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For Geoffrey Chang, New Project Studying Tiny Proteins Has Big Personal Impact

[ChangRandy]Geoffrey Chang (left), hopes his new research project will lead to the development of better cataract treatments for patients with Down Syndrome, like his brother Randy (right). Photo provided by Geoffrey Chang.

Original Posting By Alison Caldwell Jan 16, 2020

As a structural biologist, Geoffrey Chang, Ph.D. has spent most of his career focused on very small objects. As a professor at the Skaggs School of Pharmacology and Pharmaceutical Sciences, his research has included studying transporter structures in cell membranes that are so small, they are most easily studied using X-ray crystallography, the same technique used to unravel the structure of DNA.

“I study all kinds of things,” he said. “Molecules in plants, fish, corn, rice…red meat.”

But it wasn’t until he watched his brother struggle to get access to cataract surgery that Chang realized he could be using his expertise on tiny structures to have a big impact on the lives of families like his.

Chang’s brother Randy has Down Syndrome—a genetic disorder affecting 1 in every 700 infants born in the U.S., causing intellectual disability as well as a host of other medical challenges. Over the last several decades, the life expectancy for patients with Down Syndrome has dramatically increased, and many families like Chang’s find themselves facing new challenges as children with Down Syndrome age. These challenges include high risk of early-onset Alzheimer’s Disease and eye disorders such as cataracts, which can occur in up to 60 percent of patients with Down Syndrome.

Down Syndrome is most commonly caused by an extra copy of chromosome 21, which contains the gene for amyloid precursor protein (APP), so patients with Down Syndrome have an excess of APP. APP is the precursor to amyloid beta, the protein that’s connected to Alzheimer’s Disease; abnormal folding of the protein causes it to clump up into the hallmark amyloid plaques associated with the disease. In Down Syndrome, the abnormally high levels of APP and amyloid beta can cause other problems, like potentially contributing to Randy’s cataracts.

“My brother had lost most of his eyesight before the surgery,” said Chang. “But in Delaware, where my family lives, no one was willing to do the surgery for him, because patients with Down Syndrome can be uniquely challenging to work with. My brother had to go to a specialist in Philadelphia—but lots of people don’t have that kind of access to resources, and as this population is getting older, they have special needs.”

It was through watching Randy struggle to find a surgeon, and witnessing his brother’s anxiety over the impending surgery, that led Chang to consider whether or not he might be able to help. “I got curious about why this was happening, and whether or not it was a problem for others too,” said Chang. “Once I started reading up on it, I got inspired.”

Chang’s inspiration led him to collaborate with other experts at UC San Diego to apply for an INCLUDE award from the National Institutes of Health (NIH). The INCLUDE (Investigation of Co-occurring Conditions Across the Lifespan to Understand Down Syndrome) project aims to support research to better understand the pathology of Down Syndrome, with the hope that the results will inform a variety of other conditions and disorders in the future.

With the support of Bill Mobley, M.D./Ph.D. at UC School of Medicine and Daniel Chao, M.D./Ph.D. at Shiley Eye Institute at UC San Diego Health, Chang has received funding to study the potential use of nanobodies to treat amyloid beta pathologies. Originally discovered in camels, nanobodies are extra-small antibodies with the potential to be used for a wide variety of experimental techniques and treatments. In research, antibodies are often used to target and label specific kinds of cells or proteins, and can be used to direct the body’s immune system to identify, attack and break down disease-causing molecules. With their smaller size and simple structure, nanobodies can be easier to produce in the lab and are just as good or better than traditional antibodies at targeting proteins.

Chang’s group is using synthetic biology techniques to generate and screen large numbers of candidate nanobodies to bind to new or rare conformations of amyloid beta. Not all amyloid beta is created equal; different conformations may have different effects in different contexts, but researchers are just starting to identify the ways in which different kinds of amyloid beta are affecting the brain and body.

Chang hopes that this technology can help researchers detect and understand how different conformations of amyloid beta play roles in Down Syndrome and Alzheimer’s Disease—or even be used to bind to and dissolve the cataract-causing amyloid beta in the eyes of patients like Randy.

“Ideally, this technology could be used as a non-surgical alternative for treating cataracts,” said Chang.

“I didn’t know that I’d come around to studying Down Syndrome. But this project is very personal to me, and I just happened to be in the right spot at the right time. I have access to this technology, and happened to be at this amazing place full of incredible researchers studying Down Syndrome, and learned about this new mechanism for funding this kind of project.

“Watching my brother go through this—it’s a big chunk of my life, and a big motivation,” Chang continued. “I can’t imagine my life without my brother. That’s why I enjoy meeting other scientists who have family members with Down Syndrome—they really love to tackle this problem, and they want to solve this problem to make life better for people living with this condition. I’m really lucky to get to work on this.”

It is Chang’s hope that research like his and that of his colleagues will help support people like Randy throughout their lifetimes—and many others as well.

“It will take time to figure out the practical applications of this work,” he said. “But this will have applications not only for people with Down Syndrome, but maybe even someday helping to treat Alzheimer’s Disease.”


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