PEMBROKE — In May, the Obama administration unveiled its plan to defeat Alzheimer’s disease by 2025. The disease affects more than five million people in the U.S., and the human toll and cost is rising rapidly.
From the Biotechnology Research and Training Center, Ben Bahr has been watching this development with great interest. A world-class research scientist studying neurodegenerative diseases, he is The University of North Carolina at Pembroke’s William C. Friday Distinguished Professor of Molecular Biology and Biochemistry.
Of particular interest to Bahr and his team of researchers is that one major thrust of the federal initiative would support research on toxic proteins linked to dementia, beta amyloids, and how they affect the course of Alzheimer’s disease. This year, Bahr received a patent in which he co-invented a new class of compounds — lysosomal modulators — that he has found to promote the clearance of accumulating proteins in the brain, which are thought to interrupt memory encoding along neural pathways and across synapses.
Bahr hopes to discover an important new drug from this novel group of compounds his lab is developing. Arriving at UNCP in 2009, Bahr brings timely and world-class research to Pembroke, which he says is an ideal location for discovery and development of his project.
A typical day in his lab may find 4-6 researchers, some UNCP undergraduates and some post-doctoral fellows, who have recently earned doctorates from other universities. In June, Bahr won a national award from the Council on Undergraduate Research for excellence in undergraduate mentorship. Papers he published in the last 12 months included five undergraduate co-authors, four of whom are UNCP students.
Recently, Bahr took time out from his work to pull back the curtain on what he and his fellow researchers are doing. It is truly important work, and they are on the leading edge of neuroscience. Here is the interview:
Q: Tell us about your discovery. Several times you said you “stumbled” on it. What does that mean?
Bahr: I was working at the University of California at Irvine at the time. I was mimicking the aging process in a dish to see how the brain loses synaptic integrity. We, and many labs, have shown how deterioration of lysosomes, the garbage disposals of your cells, leads to neuronal disruption. Alzheimer’s, Huntington’s, ALS, Parkinson’s and other diseases are protein accumulation disorders. Lysosomes play a key role in protein clearance, and decades of work by many groups show that lysosomal function is perturbed with age.
While looking at lysosomal inhibitors to induce the changes that occur with age, one inhibitor I used at a lower than usual concentration did not produce brain aging. In fact, it protected the brain and reversed damage. I did not believe it at first. Then, a student reproduced my experiment. We were using a PADK compound at low concentrations in brain slices. In a few days, the production of lysosomal enzymes was greatly enhanced and synaptic markers returned to near normal levels. This compound positively modulated key enzymes that protect against protein accumulation pathology in the brain. It was like a slow, drawn-out ‘eureka!’ moment. That was in 2003.
Q: How did this discovery turn into a patent?
Bahr: On my own, I went to the patent office with my idea. It was just an idea at this stage. PADK was in the public domain. I didn’t get very far. UConn (University of Connecticut), where I was working then, was watching my work. They have an office to help professors file patents. They advised me to find a chemist to make patentable (unique) molecules. That was when I joined up with Dr. Dennis Wright (a medicinal chemist at UConn). He said, ‘I can make this better — a more stable version.’ We submitted a patent application in 2008. It took three years to get approved, which is typical. We developed first-in-class compounds, and UConn holds the patent. Dennis and I co-founded a company called Synaptic Dynamics, which is developing the compounds with hopes of finding an effective treatment for AD.
Q: What would a successful drug like this mean? And can you beat the 2025 target date for curing Alzheimer’s disease?
Bahr: Lysosomal modulators may be the next ‘Lipitor,’ a drug that is given to many people without a disease but are at risk for a disease. We hope that a lysosomal modulator can be safely given to older people that have early hints of AD, memory problems or have dementia in their family. Taken for years or decades, like Lipitor, it may continue to reduce the risk of age-related protein accumulation events. Life is about making and degrading proteins, and a balance between these two processes is vital for the health of cells.When there is an accumulation of proteins, it can be toxic. If we can speed up lysosomal digestion of Abeta proteins and other toxic material, and slow down synaptic pathology, we can restore memory transmissions. For whatever reason, as we age, our lysosomes are less efficient at clearing out bad stuff that accumulates. The protein accumulation interferes with memory pathways. Our research addresses many neurodegenerative diseases.
Best case scenario — we could begin human testing in two to four years, and hopefully have an approved drug long before the President’s target date.
Q: At the risk of sounding naïve, could you explain exactly what you do in your research? It has something to do with rats and mice?
Bahr: At the first stage, we use rat brain slices kept alive in a dish that minimalizes the number of animals needed for experiments. These tissues are treated in specific ways to trigger Alzheimer’s disease type events. We can then test potential drug treatments, applying an exact amount of a chemical on the brain slices and testing for a protective result. In the brain slice model, we don’t have to worry whether the drug passes the blood brain barrier or if it affects other organs of the body. The next stage is animal testing. We have used two types of genetically modified mice that either represent the early or advanced pathology of Alzheimer’s. Recently, we published a paper that contained six years of research, showing that our test compound helps both early and advanced stages of the disease. Only about five percent of AD patients have the heredity form of Alzheimer’s. No one knows who will get this disease when considering the 95 percent of patients with the non-hereditary form of the disease. The experimental mice we use are designed based on the hereditary model, although the disease looks the same as the more prevalentform. Of course, we won’t know if the mice mimic the disease enough until testing can be done in actual Alzheimer’s patients.
Q: How do undergraduate students fit into your research?
Bahr: I’ve worked with undergraduate researchers at three universities where I have been a facultymember. I got my start in research as an undergraduate at Santa Barbara, so I’ve always wanted to provide opportunities for others. When I got here, I opened the door and two undergrads showed up the next day. About half of the undergraduates that come to me catch the research bug and take off. Undergraduates need lab experience, and it looks good on their grad school applications. At UNCP, I also have been successful at recruiting post-graduate and post-doctoral researchers from other universities (Cornell, Duke, UConn among others). It is a learning experience on all levels with students getting valuable researchexperience and post-docs learning to direct a team of 2-3 researchers on a project. Undergraduates are very useful to push a project along, or to split off and continue with a side issue discovered in the results. Research never moves in a straight line, and undergraduate researchers add to the layers of data.
Q: You live in Columbus County, and Pembroke is not a center of research. Is that a problem?
Bahr: My wife, Alyson, and I have settled in at Lake Waccamaw, a wonderful community which we enjoy (we are even okay with the alligators that make their home there). Through the NCBC (North Carolina Biotechnology Center), I’ve met with many entrepreneurs and clinical scientists in Wilmington and other parts of North Carolina. I’ve also made a connection with the Marine Science group at UNCW, and we are starting an interesting pharmacological collaboration. My lab is working with a pathologist in Lumberton who works for Southeastern Regional Medical Center to help us with preliminary toxicity screening. We are also working with Professor Cornelia Tirla (a UNCP chemist) to make other patentable molecules. So, to start a new company with a drug to test in humans, it seems we’re in the right place.
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