NEW YORK – Finding the Bar Codes in Our Brains: Using Genetics to Identify the Brain’s 100 Billion Neurons, the latest lecture in the Stavros Niarchos Foundation Brain Insight Lecture series, was held at the Columbia University Forum Auditorium in Manhattan on February 7 and featured Dr. Tom Maniatis, the Isidore S. Edelman Professor of Biochemistry and Principal Investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute. The fascinating lecture, offered free to the public to enhance understanding of the biology of the mind and the complexity of human behavior, was hosted by Columbia’s Zuckerman Institute and supported by the Stavros Niarchos Foundation.
Dr, Maniatis thanked all those present and especially the Stavros Niarchos Foundation for its support, and pointed out that he would be try to sum up 20 years of work in the 50 minute lecture. He said, “People may take for granted their ability to touch their nose and know that they are touching their own face, and not another’s. What someone may not know is that each of the 100 billion neurons in your brain also have this ability of self-recognition.
“As individual nerve cells, called neurons, grow branches and connect with thousands of other neurons during brain development, their own branches distinguish between themselves and the branches of other neurons — an important adaptation that avoids entanglements. If a neuron cannot do this, it will not form a functional brain circuit — a key aspect of a healthy, functioning brain.”
Dr. Maniatis discussed the role of protocadherin proteins in brain wiring, which is complex, yet fascinating. These proteins provide individual neurons with a “barcode” that allows them to distinguish between themselves and other neurons – a complex story of gene regulation, protein structure and function, and brain wiring in mice, which has ultimately led to a connection to neuropsychiatric disorders in humans.
Dr. Maniatis, a molecular neuroscientist, studies this self-avoidance mechanism in brain wiring. He explained, “Neurons are a bit like trees. A growing tree uniformly spreads its branches to collect the most sunlight. Similarly, a growing neuron spreads its branches, known as dendrites, into specific brain regions to collect information from as many other neurons as possible.
Neurons accomplish this by creating their own unique identity tags: collections of molecules on their surfaces that Dr. Maniatis likens to a bar code. Dendrites essentially scan each other’s bar codes when they come into contact with each other, and when a dendrite recognizes another with the same bar code, it knows to stay away.
Dr. Maniatis’ interest in self-avoidance was triggered by his laboratory’s discovery, over a decade ago, of an extraordinary group of genes called the clustered protocadherins, or Pcdhs. His lab discovered that the Pcdh gene cluster functions as a generator of random combinations of Pcdh proteins in each cell.
The Pcdh proteins project from the surfaces of dendrites, and if the two dendrites from the same neuron touch each other, they recognize each other and are repulsed. These conclusions required the determination of the function and atomic structure of the proteins, which was accomplished in collaboration with the laboratories of Dr. Barry Honig and Dr. Larry Shapiro, structural biologists also at the Zuckerman Institute.
“This collaboration beautifully illustrates the power of multidisciplinary research at the Zuckerman Institute,” Dr. Maniatis said.
Dr. Maniatis and others have also created mice in which the Pcdh genes are missing. As predicted, this resulted in wiring defects: dendrites no longer avoided other dendrites from the same neuron, and instead became tangled and clumped. In addition, recent large-scale DNA sequencing studies of autistic children by others have identified mutations in the Pcdh genes. Thus, according to Dr. Maniatis, “Basic research of Pcdh genes may lead to fundamental insights into how the brain is wired, and how wiring mistakes can lead to behavioral disorders in children.”
Dr. Maniatis also contributes to clinical medicine by heading Columbia’s precision medicine initiative, created in 2015. This collaboration between Columbia and New York-Presbyterian Hospital aims to understand the relationships between human genetics and disease mechanisms, and to ultimately use this knowledge to personalize treatments for individual patients. Success will require a deep collaboration between early-stage research scientists, such as those at the Zuckerman Institute, and clinicians at Columbia University Medical Center.