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Basic Science Boom: Fundamental scientific discoveries with major therapeutic potential

May 16, 2016

Bradley Yoder holds a sample jar containing the skeleton of a genetically engineered mouse with deformities that include an extra toe, part of his research into ciliopathies.

Tuning a Cell’s Antenna

Almost every cell in the human body has a tiny, rod-shaped protuberance sticking out from its surface. For nearly a century, scientists thought these bumps, called primary cilia, had no real function—they certainly didn’t suspect that they were linked to disease. Today, studies of primary cilia are shedding light on a variety of human diseases, from obesity to hydrocephalus and polycystic kidney disease.

For years, researchers focused on motile cilia—the longer, hair-like, more dynamic cousins of primary cilia—which help sperm move, and sweep mucus from the lungs. In the mid-1990s, Bradley K. Yoder, Ph.D., the UAHSF Endowed Chair in Biomedical Research and interim chair of the Department of Cell, Developmental, and Integrative Biology, bred mice with a mutation that prevented them from generating both primary and motile cilia. He expected to see changes to the respiratory and reproductive systems, since that’s where motile cilia were known to play key roles. But the mice had far more widespread problems than he anticipated.

“The really interesting thing was these mice had problems just about everywhere,” recalls Yoder. “They had big fluid-filled cysts in their kidneys; they went blind and couldn’t smell; their pancreases basically self-digested; they had extra toes, extra teeth, and hair and skin problems.”

Mutating the long-ignored primary cilia, it turned out, affected nearly every organ in the body. Yoder and others went on to show that it’s not just mice that need the primary cilia to develop correctly and stay healthy—a set of human diseases, called “ciliopathies,” can result from genetic mutations that disturb the cilia.

Ciliopathies include Joubert Syndrome, Senior-Loken Syndrome, Meckel-Gruber-Syndrome, and Bardet-Beidl Syndrome, all of which affect some combination of the kidneys, eyes, liver, muscles, fingers, and toes. The most common ciliopathy, and the one Yoder is focused on, is polycystic kidney disease (PKD), which affects about 600,000 people in the United States. It causes the kidneys to become enlarged with hundreds or thousands of bulbous cysts, eventually leading to kidney failure in many patients.

“This collection of basic science discoveries in model organisms completely changed the direction that cystic kidney disease research was going in,” says Yoder. Based on the last two decades of research, scientists think that primary cilia act as an antenna for cells—they sense information coming in from the outside and turn it into chemical signals that travel throughout the cell. The information these antenna transmit is different depending on the type of cell—eye, liver, muscle, or pancreas cells, for instance. In essence, they’re tuned to a different channel.

To find out what kind of information the cilia normally send and receive in the kidneys, and why cilia mutations cause PKD, Yoder and his colleagues have developed a special strain of mice in which they can disrupt the cilia in only certain cells, letting the eyes and liver develop normally while studying the kidneys, for example. Early data suggest that the cilia in healthy kidneys sense changes in blood flow and blood pressure, Yoder says, but his team is still working to fully understand their function.

When it comes to treating ciliopathies, drugs that target the cilia themselves likely won’t work—that’s because cilia, acting as antennas on nearly every cell of the body, are so widespread that it would be nearly impossible to avoid side effects. But if researchers can determine what proteins in the cells are receiving signals from cilia, they might be able to create drugs to act specifically on those proteins. For now, Yoder says, that’s still far off—fully understanding cilia at their most basic level must come first.

 

Casey Morrow is among the more than 100 UAB investigators studying the links between the microbiome and a variety of diseases.

Mapping the Microbiome

Probiotics are a hot topic these days—they are heavily marketed with catchy product names like TruBiotics and Activia, and boast celebrity spokespeople such as sportscaster Erin Andrews and actress Jamie Lee Curtis.

The widely touted health benefits of probiotics are rooted in the legitimate scientific investigation of the microbiome, which is the collection of all the microbe communities on the human body. There are more than 100 investigators at UAB conducting microbiome-related research, and their discoveries show the promise of leading to new methods for improving human health.

In 2008, the National Institutes of Health established the Human Microbiome Project (HMP). This spurred scientists to paint a detailed picture of the microbes that exist in specific human environments, including the 100 trillion microbes that inhabit our gastrointestinal tract and form a community that is important for effective digestion.

“The HMP provided new information about the composition of this microbe community,” says Casey D. Morrow, Ph.D., professor in the UAB Department of Cell, Developmental, and Integrative Biology. “It also became clear that understanding how these resident microbe communities interact with the host (that is, us) would be important in human health.”

About five years ago, UAB established a microbiome analysis facility with experts from genetics, microbiology, and the UAB Center for Clinical and Translational Science. One notable example of the research that resulted is a collaboration with Martin Rodriguez, M.D. (Infectious Diseases), who treats patients with chronic, recurrent Clostridium difficile, a bacterial infection that causes severe diarrhea. The standard treatment for C. difficile is antibiotics. However, in a number of patients, antibiotics do not eliminate the infection. When this happens, the best treatment is a transplant of healthy fecal microbiota, called FMT.

“We’re giving back to these patients critical microbes that help them reestablish a relatively normal microbial community,” Morrow says. “FMT has a success rate of 90 percent. You have people who literally have not had a normal bowel movement in years, and within 48 hours after fecal transplants they are.”

With the capacity to do microbiome analysis, it is now possible to understand why this simple procedure has such a high success rate. Working with basic scientists such as Craig L. Maynard, Ph.D. (Pathology), and the UAB gnotobiotic animal facility, it is possible to derive animal models that can be used to improve FMT so that it might be used for other diseases that impact the microbiome. Numerous other projects that employ microbiome analysis have been developed in fields ranging from obesity and diabetes to women’s health and numerous cancers.

“The therapeutic applications for the microbiome rest on the idea that if we can define the microbial communities, we can manipulate them to make them closer to the normal state, which in turn leads to improved human health,” says Morrow. “Microbiome analysis has established a significant footprint in the School of Medicine for translation of basic research. Ultimately, this will lead to a program of microbiome management that may form the cornerstone of our efforts toward personalized medicine.”

UAB Medicine Magazine
By Sarah C.P. Williams and Cary Estes