07:30am Thursday 23 January 2020

Chemist Devises Imaging Technique to Unlock the Mystery of Memory

An image of newly synthesized proteins in live hippocampal neurons.In the search to understand memory, Wei Min, PhD, is looking at cells at the most basic level, long before the formation of neurons and synapses. The assistant professor of chemistry studies the synthesis of proteins, the building blocks of the body formed using genetic code from DNA. “We want to understand the molecular nature of memory, one of the key questions that remain in neuroscience,” he says.

Proteins carry out almost every biological function, and protein synthesis is a crucial step in gene expression, determining how cells respond to pathological conditions caused by cancer, autism, and the physiological stresses linked to disorders such as Parkinson’s and Alzheimer’s. Dr. Min’s lab examines the proteome (the sum of the cell’s proteins), a dynamic structure tightly regulated by both the production and death of proteins that ensures that the body functions normally. The formation of long-term memory is dependent on protein synthesis at a specific location and time in brain tissues.

Dr. Min and his team recently developed a new imaging technique to pinpoint exactly where and when cells produce new proteins. The method is significant in that it enables scientists to create high-resolution images of newly synthesized proteins in living cells. The findings were published in the July 9 issue of the Proceedings of the National Academy of Sciences; the research was done in collaboration with Baylor College of Medicine.

Despite extensive efforts, it is not yet possible to observe global protein (proteome) synthesis as it occurs, because the most widely used methods require killing cells. Dr. Min’s technique, however, opens the door to answering questions about the behavior of living cells, as it makes it possible to observe them as they carry out their functions. “Instead of looking at a static picture, we are adding a new functional dimension and tool compatible with live cells,” he says.

Proteins comprise a chain of amino acids, which consist mainly of carbon, oxygen, hydrogen, and nitrogen. In his lab in the Northwest Corner building, Dr. Min and his team replaced the hydrogen with deuterium, an isotope that is a heavier cousin of hydrogen. (Columbia professor Harold Urey discovered deuterium in 1932, for which he won the 1934 Nobel Prize in chemistry.) Deuterium mimics the properties of hydrogen with little variation, and amino acids labeled with deuterium behave almost identically to natural amino acids. Importantly, the carbon-deuterium bond vibrates at a unique frequency that differs from that of the normal carbon-hydrogen bond.

Dr. Min’s team added the deuterium-labeled amino acids to a growth medium in cell cultures, and as the deuterium-labeled amino acids were incorporated as the necessary building blocks into proteins, the researchers sought out the unique frequency to detect those carbon-deuterium bonds carried by the newly synthesized proteins.

Using a special laser-based technology called stimulated Raman scattering microscopy, they scanned a laser across the sample and created location-dependent maps of the carbon-deuterium bonds inside living cells.

“Our technique is highly sensitive, specific, and compatible with living systems, and it doesn’t require killing cells or staining,” says Lu Wei, a PhD student in Dr. Min’s lab and lead author of the paper who is currently researching where and when a new protein is produced inside brain tissues as long-term memory is formed.

Dr. Min was first intrigued by enduring neuroscience questions about memory while at Harvard, where he received his PhD in 2008 and stayed for two years as a postdoc. A native of China who studied chemistry at Peking University in Beijing, he joined Columbia in 2010. He is a member of the Kavli Institute for Brain Science, part of Columbia’s interdisciplinary neuroscience research initiative. The work on long-term memory by Nobel laureate and University Professor Eric Kandel inspired him to focus on the role of protein synthesis. “It’s a cutting-edge research question and isn’t yet resolved,” Dr. Min says. “Our technique will help open up understanding of the many complex behaviors in learning and disease.”

—This story by Beth Kwon initially appeared in Columbia University Research News.
—Image by Lu Wei, Columbia University

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