Basic research of genes provides insights into how the brain is wired, and how wiring mistakes can lead to neurological diseases.
Tom Maniatis pioneered the gene-cloning methods that gave a generation of scientists the tools necessary to identify the genes that cause disease. Today he uses advanced genetics and molecular and cellular biology to identify potential causes of neurological and neurodegenerative diseases such as ALS, also known as Lou Gehrig’s disease.Read more about Tom Maniatis, PhD >
You may take for granted your ability to touch your nose and know that you are touching your own face, and not another’s. What you may not know is that each of the 100 billion neurons in your brain also has 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.
Tom Maniatis, PhD, a molecular neuroscientist at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, studies this self-avoidance mechanism in brain wiring.
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. Dr. Maniatis says neurons accomplish this by creating their own unique identity tags: collections of molecules on their surfaces that he 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 Barry Honig, PhD, and Larry Shapiro, PhD, structural biologists also at the Zuckerman Institute. “ This collaboration beautifully illustrates the power of multidisciplinary research at the Zuckerman Institute,” Dr. Maniatis says.
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.