Developmental Biology, Neuroscience
Baylor College of Medicine
Dr. Bellen is also Professor in the Departments of Molecular and Human Genetics, Molecular and Cellular Biology, and the Department of Neuroscience at Baylor College of Medicine, where he is also Director of the Program in Developmental Biology. He is Charles Darwin Professor of Genetics and March of Dimes Professor of Developmental Biology.
Hugo Bellen is interested in the mechanisms underlying neurotransmitter release and in the molecular basis of early neural determination and differentiation. In addition, he is generating numerous new tools for the fly community.
What connects the fruit fly brain, fertilization in worms, and Lou Gehrig's disease? A few years ago, Hugo Bellen and his colleagues helped find the link. Now, understanding the association may lead to a diagnostic test and possible treatment for Lou Gehrig's disease, a neurodegenerative condition that eventually results in paralysis.
Lou Gehrig's disease or amyotrophic lateral sclerosis (ALS) is characterized by the death or dysfunction of motor neurons. These neurons originate in the brain, extend through the spinal cord, and associate with the muscles in the body to allow conscious motion. When motor neurons deteriorate, muscles atrophy and the brain can no longer control voluntary movement, including swallowing and aspects of breathing.
Bellen's research may help explain the death of motor neurons that characterizes ALS and possibly shed light on how to stop it.
Bellen's foray into ALS started in 2002 with a finding by Giusy Pennetta about VAP33, a protein that helps form the connection between motor neurons and muscles in the fruit fly. If the gene encoding the protein is missing, the neuromuscular junction structure is abnormal.
Then Brazilian scientist Mayana Zatz, who was studying the cause of Lou Gehrig's disease in families, found that a single mutation in VAPB was the cause of the disease in some patients.
"With this finding, Hiroshi Tsuda in my lab then tried to determine how the altered VAPB protein might lead to problems in the motor neuron," Bellen says.
First, a literature review revealed that a piece of the VAPB protein is similar to a major sperm protein, or MSP, a protein that the roundworm Caenorhabditis elegans secretes in its reproductive tract to orchestrate fertilization. In humans, Bellen's lab found that the MSP region is cut from VAPB and is secreted and circulates in the blood.
"MSP acts as a hormone," Bellen says. Hormones are chemical substances that control the activity of other cells and organs. The VAPB protein in humans is made in all cells, but it is unknown which cells actually secrete MSP. Bellen's lab found that MSP ultimately binds to Ephrin receptors and regulates their role in motor neurons and muscles. Ephrin receptors affect a range of cell-to-cell interactions, including the clustering of other receptors for neurotransmitters on neurons and muscle cells.
Bellen's laboratory also showed that the mutant human VAPB protein in fly nerve cells accumulates in the cells, trapping both normal and abnormal versions of the protein. Such excess protein, Bellen suggests, leads to toxicity in the neurons, a characteristic of Lou Gehrig's disease. In addition, protein aggregation prevents the secretion of MSP, which then cannot exert its proper action on Ephrin receptors.
Preliminary work by Bellen in two different groups of patients reveals that they have reduced MSP levels in their blood. "The finding indicates MSP might be a marker for a diagnostic test," Bellen says. Also, injecting MSP into patients might help the condition. Bellen is continuing to research MSP, the pathology of Lou Gehrig's disease, and possible clinical applications.
Bellen came to research after trying a few other professions: engineer, farmer, economist, bouncer, and veterinarian. After obtaining his D.V.M. degree, he decided he liked research better and went for a doctorate in genetics at the University of California, Davis, where he began his "love affair with fruit fly genetics."
As a postdoctoral fellow in Switzerland, he studied genes involved in fruit fly development. There, in the late 1980s, he helped develop a technique that allowed scientists to easily isolate genes in flies. "It became widely used," he says.
Bellen also has made other significant contributions to fruit fly neurobiology: he has characterized the genes fruit flies use in the development of the peripheral and central nervous systems, as well as genes used in nerve cell communication and nerve cell degeneration. He also continues to promote new technology development.
Reflecting on his varied research experience, Bellen notes, "My background in veterinary school has given me insight into how our bodies are put together and has allowed me to come up with hypotheses about the diseases we can test in fruit flies." "Had I just been trained as a fly biologist I might not have been able to see the relationships between the genes I study in the fly and human health as clearly."
He is particularly excited about his research on Lou Gehrig's disease. "I can bring together different ideas and many different techniques to tackle this question," he says. "Now I can also synthesize them in ways that may directly help people."