In children, respiratory, sinus, and ear disease can result from dysfunction of the cilia—tiny, hairlike structures in the lungs, nose, sinuses, and ears. Now, with help from the Children’s Discovery Institute, a unique team composed of a physician, a geneticist, and a mechanical engineer is tackling the problem.

Left to right: Brian Lewis, Susan Dutcher, PhD, Thomas Ferkol, MD, Philip Bayly, PhD, and Steven Brody, MD

Every year, a small number of children are born with primary ciliary dyskinesia (PCD). This hereditary disease prevents the movement of mucus in the lungs, causing pneumonia, bronchitis, and sinus and ear infections.

Every year, tens of thousands of children receive treatment for chronic ear infections.

These two groups of children may have something in common. A research team is homing in on genetic defects affecting the cilia. These tiny structures keep infections at bay by sweeping mucus, fluids, pollutants, and bacteria from the lungs, sinuses, and ears. Some genetic defects may be shared by children with rare PCD or relatively common ear infections.

One fascinating aspect of the research is that cilia can be studied by looking at a singlecelled organism called Chlamydomonas, which swims with a tail (flagellum). The flagellum is structurally identical to a human cilium. It offers a sophisticated, cost-effective way to test new ideas.

The team conducting this research is among the most innovative ever supported by the Children’s Discovery Institute—a wide-ranging collaboration of medicine, genetics, and engineering:

• Thomas Ferkol, MD—Professor of Pediatrics, Cell Biology, and Physiology and Director, Division of Allergy, Immunology, and Pulmonary Medicine at Washington University School of Medicine. Working with Dr. Ferkol and the entire team are Associate Professor Steven Brody, MD, from the Department of Medicine, and research technician Brian Lewis.
• Susan Dutcher, PhD—Professor of Genetics/ Cell Biology and Physiology at Washington University School of Medicine.
• Philip Bayly, PhD—Lilyan and E. Lisle Hughes Professor of Mechanical Engineering and Chair of the Department of Mechanical, Aerospace, and Structural Engineering at Washington University.

A continuum of children’s diseases
Dr. Thomas Ferkol suspects that we underrecognize respiratory diseases caused by dysfunctional cilia. At one end of the continuum, said Dr. Ferkol, “is classic PCD. Occurring in approximately 1 in 12,000 to 20,000 births, PCD is a genetic disorder resulting from abnormal cilia structure and function.”

Children with PCD suffer from persistent lung, sinus, and ear infections, because their cilia cannot sweep away bacteria-laden mucus. Their internal organs may be on the wrong sides of their bodies, called situs inversus or heterotaxy, because cilia are necessary to position organs within the developing fetus. As they grow to adulthood, patients with PCD, especially boys, are usually infertile—the flagella of their sperm, like their cilia, don’t work.

“At the other end of the continuum,” noted Dr. Ferkol, “are children who have ear infections year after year.” These children don’t outgrow their ear infections, and require repeated treatment with antibiotics and ear tube surgeries. “We think,” Dr. Ferkol said, “that these children may have genetic and functional defects of their cilia, much like those in children with PCD, but less severe.”

Deciphering the genetic code
In all these children, health problems appear to reside in the genes that code for the function of cilia. Cilia genetics are the province of Dr. Dutcher, borne of her intensive study of the Chlamydomonas organism.

“The similarity between the Chlamydomonas flagellum and a human cilium is amazing,” said Dr. Dutcher. “That means we can study Chlamydomonas to learn about human cilia.” For instance, Dr. Dutcher observed, “we can produce genetic mutations that result in a poorly functioning flagellum. Then, we can see if similar mutations occur in children who have diseases caused by poor cilia function.” Conversely, she said, “we might identify a genetic mutation in kids with PCD or ear infections, then create a similar mutation in Chlamydomonas, and see what it does to the flagellum.”

So far, the team has identified a number of genetic mutations that may affect flagella and cilia. The mutations disrupt the biochemical pathways of motor proteins that ring each cilium and make it move. As a result of this research, explained Dr. Dutcher, “we may be able to test drugs that act upon or override these pathways, potentially leading to new treatments for PCD or chronic ear infections.”

The puzzle requires one more piece—a description of how cilia and flagella move in health and disease. That’s where Dr. Philip Bayly comes in.

Motors and microtubules
“When you know how cilia or flagella move,” declared Dr. Bayly, “you know when they function normally or abnormally.” This information helps determine whether a specific mutation leads to severely dysfunctional cilia, as in PCD, or to a milder problem. “By understanding cilia mechanics,” Dr. Bayly added, “you might be able to make a more accurate diagnosis, or devise treatments targeting specific mechanical abnormalities of the cilia.”

From an engineering point of view, a cilium or flagellum is a “mini-robot” that powers itself. Each is composed of small, flexible tubes (microtubules) encircled by motor proteins—“like drive shafts powered by engines,” in Dr. Bayly’s analogy. Genetic defects compromise the protein “engines,” altering the normal, waveform motion of the cilium.

So far, Dr. Bayly has analyzed motion of flagella on high-speed video, and developed mathematical models to compare the waveform of a normal flagellum with the abnormal waveforms of flagella with genetic mutations. “This modeling,” said Dr. Bayly, “gets us closer to linking particular abnormal waveforms with a specific set of mutations.”

Putting it all together for children
“Ultimately,” said Dr. Ferkol, “our goal is to connect specific abnormalities of cilia motion with a child’s genetic profile, then connect that with a child’s disease.” One day, “we could potentially personalize treatment to the genetics and cilia motion abnormalities present in the individual child.” For example, in one group of children, a drug might interrupt a genetically encoded biochemical process that harms the motor proteins. In another group, a drug might improve the flexibility of microtubules—improving cilia function despite underlying problems with motor proteins.

To date, the team’s collaboration has resulted in scientific insights that, in the words of Dr. Ferkol, “we could never have achieved alone.” Dr. Bayly concurred, noting that he is “honored that mechanical engineering can make this contribution to children’s health.” The team started working together in anticipation of an Institute award, so their research paths converged thanks to this funding.

“Having different scientists from different disciplines takes you out of your comfort zone,” said Dr. Dutcher. “You look at things in new ways, and come up with new ideas.”

MORE INFO:

• Thomas Ferkol, MD, reflects on research that may help kids with cilia dysfunction breathe easier... see video
• More on research in cilia function and genetics... read more