Alumna Biologist Lisa Boulanger on the Adventure of Scientific Experimentation
For Lisa Boulanger, an alumna (Ph.D., 1999) who returned to UCSD in 2004 as an assistant professor in the Division of Biological Sciences, the thrill of science stems from its open-ended nature: from the mystery, creativity, and unpredictable adventure of experimentation. Her first opportunity to design and perform her own experiments came as an undergraduate in the Boston University Marine Program, at the Marine Biological Laboratory in Woods Hole, Massachusetts. While there, she learned that in the laboratory, in contrast to the classroom, “There’s no set answer. In fact, there’s no question yet–you have to design the question. The fun, and the challenge, is to design a good question and to be ready for unexpected answers.”
This appreciation for the surprises of research served her well, especially during her postdoctoral research in the laboratory of Dr. Carla Shatz at Harvard Medical School. In a screen to identify genes that drive the final stages of visual system development in the mammalian brain, the top hit turned out, unexpectedly, to be from the Major Histocompatibility Complex (MHC) class I family of genes. These genes encode key components of the adaptive immune system that permit identification and elimination of infected and cancerous cells. In the words of Boulanger, “This result was a little bit annoying, actually, because not only are these immune system proteins, but according to the literature, they aren’t supposed to be expressed in the normal brain at all.”
One reason MHC class I was not thought to be expressed in neurons is that the brain is functionally “immune privileged.” For example, transplants into the brain are partially resistant to MHC class I-mediated tissue rejection, and many infections can persist longer than usual in the brain. In addition, initial attempts to detect MHC class I in brain tissue using standard techniques had been unsuccessful. Fortunately, since the MHC class I proteins had been extensively studied in the immune system, a multitude of tools for detecting MHC class I were already available, allowing researchers in the Shatz lab and elsewhere to determine that MHC class I is actually expressed in the normal, uninjured brain. The reasons it was previously missed likely include the unusually dynamic nature of MHC class I expression in the brain, as well as inherent technical limitations of certain common approaches when applied to neurons. Recent studies now suggest that rather than failing to produce MHC class I, the brain is immune privileged because it actively suppresses some immune responses.
Boulanger’s main contribution during her postdoctoral research was to discover that MHC class I plays a surprising, critical role in the development and functioning of the brain. “It was very exciting,” Boulanger reminisces. “This was the first evidence that these proteins, which are famous for their immune system function, are also doing something completely different, but also essential, in the brain.” Looking again at the visual system, she and her colleagues found that mice lacking MHC class I fail to separate the neuronal projections from the two eyes into the normal adult pattern of two distinct, eye-specific layers. This was apparently because the MHC class I-deficient brain was unable to prune away inappropriate connections (called synapses) between neurons, as it normally does during development.
Both the formation and removal of synapses is critical to brain development. Formation of new synapses in excess is normally followed by removal of inappropriate or redundant synapses, resulting in highly precise circuitry. This process is required for normal brain development in mammals, but it is still unclear how, exactly, synapses are eliminated. According to one hypothesis, prior to physical separation, electrical communication at the synapse grows weaker, a process called synaptic depression. Since Boulanger found that MHC class I is required for the physical removal of connections, she wondered if this effect arose because MHC class I was involved in synaptic depression. She chose to look at this in a part of the brain called the hippocampus, where these changes in synaptic communication are relatively well-understood.
When Boulanger examined synaptic plasticity in adult mice genetically deficient for cell surface MHC class I, the importance of neuronal MHC class I became clear. In her words, “In the absence of MHC class I, there’s not enough depression–actually, we couldn’t get the synapses to weaken at all. So MHC class I is required to both weaken and eliminate connections. Although eliminating synapses sounds bad at first, in fact removing excess connections is a critical step in normal brain development. Extra connections can lead to mistakes as the brain tries to transmit electrical signals from one place to another.”
Having returned to UCSD, Boulanger has established her own lab to further investigate this fascinating new discovery. Says Boulanger, “I’ve been at six different universities [including Columbia, Berkeley, and Harvard Medical School] over the last 10 years, and it was very clear to me that I wanted to come back to UCSD. There are a lot of wonderful things about Neurosciences at UCSD.” In particular, the large number of excellent researchers in the San Diego area provides a collaborative and supportive environment. “The group here in Neurobiology has a very strong community feeling.” She also cites the high quality of the graduate students as an important factor in her decision, since “graduate students form the core of most new labs.”
Research in her lab currently revolves around three main questions: 1) What does MHC class I do in the normal developing and adult brain? 2) How does MHC class I signal in the brain on a molecular level? and 3) What implications do MHC class I’s roles in the brain have for the origins of specific neurological disorders? In regard to the first question, Boulanger has already established a role for MHC class I in the development of the visual system and in hippocampal synaptic plasticity, and she considers it likely that it is involved in other plasticity processes as well. The MHC class I family has approximately 50 members in the mouse, and in most nucleated cells throughout the body, MHC class I is uniformly expressed at relatively low levels. In the brain, however, different family members display unique and dynamic expression patterns, suggesting the potential for novel functions. In her words, “There’s a lot of MHC class I turning on and off in other parts of the brain besides the visual system and the hippocampus. What is it doing there?”
The second question is even more basic. MHC class I performs all of its known functions by binding to other proteins on the cell surface, which in turn relay information to the inside of the cell. Uncovering the identity of these MHC class I receptors in the brain is vital to understanding the function of MHC class I in this novel context. Intriguingly, some classical immune receptors, and many of the intracellular proteins that MHC class I uses to signal in the immune system, are also found in neurons and are even already known to be involved in activity-dependent synaptic plasticity. According to Boulanger, “On a molecular level, T-cells look in some ways like traveling neurons: they have a lot of the same molecular machinery. The conservation of the molecular signaling is fascinating. It’s not simply that these are ubiquitous proteins; for a lot of them, the immune system and the brain are the only two places that they’re found.” Discovering the signaling cascade through which MHC class I acts in neurons is a crucial step in understanding how these immune proteins affect brain development and function.
The third question is exciting in terms of its clinical applications. Scientists have known for some time that patients with certain neurological disorders, including autism and schizophrenia, often also have abnormal immune function. This correlation is puzzling, since (unlike disorders such as multiple sclerosis, where the immune system attacks the brain) there is no evidence for a direct, causal link between immune activation and nervous system dysfunction in these disorders. Says Boulanger, “I think our findings that some immune system proteins ”moonlight” in the brain raise an interesting new possibility about the source of these disorders. If MHC class I signaling is abnormal, we expect it would affect both the immune system and the nervous system.”
The discovery of shared signaling between the immune and nervous systems may also shed light on the observation that the maternal immune response can in some cases impact the developing fetal brain. Both autism and schizophrenia are complex disorders which result from a combination of genetic and environmental factors. Yet for both, one clear risk factor, for genetically predisposed individuals, is a maternal viral infection at mid-pregnancy, though the reason remains unknown. Boulanger wonders if the dual functions of MHC class I in the brain and immune system provide a key to this mystery. Boulanger’s work demonstrates that MHC class I helps sculpt newly formed circuits. Infections cause chemical signals known as cytokines to flood the body, and one consequence of these signals is to modify the levels of MHC class I. Some cytokines can cross the placenta, leading Boulanger to speculate, “If those cytokines affect the level or pattern of MHC class I expression in the fetal brain, our results suggest they could lead to neurodevelopmental disorders, since at those times MHC class I molecules are busy building the developing brain.” Boulanger’s lab is currently testing this possibility.
Boulanger’s work uncovering the interplay between the immune and nervous systems suggests novel possibilities for the origins of neurological disorders such as autism and schizophrenia, which, despite extensive study, remain poorly understood. Hopefully she will continue to design the right questions to figure out the mysteries of these debilitating disorders.
More information on research being conducted in the Boulanger Lab.
Contributing Writer: Matthew Busse
From BioSphere Magazine, 2007-2008 issue, page 22.