Jon’s Worms

 

Could microscopic worms be the key to identifying which genes cause problems in people with Down syndrome? For UT researcher Jon Pierce-Shimomura, whose son has the condition, the search is more than just academic.

Seen through a high-powered microscope, a transparent S-shaped creature elegantly slips through a monochromatic landscape of gray snow. Its sinuous movements are soundless and smooth, its fluid path vanishing soon after it appears. Underneath its fine translucent skin, a series of see-through eggs is visible, looking like peas tucked into the narrow neck of a diaphanous pod.

The creature is the common roundworm (no relation to its fellow dirt-dweller, the earthworm); its scientific name is Caenorhabditis elegans, or C. elegans for short. Measuring one millimeter in length, these minuscule critters may hold critical answers to the symptoms and possible cures to degenerative conditions like Down syndrome, Parkinson’s, and Alzheimer’s. And these worms are the heart of Assistant Professor Jon Pierce-Shimomura’s pioneering lab, established in 2008 at The University of Texas.

Through cutting-edge research, Pierce-Shimomura and his team isolate, modify, and observe the behavior of specific genes and hope to discover potential drug treatments. For example, a person with Down syndrome carries an extra chromosome. Shimomura is using worms to test, one by one, each and every gene on the chromosome to identify which cause problems like motor-function difficulties. What’s both brilliant and revolutionary about this kind of research is that it takes considerably less time and is far more cost-effective than traditional lab methods. A process that would take decades to complete using mice can take a fraction of the time using C. elegans, because the worms have a much shorter life span.

Pierce-Shimomura, 40, an unassuming man with boyish features, first became interested in science during his high school years in Holden, a town not far from Worcester, Mass. “I thought that I would like to go medical school,” he recalls. “But then I became more excited about making my own discoveries through cutting-edge research than applying old discoveries to heal people through medicine.” After studying biology and neuroscience at SUNY Binghamton and the Marine Biological Lab in Woods Hole, Mass., Pierce-Shimomura started working with worms while pursuing his Ph.D. at the University of Oregon in 2001.

By this time, it was becoming clear to scientists around the world that roundworms proved ideal for groundbreaking scientific study. Cultivated in petri dishes of gelatinous agar, the worms have a two- to three-week lifespan. They are cheap to cultivate and easy to store; thousands can exist in a single Petri dish. But perhaps most importantly, these tiny organisms have relatively simple brains, with 302 neurons and 8,000 synapses. This cellular structure is consistent from worm to worm, making it much easier to understand than the complex mechanisms of the human brain, which is made up of billions of neurons and 100 trillion synapses.

A majority of the worms also feature an unusual sexual system; many are hermaphrodites and impregnate themselves with their own sperm. “It’s very convenient,” Pierce-Shimomura says. “They don’t need to move in order to reproduce, so you can still study nervous system mutations that paralyze them.”

As it turns out, the worm has a genetic rapport with humans, sharing a similar battery of sensory nerve cells that respond to taste, smell, temperature, and touch. The human brain—though far more intricate than the worm’s—uses many of the same mechanisms.

Scientists believe that worm and human genes evolved from the same parent DNA via a distant ancestor. Even after hundreds of millions of years, the closeness is real enough that biologists have been able to insert a human version of a gene in place of the worm’s own copy, and the C. elegans continues living.

In 1986, John G. White of the University of Wisconsin mapped how the 302 neurons of its brain are interconnected. At the moment, C. elegans is the only animal for which there is such a wiring diagram. Though the map itself looks like an enormous tangled spider web, it precisely identifies all the neurons and how they are connected to each other via chemical and electrical synapses. With this valuable information in hand, biologists all over the world can track specific responses of the nervous system because they know the exact name and location of every neuron.

Nine years ago, Pierce-Shimomura’s research interests shifted to the neurological aspects of Down syndrome when his first son, Ocean, was diagnosed. A week after his birth, he developed jaundice, a common condition for newborns. Pierce-Shimomura and his wife didn’t suspect anything grave until they looked at his chart and saw “Noonan’s or Down’s?” written there. “It was a bad way to learn the diagnosis,” Pierce-Shimomura recalls. (Since then, Pierce-Shimomura has worked with the Down Syndrome Association of Central Texas to help train doctors on how to deliver news more compassionately.)

At first, Pierce-Shimomura was skeptical about the diagnosis because their primary care physician was, too. “My son was a chubby, healthy baby without the telltale signs of Down’s,” he remembers. A week later, the doctors performed the definitive karyotype test to find the extra 21st chromosome.

“My whole view of our life changed, like an earthquake,” Pierce-Shimomura says. “Despite being a neuroscientist, I hardly knew anything about Down syndrome.” He remained in a temporary state of denial. Strangers in a store or at the park couldn’t see anything different about his son. As the realities of Ocean’s condition settled in, Pierce-Shimomura joined a small support group of families with children with Down syndrome. “I could see that the more experienced members were not only doing okay, but were inspiring,” he says.

Soon, Pierce-Shimomura talked to his fellow scientists about how he might perform research related to the debilitating condition. “I was trying to think of ways to help out with the critically unmet needs of people with Down syndrome,” he says. “Despite it being a very common disorder, there is hardly any research money spent on it compared to other disorders.”

During the past 30 years, a majority of the efforts being made were related to education and promotion of society’s acceptance of these children. For example, it’s common to see children with Down syndrome in the bustling classroom of a public school; Pierce-Shimomura’s son currently attends Brushy Creek Elementary in Round Rock. Ocean also attends regular kung fu classes and recently earned his orange belt. “People have focused on celebrating their abilities rather than their disabilities,” says Pierce-Shimomura.

But physical complications abound for people with Down syndrome: the condition is the leading cause of congenital heart problems. Other health issues include gastrointestinal problems and celiac disease, an autoimmune disorder causing gluten intolerance. Doctors have found ways to treat these problems, but there are many more challenges to explore, such as motor and muscle issues related to speech and early-onset Alzheimer’s. “I’m very curious what else is out there that is known and unknown—and how we can help individuals to the next level,” Pierce-Shimomura says.

As he learned with his son’s diagnosis, Down syndrome is caused by the presence of all or part of an extra 21st chromosome. “Because there are 226 genes on the 21st chromosome, it’s anyone’s guess what genes are causing problems,” explains Pierce-Shimomura. “Maybe it’s four or 40, or all 226 genes. It would be prohibitively expensive to test these different genes with mouse models, but we can make these worm models very easily.”

In addition to studying Down syndrome, Pierce-Shimomura’s lab focuses on three other areas of research: Parkinson’s, intoxication, and moisture sensation. This past summer, the lab won $1.5 million from the National Institutes of Health to study Parkinson’s. Over time, Pierce-Shimomura hopes to identify the  genes that contribute to the degeneration of motor movement.

On the third floor of the Neural Molecular Science Building, Pierce-Shimomura’s team plugs away at its quiet but urgent research. Miriam Reyes and Alfredo Serrato, two students from Travis High School, prepare plates for an experiment to determine which molecules in the worms might respond to humidity and moisture. Ashley Crisp, a graduate student, tests which drugs prevent neurons from degenerating in worms with an extra copy of the APP gene, which mimics Alzheimer’s disease in people with Down syndrome.

In a windowless lab across the hall, postdoctoral researcher Andrés Vidal-Gadea studies the movement of a worm through an inverted microscope. Here, Vidal-Gadea and other researchers work with transgenic worms, or worms with specific neurons that glow in the dark like the DayGlo strands found on the necks of spectators at a college football game. A nearby computer screen shows the creature’s green pulses as it sucks away at the bacteria food on the plate.

“It’s helpful that the animals are translucent so you can see through them,” says Pierce-Shimomura. “But it’s really convenient when you can color-code a neuron and see exactly what the neuron is doing. Essentially, you can see when the worm is thinking.”

As a part of the Parkinson’s project, Pierce-Shimomura hopes to secure further funding, so he can employ a few adults with Down syndrome. The lab has engineered a strain of worms with Parkinson’s by killing their dopamineneurons and making it difficult for the worms to move. Adults with Down syndrome could help screen for new mutations—or drug treatments—that allow the worms to move again. With this study, Pierce-Shimomura hopes to identify drugs or drug targets that can prolong motor functions in Parkinson’s patients even if they lose their dopamine neurons.

“The nice thing about this is that you don’t have to be a genius to get the answer,” he says. “Most of science is hypothesis-driven, but with this kind of study, you get the right answer and figure out which genes are broken or tweaked.”

“We’re hoping that our research opens up possibilities to test different drugs that can help to cure or treat problems, like Down syndrome, Parkinson’s, and Alzheimer’s,” adds Pierce-Shimomura. “If we can cure these problems in the worm model, eventually we will be able to transfer these solutions to humans.”

Opening photo by Sarah Wilson

 

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