Profile of Lora V. Hooper

Lora Hooper, a professor of immunology at the University of Texas Southwestern Medical Center, describes her career as “a random walk in science.” Her pursuit of science was aided by inspirational mentors who pointed her in directions she might not otherwise have taken. These unexpected turns ultimately led her to study the microbiome: the community of microorganisms that reside in and on multicellular organisms, including humans. When she began her studies, the microbiome was poorly understood and received little attention, but it has increasingly become apparent that the microbiome is essential for human health. In recognition of her work, particularly on how the microbiome manages to safely coexist with its host, Hooper was elected to the National Academy of Sciences in 2015.

Image courtesy of David Arellano (photographer).

From Stars to Enzymes

Hooper describes her upbringing in Nashville, Tennessee, as artistic: Her father was a graphic artist, and her mother was a church organist. Given this background, an early interest in science might not be expected. However, when Hooper was about eight or nine years old, she happened upon a National Geographic book on astronomy. “It was beautifully illustrated,” she recalls. “The photographs were just stunning pictures of the stars, and I became fascinated with the idea of these other worlds out there.” It was through astronomy that her interest in science developed. Hooper pursued her love of astronomy through junior high school and high school by subscribing to astronomy magazines and building a telescope with her father’s help. She used the telescope to observe the surface of the moon and the rings of Saturn. Hooper also credits her high school chemistry teacher, Jackie Turner, for furthering her interest in science.

Given her interest in astronomy from an early age, Hooper naturally considered a career in astronomy. At Rhodes College in Memphis, Tennessee, her fascination with the stars gave way to a fascination with the inner workings of living cells, thanks, in large part, to her cell biology professor, Terry Hill. “He was a spectacular teacher and really made this subject come alive,” Hooper recalls. To her, biology seemed “almost magical. Everything… is encoded in a genetic program, and then sort of unfolds into this very complex dance of different molecules and cellular parts that ultimately can yield a very complex organism. It’s in a small package to begin with, and, out of that, you can get something like an elephant.”

With her newfound enthusiasm for biology, Hooper spent summers during college working in various biology laboratories, including those of Charles Rock and Suzanne Jackowski at St. Jude Children’s Research Hospital and Eric Brown at Washington University in St. Louis. Working in these laboratories stimulated Hooper’s love of biological laboratory work. By the time she went on to graduate school in biochemistry at Washington University in St. Louis in 1989, Hooper says, “I was hooked.”

In graduate school, Hooper’s main research interest was in enzymes, at a time when many people were pursuing genetics. Her mentor, Jacques Baenziger, focused on glycobiology, the study of the structure and function of carbohydrates attached to proteins. Hooper worked on purifying and characterizing the enzymes involved in synthesizing these carbohydrates. “I had to go to the slaughterhouse, pick up various cow parts, bring them back to the lab, go to the cold room for six hours at a time, grind these things up, and purify the proteins,” she recalls. She enjoyed confronting some of the particular challenges that protein research presented. “With proteins, each one is an individual. You have to get to know it, and sometimes that takes time in terms of being able to purify it and understand its quirks, but I found that a lot of fun.”

Microbiome Research

After receiving her PhD in 1996, Hooper stayed at Washington University in St. Louis as a postdoctoral fellow in molecular biologist Jeffrey Gordon’s laboratory. Gordon was just beginning research into the microbiome, and Hooper, having spent years studying enzymes in test tubes, wanted to switch gears and study living organisms. Hooper chose Gordon’s laboratory partly because of Gordon himself; according to Hooper, “he brings verve and life to whatever he’s studying.” The idea that resident microbes could influence mammalian biology intrigued her as well, however, despite it not being a popular field of study at the time. In fact, the field’s lack of popularity might be part of what attracted her in the first place. “I don’t like working in a crowded field,” she explains. “I never have. I feel too much pressure to get a result quickly.” Also, because microbiome research was getting relatively little attention, the field was wide open and full of opportunities. “You could ask so many interesting questions and get interesting answers for all of them.”

One of the most important tools Hooper and others use to study the microbiome is germ-free mice, which are raised in sterile conditions from birth. Even beneficial microbes never have the opportunity to colonize such mice, so they never develop a microbiome. This allows researchers to see how the physiology of the mice differs in the presence versus absence of a microbiome. It also allows researchers to observe the effects of selectively introducing individual microbes or combinations of microbes. “Germ-free mice have been really important in vivo ‘test tubes’ to test how microorganisms influence mammalian health and development,” Hooper says. While in Gordon’s laboratory, Hooper showed that colonization of germ-free mice by gut bacteria altered the expression of numerous genes involved in diverse functions, such as nutrient absorption and angiogenesis (1). Hooper’s laboratory has notably derived germ-free versions of various genetic knockout strains, enabling the study of interactions between genes and the microbiome.

Keeping the Microbiome at a Safe Distance

Hooper left Gordon’s laboratory in 2003 to join the faculty at the University of Texas Southwestern Medical Center, where she continued to study the microbiome. One of the first problems she tackled in her new laboratory was how the host body ensures that symbiotic gut bacteria remain in the gut. Even though gut bacteria are essential for health in many ways, they are foreign agents; if they enter human tissues, they can cause inflammation, disease, and even death. Inflammatory bowel disease, for instance, is thought to be caused by gut bacteria entering tissues through a weakened intestinal barrier. To find out how the body prevents this from happening, Hooper put her well-honed protein purification skills to work, looking for proteins in the gut lining whose expression levels increased in the presence of gut bacteria. She identified a protein in mice that did just that. What’s more, this protein, called RegIIIγ, belonged to a class of proteins that bind to carbohydrates, which Hooper knew well from her graduate work in glycobiology. She surmised that RegIIIγ was probably binding to carbohydrates on bacterial cells. Over the next several years, Hooper’s laboratory confirmed that this protein was produced at the surface of the intestinal wall, bound to carbohydrates on the surface of bacteria, and subsequently killed its bacterial targets (2). RegIIIγ turned out to be one of several antimicrobial proteins in the gut, which are expressed in humans as well as mice, and which are essential for keeping gut bacteria away from the intestinal surface (3). Specialized intestinal cells called Paneth cells detect gut bacteria through a receptor on the Paneth cell surface and secrete antimicrobial proteins in response (4). Hooper’s laboratory has also shown that these proteins kill bacteria by creating holes in bacterial cell membranes (5). “These antimicrobial proteins act like little land mines at the surface of the gut,” Hooper explains. “They create this ‘demilitarized zone’ at the surface of the intestine so bacteria are kind of kept at arm’s length.”

Hooper continues to study the role of antimicrobial proteins in human interactions with gut bacteria. In her Inaugural Article (6), she describes a family of antimicrobial proteins distinct from and complementary to RegIIIγ, called the resistin-like molecule family. RegIIIγ preferentially targets gram-positive bacteria, so Hooper wanted to find out what protects the host against gram-negative bacteria. As in the investigations that uncovered RegIIIγ, Hooper’s laboratory screened for proteins whose expression was induced by the presence of gut bacteria, examining which ones had features characteristic of antimicrobial proteins. Hooper’s years of experience studying these proteins have made her good at recognizing them. This time, she identified resistin-like molecule β (RELMβ). Resistin-like molecules had been extensively studied in the context of metabolism, where they were initially thought to help regulate insulin action, but had not been examined for antibacterial activity. A postdoctoral fellow in Hooper’s laboratory, Daniel Propheter, showed that purified RELMβ killed gram-negative bacteria in vitro. Furthermore, when he knocked out the gene encoding RELMβ in mice, he found that gram-negative bacteria invaded the mouse tissues. These findings further underscore the importance of maintaining a barrier between the host and microbiome.

Future of Microbiome Research

Hooper hopes that her discoveries about antimicrobial proteins might help address the growing problem of antibiotic-resistant bacteria. Unlike the small-molecule antibiotics that are used therapeutically, these innate antimicrobial proteins in the gut do not appear to elicit widespread resistance. Hooper suspects that the mechanism by which these proteins kill bacteria, one that involves disrupting bacterial cell membranes, is difficult for bacteria to thwart. So, even if bacteria are resistant to multiple antibiotics, they might be vulnerable to these antimicrobial proteins, rendering the proteins a powerful tool for fighting infections.

Interest in the human microbiome has grown by leaps and bounds since Hooper first began studying it more than 20 years ago. She notes that, “when I joined the field, we knew almost nothing about even the kinds of bacteria that occupy the intestine.” Today, even the general public is aware of the importance of gut bacteria for health, and researchers continue to discover unexpected roles for the microbiome in human health. Hooper herself is currently exploring how the microbiome influences metabolism. “The gut microbiota is a huge determinant of leanness and obesity,” says Hooper. “You can almost think of obesity as being an infectious disease. That’s something that kind of gobsmacked people when it first came out.”