Heart disease and the church were two forces that shaped the teenage years of cardiovascular biologist Robert W. Mahley. The first, in the form of a massive heart attack, stole his 37-year-old father; the second provided support through a community of men in his congregation who took the 13-year-old boy under its wing. Originally drawn to become a Presbyterian minister, Mahley instead found a stronger calling in the deep beauty of biology. “I don’t remember actually thinking, ‘I’m going to become a heart disease doctor and cure my father’s illness,’ but to be a 13-year-old and lose your father—that most likely planted something pretty deep in my subconscious,” Mahley says. “When I started working on lipids in the early 1960s, I was immediately attracted.”
Not long after he began studying animals fed high-cholesterol diets, Mahley found an intriguing protein in high concentrations in lipoproteins. Eventually known as apolipoprotein (apo) E, this 34,000-kDa glycoprotein was found to play a critical role in cardiovascular disease as well as neurobiology. Mahley has spent nearly 40 years studying the structure and function of apoE, leading to an understanding of the isoforms associated with type III hyperlipoproteinemia and Alzheimer’s disease. His Inaugural Article in this issue of PNAS (1) discusses the future of therapeutics for apoE in neurobiology.
Elected to the National Academy of Sciences in 2000 and the Institute of Medicine in 2001, Mahley was the first M.D./Ph.D. student to formally graduate from Vanderbilt University School of Medicine (Nashville, TN). In 1979, he was recruited to become a founding director of the Gladstone Institute of Cardiovascular Disease in San Francisco, where he remains today as both a senior investigator and as president of the J. David Gladstone Institutes, newly housed in an architecturally acclaimed building overlooking the San Francisco Bay.
Although he now calls northern California home, Mahley spent his first 30 years in the midwestern and southeastern United States. His family kept a small farm in Shelbyville, a rural town in central Indiana, and Mahley’s father also ran a modest furniture business nearby. After his father’s first heart attack, however, the family dropped both enterprises and moved south in search of a less stressful lifestyle. Mahley’s father opened a restaurant in Lake Worth, FL, ultimately “a serious mistake,” Mahley says, because the work proved to be too much for his heart. A second, massive heart attack killed Mahley’s father a year later.
Robert W. Mahley
With the breadwinner gone, the family lost virtually everything, Mahley says. His mother, “a saint” who had never worked outside the home, took a job as an x-ray technician. To help support her and his younger brother, Mahley immediately went to work, first selling newspapers on the street and then apprenticing in a neighborhood garage. Mahley worked on motorcycles about 4 hours after school every day, all day on Saturdays, and full-time during the summers, including one exciting stint as a pit mechanic for the 1959 Daytona Beach motorcycle races.
Mahley scraped by in his studies until early high school. “I woke up one day when one of my teachers said, ‘Mahley, if you don’t shape up, you’re going to be a ditch digger.’ He got my attention,” Mahley says. “I didn’t think I wanted to be a ditch digger—it looked like too much work.” Although neither of Mahley’s parents had formal education beyond high school, Mahley decided to go to college, a goal applauded not only by his family and teachers but also by his church community.
“When my father died, the men in my church really adopted me,” Mahley says. “They became my friends, and they mentored me and encouraged me.” Besides providing a set of crucial role models for the teenage boy, the men also inspired Mahley to continue his service to the church. The community thought Mahley might do well to attend Maryville College (Maryville, TN), a small Presbyterian church-sponsored school in eastern Tennessee. Mahley pooled his motorcycle-mechanic earnings—a total of $4,000, exactly the cost of tuition for 4 years at the school—and entered Maryville, planning to study English and to become a Presbyterian minister.
Mahley’s freshman English teacher at Maryville, Elizabeth Jackson, saw another destiny for him, however. “At the end of the first year, she called me in and said, ‘Bob, are you going to be happy making B’s in English?”’ Mahley recalls, “and I said, ‘No, ma’am, Dr. Jackson, I don’t really think that’s what I’m called to do, is get by,’ and she said, ‘Well, then, change your major.”’ This was blunt advice, but Mahley appreciated it. He told Jackson that he had in fact become enamored with his science course, which was a surprising development because in high school Mahley had never given much thought to biology. But at Maryville, he was excited by the freshman biology course, taught by a young professor, Donald Williams, who challenged his students to see beyond the textbook. “I think it was one of the first times I understood the real beauty of the human organism, the beauty of biological systems,” Mahley says.
He felt a call to turn this passion into a career. “I developed an absolute burning desire to do something in science,” he says. Mahley saw no contradiction between this passion and his previous career goal of becoming a minister, and in fact he saw biology as a way to better understand the world that God created, he says. “For me, there is no conflict between religion and science,” says Mahley.
Mahley declared a major in biology (premedicine) and took a job sweeping floors in the science building. “That’s where I started in science—at the bottom,” he says. But he did not stay there long. By the end of his second year, he was paid to assist with biology laboratory classes, and by the end of his third year, he found a job doing research in a laboratory at Vanderbilt University (Nashville, TN), where he would eventually do his doctoral work.
When Mahley first looked for summer laboratory experience at Vanderbilt, he was invited to join the laboratory of Virgil LeQuire, a fellow Maryville alumnus who wanted to help another student from his alma mater. LeQuire studied lipids in the early days of lipid metabolism research, “back when we didn’t even know where the lipoproteins in the plasma came from,” Mahley says. From the start in LeQuire’s laboratory, Mahley was immediately hooked on both research and lipids.
Mahley decided he wanted to attend Vanderbilt for medical school, after receiving his bachelor’s degree from Maryville in 1963. He confidently applied only to the Vanderbilt University School of Medicine, with no backup schools. “I still cannot believe that I did that,” Mahley says now. He was accepted for the entering class of 1963. But 6 weeks before classes started, a Maryville professor, A. Randolph Shields, invited Mahley back to campus to teach three courses for a year. It was a good opportunity, Mahley says, because he loved teaching and also because his fiancée, Linda Kenzie, was still at Maryville finishing the last year of her medical technology degree.
Mahley, in Turkey in 1993, teaching medical students about cardiovascular disease as part of a long-term Turkish Heart Study.
Mahley informed Vanderbilt that he was postponing medical school. In one sense, he says, “that was one of the more foolish things that I’ve done in my life.” But in fact this decision turned out to be advantageous, because when he applied again to Vanderbilt a year later, the school offered him admission plus a full scholarship with stipend for its new joint M.D./Ph.D. program. Mahley accepted and happily returned to his work in LeQuire’s laboratory.
“It was one of the first times I understood the real beauty of the human organism, the beauty of biological systems.”
Even throughout his grueling medical school years, Mahley made time for research. His work involved isolating the Golgi apparatus in rat liver, a now-routine task that at the time had been achieved only in onion root tip cells. Mahley was able to show that particles contained in the Golgi apparatus were indeed precursors of plasma very low-density lipoproteins (VLDL), which was proof of the origin of this class of lipoproteins (2). Interestingly, Mahley would later discover that one of the proteins he identified during these experiments was apoE, the significance of which he would spend decades exploring. Mahley went on to receive his Ph.D. in pathology and anatomy in 1968 and his M.D. in 1970.
The hotbed for lipoprotein metabolism research in the late 1960s and early 1970s was the National Heart Institute (now the National Heart, Lung, and Blood Institute) at the National Institutes of Health (NIH; Bethesda, MD). Donald Fredrickson, the institute’s head, had published a series of classic articles in the New England Journal of Medicine that laid out the foundations of the new field (3). Mahley greatly admired the articles and Fredrickson, whom he met during the researcher’s visits to Vanderbilt. So when Fredrickson invited him to interview for a clinical position, Mahley jumped at the chance.
Yet Mahley’s heart was in research and not the clinical responsibilities this position required. The selection committee, probably sensing his apprehension, did not offer him the job, Mahley says. Several months later, however, on Christmas Eve 1970, Fredrickson called with another proposal: Would Mahley be interested in a research-only position at NIH, working in Donald Fry’s laboratory, with free reign to pursue his own work on VLDL? Mahley was so quick to accept this “dream job,” he says, that he neglected to inquire about the salary, as he sheepishly admitted to his wife that night. They did not learn the salary amount until his first paycheck arrived months later.
When Mahley arrived at NIH, he continued his previous work studying the effect of dietary cholesterol on lipids and atherosclerosis in a variety of animals. “That’s when apoE really popped up. As soon as I started looking at the plasma, I recognized that there was a protein there in low concentrations normally, but when you fed fat and cholesterol to animals, this became a major protein, so major it was impossible to ignore,” he says. The protein was first referred to as the arginine-rich apoprotein and ultimately as apolipoprotein E. “My first lab notebook page in which I went on and on about this protein is dated March 15, 1972, and since then I’ve never stopped studying it,” says Mahley.
Mahley remained at NIH for 8 years, first as a staff scientist and then as a section head. His research evolved from studying atherosclerosis in animals to focusing specifically on apoE. In 1975 and 1976, his team found that apoE regulates the clearance of plasma lipoproteins by mediating their binding to low-density lipoprotein (LDL) receptors, which were then just being explored by Joseph Goldstein and Michael Brown (4, 5).
Before long, Mahley was recruited by the trustees of the J. David Gladstone Institutes, named for and endowed by a southern California shopping mall developer, to help establish a research institute in San Francisco. Mahley brought his team of six researchers from NIH, and the Gladstone Institute of Cardiovascular Disease opened in 1979.
Mahley continued his study of apoE. His team made a number of cellular and molecular advances, including the determination of apoE’s protein and gene sequences and the mapping of the amino acid residues involved in receptor binding (6–8). Of particular interest were apoE’s three common isoforms, and Mahley’s research helped to unravel the link between the isoform apoE2 and type III hyperlipoproteinemia, a condition marked by premature heart disease. “The simple story is that I followed where the protein led,” Mahley says.
Following apoE eventually took Mahley into the relatively unfamiliar field of neurobiology. In the mid-1980s, he and his team observed that apoE was synthesized in the brain in high concentration, second only to the liver. Only a year later, when Mahley accidentally met Eric Shooter, the head of neuroscience at Stanford University (Stanford, CA), was he was able to fully explore why this was so.
Mahley recalls that he had been invited to a formal dinner at Stanford and was seated next to Shooter, whom he had never met before. “We were stuck together for this formal affair, and so I told him all about apoE, and he told me all about his work in the neurosciences,” Mahley says. Shooter described his current research, in which a mysterious protein appeared 200-fold over normal concentration when a rat’s major nerve was injured. “As the evening went on, and as the days followed, [Shooter] said to me, ‘I think that protein is apoE,”’ Mahley recalls, “and it was.”
Mahley and Shooter began collaborating, first demonstrating that apoE was indeed produced after peripheral nerve injury and regeneration (9, 10). In a review article in 1988, Mahley postulated that apoE would be shown to play an important role in neurobiology (11). In 1992, this finding was validated with the genomic association between apoE4 and the pathogenesis of Alzheimer’s disease, made by Allen Roses’s team at Duke University (Durham, NC) (12).
Neurobiology is now a major focus of Mahley’s research (13), occupying approximately 80% of his time, he says. He is especially excited by the potential for apoE in clinical applications. “I believe that apoE is an important therapeutic target for not only Alzheimer’s disease but other neurological disorders. We know there’s an association with Parkinson’s and multiple sclerosis and others. I believe because we’ve invested so much in apoE—we understand so much about the structure and function of this protein from 30-plus years of work—that we can help the field to unravel important therapeutics,” he says.
Mahley’s PNAS Inaugural Article (1) reviews the history of apoE in neurobiology and suggests potential therapeutic strategies, including using “structure correctors” to convert apoE4, which is linked to Alzheimer’s disease, to an apoE3-like molecule; protease inhibitors to prevent the generation of toxic apoE4 fragments; and “mitochondrial protectors” to prevent cellular energy disruption.
Mahley served as director of the Gladstone Institute of Cardiovascular Disease from its founding until 2005. During that time, he helped to expand the institute through the creation in 1992 of the Gladstone Institute of Virology and Immunology, and in 1998 of the Gladstone Institute of Neurological Diseases, where he is also a senior investigator. Since 1992, he has served as president of the expanded J. David Gladstone Institutes.
Mahley was instrumental in finding a new home for the J. David Gladstone Institutes at the University of California, San Francisco’s Mission Bay campus. The new, six-story, 200,000-square foot building, named by the San Francisco Business Times as the city’s “best new office,” finally allowed the institutes to exist under one roof. “Previously, it was very hard to get the synergy that we now have in this building,” Mahley says. He is particularly proud that The Scientist magazine named Gladstone in 2006 the best place in the United States for training postdoctoral scientists. The magazine singled out for special praise its courses in time management, mentorship, and “even one by Gladstone president Robert Mahley on the art of lecturing” (14).
Mahley lives with his wife in downtown San Francisco. Their son, trained as a French chef, lives in Minneapolis, MN, and their daughter, who (like her husband) is an ordained minister, lives in the San Francisco Bay area. Mahley and his wife enjoy spending time with their teenage granddaughters and escaping some weekends for a jaunt on the Pacific Ocean North Coast.
Despite his administrative responsibilities, Mahley’s passion for biology has not flagged. “I’ll never give up my science,” he says. In fact, his research group is still as small as when he first started his career. “I have eight now, and I had eight at the NIH,” he says. “I don’t believe in big labs.” His role is largely to train and nurture others, he says, and working in smaller, more intimate groups helps him accomplish these goals—by interacting with people as personally as possible, just as he had been similarly guided by mentors and role models from boyhood on.
This is a Profile of a recently elected member of the National Academy of Sciences to accompany the member’s Inaugural Article on page 5644.
