’47, a dean at Loma Linda University, inviting him to come to develop a laboratory for research in obstetrics and gynecology at the University. Dr. Longo credits Dr. Hinshaw and Dr. Gordon G. Hadley ’44-B with providing much of the initial support for what would become the Center for Perinatal Biology. Fresh out of Dr. Forster’s lab, Dr. Longo envisioned his role: to recruit bright young colleagues who had a passion for biomedical science, to give them a place to work with ancillary facilities, and finally, as Dr. Longo candidly says—“for me to stay the heck out of their way.” In 1973, Dr. Hinshaw suggested that the group, then four investigators, form a research center.
Today the Center for Perinatal Biology is home to thirteen core faculty members, all of whom are national and international leaders in maternal and fetal physiology, endocrinology, and neuroscience, experts in their individual disciplines. Over the past four decades the faculty of the center have published 1,448 scientific reports—55 of those papers being published just this past year. Not only is the center highly productive in terms of publications, but they are rearing the next generation of scientists in the field. The faculty teach basic science courses at LLU’s School of Medicine, and have trained 135 graduate students. In addition, 176 postdoctoral fellows from over 20 different countries have spent two to three years at the center before returning to their home country’s academic institutions. At least 212 medical students also have been trained in research. “It’s not a typical nine to five job,” says Charles A. Ducsay, PhD, who has served on the faculty for 27 years. “Most of us work 60- to 70-hour weeks.” Some days investigators are in the laboratory performing experiments or scrubbing in for surgery; some days they edit papers for publication; and some days they work with students and colleagues in the laboratory. Vascular biologist and faculty member William J. Pearce, PhD, says that a wonderful balance of having fun and doing hard work has been preserved at the center. “Students come over to our house, we go out to eat, we joke. Feeling a sense of kinship with brethren around the world is one thing that makes it really satisfying.” Many of the core faculty can be found at the gym on their lunch break getting a bit of exercise. Dr. Longo is no exception and you will find him logging miles on the rowing machine.
The Center for Perinatal Biology is nationally and internationally recognized as a leader in its field—and yet, even under the waving banner of success, the Center is not immune to the challenge of sustaining its funding. Dr. Gordon G. Power, one of the first scientists to join Dr. Longo at the center during those early years, describes the trials of grant application by saying, “You work on a grant for maybe a week, two weeks, sometimes four weeks, sweating in your armpits, going psychotic, and then you lay your head on the chopping block and your worth as an investigator is put on the line.” Dr. Longo says that with the extreme budget cuts and the pay-line being drawn at the fifth or sixth percentile (of 100 grants submitted only five or six are funded), he worries about young investigators. There are so many new opportunities, new techniques, and good ideas arising. To put it into perspective, the entire National Institutes of Health (NIH) budget for a year for all of its work on cancer, heart disease, diabetes, and other maladies only amounts to about two weeks of the wars in Iraq and Afghanistan. Dr. Pearce said, “You hear in the press a lot of hesitancy about the figure, but you always have to remember the tremendous opportunities, the huge revolution in genetic biology. We’re talking about in the next 10 years doing a complete genome sequence on every baby at birth.” Dr. Power agrees by saying, “It doesn’t mean you quit, but it is hard.”
Over the past four decades, faculty at the center have been awarded over $135 million dollars in extramural funding. Most investigators at the center holdpersonal NIH R01 grants. These allow them to lead their own laboratory groups, publishing their discoveries regularly in high-impact scientific journals. In addition, in 1988 Dr. Longo was awarded a NIH Program Project Grant to explore the cellular and molecular mechanisms by which the body acclimatizes to high altitude, long-term hypoxia (e.g., oxygen deficiency). These studies involve acclimatization responses in the fetus in utero, as well as in the newborn infant, and the adult. This award not only has funded the bulk of the center’s work for the past several decades, but also has provided a common focus and goal for the center investigators. Every year, the center’s family of scientists gathers together to discuss new ideas and the direction of the project. The investigators survey the progress that has been made, discussing what strategies should be adopted in the future. Dr. Pearce says, “It’s not a static approach to academia. It’s constantly evolving, constantly changing.” Dr. Longo observes that as researchers, they have to “reinvent” themselves with each new grant cycle. While individual investigators have limited resources, the Program Project Grant has allowed the center to pool the expertise and energy of its investigators, dramatically increasing the scope and ability to pursue important problems and questions. It also has allowed them to support a Visiting Scientist Program, whereby outstanding leaders in the basic and clinical sciences spend two or three days at LLU giving several seminars and meeting with faculty and graduate students.
A challenge for scientists throughout history has been to facilitate the translation of laboratory discoveries into improved clinical care of patients. Although most discoveries in the center are made by studying the fetuses and adults of sheep and mice, scientists partner with clinicians to apply those findings to current practices in healthcare. “Such research centers are responsible for updating how perinatologists, obstetricians, and neonatal intensive care unit neonatologists and pediatricians respond and improve clinical management of patients,” says Dr. Pearce.
One of the greatest global health challenges for women and children today is nutrition. Dr. Longo believes “we now know that antenatal and neonatal caloric and/or protein deprivation has a profound effect on infant and adult development.” The World Health Organization reports that almost one billion people in the world do not have enough to eat. For a pregnant mother, hunger is a problem that extends beyond its implications for her own health. “It’s not just that she’s hungry,” Dr. Longo says, “it’s that she has an infant growing inside of her, and antenatal nutritional deficiency has significant effects throughout the offspring’s life.” Dr. Longo is working with an associate, Dr. Ravi Goyal, and a post-doctoral student from India with experience studying embryonic development of the water buffalo. Currently they are applying some of their previous techniques to mice in order to understand conceptual stresses on mothers before and during pregnancy. “There is now evidence that protein deficiency, or other stress even a week before a woman ovulates can affect the whole process of gene regulation during embryonic and fetal development.” Dr. Longo notes that a major issue in world health that is not receiving sufficient attention is adequate nutrition.
Another uterine stress currently being researched by the center investigators is that of chronic hypoxia on a fetus—when respiratory gas exchange in the placenta is somehow compromised. This applies to women who live at high altitude, as well as those who smoke or suffer from heart or lung disease. Researchers are attempting to understand what happens to the fetus under these conditions. By what mechanisms does the fetus adapt to oxygen deficiency and what can be done to improve the developmental environment? The sheep fetus, which parallels that of a human in both size and anatomy, has served these studies as a useful animal model for human translation. For these studies, the center’s investigators use the University of California-maintained White Mountain Research Station located in the mountains near Bishop, California. The animals are kept above 12,000 feet (3,800 meters) before being brought to Loma Linda to study the effects on fetal development and responses in the adult. Dr. Longo says, “We are attempting to move beyond phenomenology—which is saying, ‘Oh gee-whiz, you give hypoxia, protein deprivation, or other stress and the child develops hypertension, heart disease, metabolic syndrome, and other diseases’—and instead trying to understand the mechanisms these genes regulate. What is going wrong with the epigenetic regulated transcription, elongation factors, or the telomeres?” Dr. Longo says that the mechanisms are so complex, but that it is precisely what makes it so exciting. “That’s why I am still working. It’s a great life,” he says.
But science at times requires a steady and patient endurance and seeing the translation of scientific research can take years—sometimes decades. Even Dr. Longo at times pauses to remember his early years of clinical training and work. Following his residency at USC-LAC County Hospital, Dr. Longo worked in Nigeria, West Africa. While most days he did gynecologic or general surgery, at times he traveled to hospitals in other areas where 20 or 30 women had gathered—all suffering from vesico-vaginal fistulas, which left them incontinent and marginalized in society. Dr. Longo performed the reparative surgery and says, “That (surgery) changed these women’s lives.”
His reflections are laced with a melancholy as he admits that the question at times persists even now, “Could I do more good if I returned to Africa and performed those surgeries, rather than being a lab rat?” The question is an honest one. But haven’t good scientists always asked provocative questions? And isn’t this the case for most of us? At times we reflect on the directions we didn’t go because of those in which we went. While Dr. Longo’s reflections spur our own, it is clear that his passion for discovery, and for training the next generation of scientists responsible for shaping the future of medicine, continues to be the driving force sustaining him in his long and productive career.
Recently, Dr. Longo passed his 40-year-hat as center director on to Lubo Zhang, PhD. This is not retirement for Dr. Longo, but simply an effort to focus more of his attention on his own research. Dr. Zhang says that it is because of Dr. Longo’s leadership over the years that the center continues to grow. He says, “Most of us came to the Center and we will stay our whole lives. That says a lot about what the LLU environment is like.”
Dr. Ducsay speaks the sentiment of Dr. Longo’s entire professional family when he says, “When I think of Dr. Longo, I start smiling. He is the quintessential energizer bunny. He is always pondering, always thinking, always coming up with new ideas. His mind works in ways I can’t understand.”
Most humans search their whole lives for something—whether it be answers or purpose or meaning. And perhaps Dr. Longo and his team of researchers have embodied some truths relevant to us all: that the art of discovery is playful and communal, that it is laden with challenges but also opportunities, and that passion and perseverance will be sustaining qualities to carry us into a better future.