The Researchers

Birmingham is at the center of medical research and breakthroughs. Meet some of the people leading the way.

Written by Richard James

Photography by Liesa Cole

Dr. Louise Chow

Dr. Louise Chow

Turning the tide on HPV

Dr. Louise Chow’s focus is razor sharp. The object: human papillomavirus.

“Our lab has been conducting basic research on the pathobiology of the human papillomaviruses (HPVs) for over 25 years. These prevalent human pathogens establish persistent infections in epithelial tissues. Productive infections lead to warty lesions that may regress. Lesions recur during temporary or long-term immunosuppression. Mucosotropic HPVs can be sexually transmitted and are of particular medical importance, as a low percentage of infections by oncogenic virus types, such as HPV-16 and HPV-18, can progress to high-grade dysplasia and cancers, in particular, cervical, penile, anal laryngeal and tonsillar cancers,” Dr. Chow says.

“While there is a vaccine now, it does not help with pre-existing infections. We are working on the basic biology to understand the host/virus interaction. How the virus works is what we are focused on,” Dr. Chow says.

Louise Chow, Ph.D., professor in the Department of Biochemistry and Molecular Genetics at the University of Alabama at Birmingham and senior scientist at the UAB Comprehensive Cancer Center, was elected a foreign associate of the National Academy of Sciences for excellence in original scientific research. Membership in the NAS is one of the highest honors given to a scientist or engineer in the United States.

Chow’s efforts as a pioneering scientist have drawn talented graduate students and junior faculty from across the nation and around the world to UAB to work and study with her. “Our lab is excited, and I’m very pleased to be recognized by my colleagues and fellow scientists for my contributions to science to which I have dedicated my life,” Chow says.

Chow, elected along with 84 new members and 20 other foreign associates, is the only member located in the state of Alabama and the second ever elected from UAB (the other was Max Cooper, M.D., presently at Emory University, in 1988). There are currently 2,152 active NAS members. Among the NAS’s renowned members are Albert Einstein, Robert Oppenheimer, Thomas Edison, Orville Wright and Alexander Graham Bell. Nearly 200 living Academy members have won Nobel Prizes.

As one of today’s pre-eminent leaders in the study of the human papillomaviruses, the virus responsible for cervical cancer, Chow has worked on bacterial, animal and human viruses for more than 43 years.

Chow, who was born in China and came to the United States from Taiwan in 1965, obtained her graduate degree from the California Institute of Technology in Pasadena, Calif. As a post-doctoral fellow at the University of California at San Francisco, she investigated the presence of defective DNA of the monkey tumor virus SV40, beginning her career focusing on DNA tumor viruses.

In 1975, she and her husband, UAB Professor Thomas Broker, joined the Cold Spring Harbor Laboratory in Long Island, N.Y. Initially, her work focused on the genetic organization, RNA transcription and DNA replication of human adenoviruses, which cause common respiratory and gastrointestinal tract infections. While using an electron microscope to examine the structures of viral mRNA in a complex with the viral DNA, a relatively new method at the time, they and their colleagues determined the coordinates of all the early and late adenovirus mRNAs. In the course of this work, in 1977, she and her collaborators discovered the totally unexpected phenomenon of split genes and RNA splicing. This work became the foundation for understanding human and other eukaryotic genomes, the origin of most of their encoded proteins and the cause of many different genetic diseases.

Chow joined the University of Rochester in 1984, where her team concentrated on distinguishing the growing number of human papillomavirus genotypes, as well as the spliced structures of their mRNAs. These viruses cause laryngeal papillomas, genital warts, cervical dysplasias and genital cancers, as well as a significant fraction of head and neck cancers in women and men. The team developed approaches to determine the patterns of HPV RNA expression and DNA amplification in the spectrum of patient lesions and from this invented a novel strategy for detection of HPV in patient cells and tissues that has become a global standard for molecular diagnosis.

Chow and Broker joined UAB in 1993 and continued their work in understanding the pathology biology of the human papillomavirus. Culminating more than 25 years of research, at UAB she and her team developed a process to produce abundant infectious HPV-18, one of the dominant HPV types that cause cancers. The new method allowed researchers to reproduce the entire infection cycle of HPV-18. This discovery has further paved the way to study HPV pathobiology and to advance genetic analysis. Currently, their lab is investigating virus-host interaction, which is crucial for identifying potential therapeutic agents to treat benign infections prior to progression to cancers.

Brad Yoder

Dr. Bradley Yoder

The Secrets of the Cilium

UAB researcher Dr. Bradley Yoder has been one of a handful of cell biologists working to uncover the mysteries of primary cilia, the rigid projection on the external walls of cells that were once written off as non-functioning vestigial structures without any real purpose.

Yoder and the cell biologists working with him are discovering that primary cilia, far from being unimportant, are instead vital links to a range of human ailments from kidney disease to obesity to cancer.

“Human patients with ciliary defects are often blind, they can’t smell and they have difficulty hearing,” Yoder says. “It turns out that the cilia are loaded with receptors and channels that allow a cell to sense its environment and communicate with that environment.”

Working for the past decade, at first with green algae and now human samples, scientists have made a startling connection: Bad things happen to a cell that loses its cillium. Primary cilium is actually an important communications device — and a major player in human growth and development, kidney disease, obesity, wound healing and even cancer.

Now called “the antennae of the cell,” cilium determine the overall body structure of where organs develop in the embryo. In the eye, they respond to light. In the nose, they react to odor. In the kidneys, they prevent the development of cysts that keep the organ from performing its primary filtering function. In fact, defective cilia lie at the heart of polycystic kidney disease, “one of the most common genetic disorders in humans and one of the leading causes of dialysis,” Yoder says.

Yoder has even established a link between defective cilia and obesity. Cilia on brain neurons contain receptors for understanding when the stomach is full and does not need any more food. Mice with damaged cilia “can’t control their eating,” Yoder says. “They don’t understand when they’re full.”

Yoder also helped break the news that the cilia antennae are responsible for receiving one of the most important signals in the body — the so-called Sonic hedgehog protein, which promotes cell growth. Hedgehog is crucial to normal development, but because it is so powerful, it is also tightly regulated. If the protein signals are too strong during the embryonic stage, a child may be born with excess fingers on each hand, or cyclopia (a single eye), or cleft palate, or a highly malignant form of brain tumor called medulloblastoma. If the hedgehog pathway is over-activated in adulthood, it can lead to abnormal cell growth and cancer, including basal cell carcinoma, the most common form of skin cancer. Research by Yoder and others suggests that cilia not only receive hedgehog signals but that they also are deeply involved in this regulatory process.

At least one pharmaceutical company is already testing a compound that dampens hedgehog signaling to gauge its effectiveness against basal cell carcinoma, colorectal cancer and ovarian cancer.

Cilia also play a crucial role in cell division, which is a key to healthy growth but also to cancer, when cells start to reproduce uncontrollably. “For a cell to divide, the first thing it has to do is bring in the cilium,” Yoder says. The entire complex cilia apparatus is disassembled and then reassembled in the cell’s progeny.

That makes the cilium a potentially inviting target for new cancer treatments, Yoder says. “If we could find a way to make sure that the cilium can’t be reabsorbed, we should be able to stop that cell from dividing, and we would not have cancer. There are signals that tell a cell to bring in the cilium,” Yoder says. “If we could figure out what those are and how to block them specifically, we may have a better handle on regulating cancer and cell-division rates.”

Despite the recent exponential growth in cilia research, scientists keep uncovering fresh surprises. Yoder is particularly excited about the possibilities in the brain. “One of the mysteries we are tackling in my lab is the function that cilia play on neurons,” Yoder says. He has a hunch that neuronal cilia could be important in regulating mood and behavior, learning, and memory.

“There’s a single cilium sticking off the cell body of almost every central nervous system neuron,” he says. Suggestively, these cilia are packed with receptors for serotonin, somatastatin and other key neurotransmitters involved in mood response and depression, for example. But their function remains a mystery. “What’s the cilium doing there?” wonders Yoder. “Why does a neuron need it, when it has all these other processes that specialize in communication? Is this another, under appreciated communication role that we need to understand?”

These are the kinds of endlessly intriguing questions that originally attracted Yoder to cilia in the first place and have kept him busy ever since. “The data is clear that cilia are doing absolutely essential things,” he says. “We just need to figure out exactly what they’re doing. Then we can start to figure out how to repair or manipulate them.”

Rita Cowell, Ph.D.

Dr. Rita Cowell

The Fine Balance

Both environment and genetics play a role in the development of autism and schizophrenia.

To determine how the loss or overexpression of PGC-1α influences the brain circuits for movement, learning and memory, Dr. Rita Cowell’s lab “determined that the transcriptional coactivator PGC-1a, a protein involved in the control of metabolic gene expression in non-neuronal tissues, is concentrated in inhibitory interneurons during early postnatal rat brain development,” Cowell says. “Interestingly, inhibitory interneurons are dysfunctional in a variety of disorders, including autism, schizophrenia and epilepsy.”

These studies are aimed at elucidating how perturbations in gene expression during development contribute to the progression of neurodevelopmental disorders. A fine balance between excitation and inhibition is required for higher cognitive function.

Rita Cowell, Ph.D., Assistant Professor in the UAB Department of Psychiatry and Behavioral Neurobiology, received the coveted McNulty Scientist Award from Civitan International during the annual Civitan Board reception hosted by Dr. Harald Sontheimer and the Civitan International Research Center in October 2011.

Cowell’s research focuses on how environmental stimuli can influence genetics to cause abnormal brain development, resulting in disorders such as autism. Her studies are aimed at understanding how changes in gene expression during development contribute to the progression of neurodevelopmental disorders.

The Chesapeake Civitan McNulty Scientist Award was established in 2004 to support the research of outstanding scientists with long-term commitments to do research on developmental disabilities. The award is given each year in honor of the McNulty family. Tom and Mary McNulty and their son, Tommy, were the driving force behind the creation of the Civitan International Research Center and the research focus of Civitan International Foundation. To date the award has provided critical support to several successful research projects and help to develop successful clinical programs benefiting individuals with developmental disorders.

Molly Bray Ph.D

Dr. Molly Bray

Eye of the Tiger

More than 99 percent of human DNA is identical. It is only the one percent that makes us who we are: fat, thin, beautiful, brown-eyed, tall or short. These small differences in the DNA sequence influence, at least in part, the reason people look different, have differing risks for some diseases and conditions and respond differently to the same medical treatment or training program.

Although we know that genes are important in our overall fitness, the ways in which they alter response to exercise and diet interventions are not known. A five-year UAB study hopes to incorporate the exercise patterns of 3,200 students to bring further understanding of the reasons individuals respond and/or persist in exercise and formulate better and more efficient  interventions to combat obesity.

The TIGER (Training Interventions and Genetics of Exercise Response) Study will investigate the influence of variations in DNA sequence on body fat and fitness, both prior to and following a 35-week exercise program. The groundbreaking study is one of the few of its kind in the United States.

Molly Bray, Ph.D., professor of public health, is the principal investigator for the five-year, $3.5 million Phase II study funded by the National Institute of Diabetes and Digestive and Kidney Diseases. The first phase of the study began in 2003 at the University of Houston and identified preliminary associations between gene variation and exercise dropout. Almost 2,000 University of Houston students have participated in the study to date. Now UAB students will have the opportunity to participate in Phase II.

Subjects will undergo 35 weeks of exercise training; then six, 12 and 24 months after completing the study protocol, they will be contacted and questioned about their current exercise habits and body weight.

“The recommendations for exercise seem to change frequently, but we’re showing that people see more results when they work out harder,” Bray says. “They don’t have to work out as long that way, and they are more likely to stick with the program. That’s exercise adherence. Everyone knows you will lose weight if you diet and exercise. The hardest part of that equation is doing it.”

That’s where Bray believes genes come into play. Research has shown that the FTO gene has been associated most robustly with obesity. TIGER research shows the gene also is associated strongly with exercise adherence.

“We want to answer the question of whether or not genes, gene variation and DNA sequence predict whether or not people persist in exercise following the completion of a formalized exercise program,” Bray says.

In addition to understanding the role genes play in changing our physiology, researchers are becoming more interested in the possibility that genes change our behavior.

“Imagine if we knew something about the genetic makeup of people prior to giving them the generic ‘you need to exercise, diet and lose weight,’ mantra,” Bray says. “Both physicians and patients feel frustrated when this standard recommendation doesn’t work. But if our genetic makeup influences our behavior, knowing a person’s DNA sequence in genes related to exercise adherence may help the physician to select the type of program that is most likely to produce positive results for each individual.

“This kind of idea sounds far-fetched until one considers that, at one time, no one knew the predictive value of a cholesterol measure, something now routinely tested as part of health screening,” she says.

Students in the study will receive a free evaluation of their physical fitness and body composition by the dual-energy X-ray absorptiometry (DXA scan) and blood test for cholesterol, blood sugar and DNA analysis, plus exercise with fitness experts and instruction on goal setting.

“A large number of 18-year-olds have never been active,” Bray says. “You assume most have been active through playing sports and other activities, but that’s not always the case. Most young adults have never been taught to exercise in a way in which they can tolerate comfortably and see results. That’s one of the best things about this study, aside from the genetics. Students learn how to exercise effectively.”

After students complete the 15-week course, they will continue to have access to the study heart-rate monitor checkout system for the remaining 20 weeks of the study, without having to enroll in a formal class.

“Some students may say, ‘I suffered through 15 weeks, couldn’t wait until it was over, and I never want to exercise again in my life,’ and maybe part of that is driven by genes,” Bray says. “But I’m also sure there will be some who discover they love it, and it makes them feel and function better. We have lots of anecdotal evidence that shows that can happen, too, and perhaps it’s also driven by genes.”

Molly Bray comes to UAB from Texas, having received a PhD in human and molecular genetics from University of Texas Graduate School of Biomedical Sciences and Bachelor’s and Master’s degrees (kinesiology and exercise physiology, respectively) from the University of Houston. She has held faculty positions at the UT Health Science Center at Houston and at Baylor College of Medicine.

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