Making the Right Connections
Seated with his colleagues at a conference table, Anthony-Samuel LaMantia, Ph.D., founding director of the new George Washington Institute for Neuroscience (GWIN), intuitively used his hands when describing a stage in brain development.
His fingers articulated pinching, shifting, and stretching motions around his head to mime a dynamic series of cell migrations between the developing face and brain that occur roughly halfway through embryonic development in a mouse.
“The brain is sending out a set of cellular ambassadors to instruct the periphery on how to develop so it’s ready for the brain and the brain is ready for it,” later explains LaMantia, an internationally renowned neuroscientist who came to GW’s School of Medicine and Health Sciences (SMHS) in 2010 from the University of North Carolina School of Medicine. “The idea that this is a target for disorders should be something everybody embraces. We have known for years that patients with a variety of behavioral disorders, including autism and schizophrenia, also have mild to severe facial anomalies that are thought to arise during development.”
GWIN was established with the aim of revealing many such “targets” for mental illness through a focused, multidisciplinary approach. LaMantia has assembled two dozen researchers from across GW and partner institution Children’s National Medical Center with a wide range of neuroscience backgrounds to take on collaborative projects, including the basic science of brain development, its clinical relevance, and others. Specialist Norman Lee, Ph.D., professor of Pharmacology and Physiology, for example, draws from his research on gene networks and pathways relating to behavior, while Sally Moody, Ph.D., professor of Anatomy and Regenerative Biology, provides insights into genes involved in neural tube and craniofacial birth defects.
Researcher Molly Huntsman, Ph.D., principal investigator at the Center for Neuroscience Research at Children’s National, provides insight from her work on the development of inhibitory neurons in neural circuits. Vittorio Gallo, Ph.D., the Wolf-Pack Chair of Neuroscience and director of the Center for Neuroscience Research at Children’s National, contributes his experience exploring neural progenitor development and injury responses in the immature and adult brain.
By synergizing all this expertise, GWIN seeks to understand mental illness from a holistic perspective, including the molecular, cellular, and behavioral elements. “Putting together these labs will make a whole that is much bigger than the sum of its parts,” Gallo predicts.
The institute’s multi-front approach reflects a growing philosophy in neuroscience: By finding common ground, formerly disparate labs from various fields can collaborate and jointly delve deeper into heritable, genetic disorders that disrupt brain function, and, therefore, behavior. New ideas are in demand, as the true cause of mental illnesses remains a mystery. Disorders like autism, fragile X syndrome, pediatric epilepsy, perinatal brain injury, and attention deficit hyperactivity disorder (ADHD) remain largely unsolved, but their symptoms demonstrate that complex behaviors, when disrupted, have a big impact on the quality of life. “That’s what we’re ultimately trying to shed light on,” LaMantia emphasizes.
GWIN’s translational approach to neuroscience research puts a focus on the developing brain. While the institute will not exclusively focus on children, its work will be caged in the understanding that the onset of neurological diseases comes much earlier in life than scientists have previously believed. One disorder of keen interest to GWIN is DiGeorge syndrome, a disease with wide-ranging signs and symptoms caused by a deletion of one copy of a small subset of the normal complement of genes on chromosome 22. Those who lack this network of genes often suffer physical malformations and various types of mental illness, showing that the missing genes are vital during early stages of development. Numerous mental symptoms arise: 50 to 60 percent of children with DiGeorge syndrome suffer a psychotic break in late adolescence, 30 to 40 percent are diagnosed with an autistic spectrum condition, 30 to 40 percent are diagnosed with ADHD, and roughly 10 percent are diagnosed as intellectually disabled.
The localized nature of the deletion that causes DiGeorge syndrome provides an opportunity to zero in on genetic and molecular mechanisms that underlie normal and deviant development. “This genetic lesion gives us a node where a fairly small group of genes modulate cell proliferation, adhesion, and mitochondrial function,” LaMantia explains. “The missing genes set a dynamic range for other aberrant things to happen.”
But despite the actual genetic deletion of DiGeorge syndrome being consistent, the consequences are not. Tracing what happens isn’t simply a matter of identifying a wrongdoing mechanism. LaMantia suspects that a person’s unique genetic makeup, such as a missing set of genes — along with distinct environmental factors — plays into the behavioral outcomes of the disease. Further complicating matters is the possibility of a mutation altering brain development at several points throughout its orchestration. “It’s a nightmare thinking about this in terms of therapeutic interventions. Where do you fix it?” he asks.
Discernible behavioral symptoms of psychiatric illnesses ultimately arise from disrupted electrical connections between nerve cells, much as palpable chest pains are elicited by a clogged coronary artery. The detective work needed to understand the cause of, say, schizophrenia demands a nuts-and-bolts, neurobiological understanding of the disease. “It’s clear that there is a neurogenetic component,” observes Gallo, “but how does the genetic component become expressed, manifested, and translated into abnormal cellular structures?” Once a specific gene or set of genes is identified, Gallo says, the next step will be to understand how those irregular genes generate abnormal proteins, and how those proteins, in turn, generate aberrant nerve cell connections and functions.
Nerve cell interaction, or connectivity, is a key component in understanding how complex behaviors are disrupted in mental disorders, according to LaMantia. “My guess is that for all of these diseases,” he says, “some aspect of the basic rules of connectivity is broken.”
In fact, LaMantia and many other neuroscientists now believe that most, if not all, behavioral and psychiatric diseases — including autism, ADHD, bipolar disorder, and schizophrenia — are part of a broad class of diseases referred to as “disorders of cortical connectivity.” All these disorders arise from the improper development of the cerebral cortex, particularly regions of the frontal cortex, which occupies the most anterior part of the brain. LaMantia describes this region as “the heavy lifter” because it’s the throne of executive functions that include memory, selective attention, social interaction, language, learning, and cognition.
Deciphering the link between the improper wiring of the frontal cortex (and the associated behavioral consequences) and a genetic source would be a huge step toward understanding psychiatric disease. A key goal of GWIN will be to define and assign specific functions to genes and sort out how they work together to control various aspects of cortical circuits’ wiring. “We have to understand how normal development occurs,” explains Gallo, “because it is the disruption of these pathways and their interactions that is modified in neurodevelopmental disorders.”
LaMantia likens the business of gaining a molecular understanding of neural development to that of cancer biology research 20 years ago, when it delved into signaling pathways that regulate cell proliferation, apoptosis, and migration motility. “In the isolated instance of each of these detailed molecular experimental paradigms, you’re not necessarily identifying the target for therapy,” he says, “but rather looking at a piece and understanding how it goes slightly awry.” The subsequent step, he adds, would be to see what happens when they adjust this piece therapeutically and apply it to the brain.
Arriving Late to the Party
Despite the neurodevelopmental hypothesis of mental illness that began to take hold in the late 1980s, this paradigm shift hasn’t translated into effective medicine for many people with mental disorders. Overall, progress in reducing the morbidity and mortality of psychiatric diseases has been slow in comparison to that of cancer and cardiovascular disease. When speaking at GWIN’s inaugural seminar series in mid-September 2010, Thomas Insel, M.D., the director of the National Institute of Mental Health and a friend of LaMantia’s, described existing treatment options as “not so good.”
Insel conveyed that the challenges of diagnosing and treating mental illness are based on its lack of reliable biomarkers, the essential tools of objective diagnosis, making it one of the few areas of medicine that still relies on skills of observation. Since the cause of most mental disorders remains largely unknown, so, too, is a psychiatric patient’s response to treatment. And cure and vaccine are terms that still seem to have no place in the lexicon of treating mental disorders.
These disadvantages have snowballed to make mental illness the largest source of disability of all medical disorders in the United States. Ninety percent of all suicides are due to mental illness, a total that surpasses the yearly death toll from homicides and AIDS, and the fiscal toll of mental illness is around $300 billion per year.
When LaMantia considers the Herculean task that lies ahead of neuroscience, he thinks again of cancer. Oncology’s identification of targets for chemotherapeutics is based on the understanding that the ways in which cells divide, move, and die are expressions of transformation and malignancy.
Similarly, LaMantia sees the need to understand neuronal circuitry in terms of neurons themselves and how their processes grow. He wants to grasp how neurons initially become specified to be what they are and — importantly — how they construct synapses to wire up with other neurons.
GWIN already employs strong scientists recognized for probing neuronal precursor specification and early patterning in morphogenesis, the stage when cells acquire the potential to blossom into a mature neuron. LaMantia intends to complement this effort by bolstering research that focuses on the next step in neuronal development: synapse building.
As a neuron differentiates, it puts out processes and makes connections with other neurons. LaMantia thinks this step is a crucial component in the origins of frontal cortex disorders. “We all believe that there are neurogenic proliferation and migration deficits in these disorders,” he says. “But where the rubber really meets the road is when they don’t wire up properly.”