Q&A with Ivo Spiegel

Meet the Zuckerman Faculty Scholar Ivo Spiegel at Weizmann Institute of Science, studying “How Experience Regulates Brain Function

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“Our research will hopefully allow us to untangle how nature and nurture cooperate to regulate adaptive behavior and help us understand how mutations in the genome contribute to psychiatric disorders and individual variations in cognitive capabilities.”

Dr. Ivo Spiegel is a member of the faculty in the Department of Neurobiology at the Weizmann Institute. His position marks a return to the institution where he received his MSc and PhD in Molecular Cell Biology. Born in Basel, Switzerland, Dr. Spiegel moved to Israel after high school and enrolled in Tel Aviv University, where he became fascinated by molecular and cellular biology and neuroscience. While he did postdoctoral work at Harvard Medical School he shifted his focus to finding out how gene regulation programs control circuit formation in the brain. Dr. Spiegel established his own independent research group at the Weizmann Institute, “How Experience Regulates Brain Function.” 

Please describe your current research, the focus of your lab, and the practical implications of your research

Our lab seeks to identify the molecular mechanisms through which experiences, such as our sensory and emotional experiences – change the neural circuits in our brain so that we can learn new information and skills without losing previously acquired information. Specifically, we are interested in how our genes regulate these fundamental processes: what genes change in which types of cells for a given experience; what these genes do in the respective cells; and how these cellular changes affect the function of the neural circuits in our brain. Understanding these mechanisms fundamentally contributes to our understanding of how nature – i.e., our genome, and nurture – i.e., our experiences and the world around us cooperate to shape our cognitive capabilities as we grow up and as adults. Our research explains how even subtle mutations in the genome can lead to variations in neural circuit function across individuals, and in extreme cases, lead to psychiatric disorders such as autism or schizophrenia.

We focus on the visual system of mice, one that is relatively well understood at the level of genes, cells, synapses and neural circuits. This allows us to track changes at any of these levels upon subtle genetic mutations at high resolution. Our research combines genomes, molecular and cell biology, electrophysiology and in vivo imaging in an integrated approach we call Molecular Systems Neuroscience, which allows us to gain insights we believe could not have been obtained otherwise.

A recent finding that excites us most concerns the neural circuit functions of genes that change with sensory and/or emotional experiences (so called “experience-regulated genes”). These genes were thought to drive changes in neural circuit function and thus drive processes such as memory formation. Our findings, however, suggest the opposite: we think these genes do not actually generate new memories per se, but rather stabilize the function of neural circuits, allowing for the formation of new memories via other molecular and cellular mechanisms while they ensure previously stored information is not lost during this process. We are currently in the midst of key experiments testing this idea.

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In another project, we identified a novel molecular marker for neurons in the cortex that previously could not be manipulated in mice and whose function remained unknown. Based on this molecular marker, we generated genetic tools to manipulate these neurons in behaving mice. We discovered that these neurons can modulate the responses of entire brain areas to sensory stimuli according to an animal’s arousal state. We were excited to learn that at the same time, another group of investigators – good friends of ours – found that genes with schizophrenia-associated mutations are expressed in these neurons much more than in other brain cells. This suggests that genetic deficits in the neurons identified by us are key drivers of schizophrenia and of schizophrenia-related deficits in cortical function, such as the integration of sensory and contextual information. We are now testing this hypothesis, that if correct, would be a major breakthrough in our understanding of this severe brain disorder.

Moving forward, I hope we can dig deeper into the basic molecular, cellular and circuit mechanisms we are studying. At the same time, I hope we will be able to apply our insight and know-how to dissect the etiology of disorders such as schizophrenia and autism and identify access points for therapeutic interventions.

What do you enjoy most about your research?

Working with my students by far is best part of my day! I am fortunate to work with the cream of the crop – my students at Weizmann are at least on par with students I worked with at Harvard Medical School. That being said, I would like to see more students from the US at Weizmann.

What inspired you to pursue this area of research?  

I initially became fascinated by molecular and cellular biology and neuroscience while I was a student at Tel Aviv University. When I got to Harvard for my postdoc, we explored gene regulation in the circuits of the brain, and I shifted the focus of my research. Genes are the mechanism for changes in the brain and the key to so much.

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What has it meant to you to be part of the Zuckerman Faculty Scholars Program?

The program provides crucial support for my research and provided the financial support to establish my lab. Research takes time, and it is phenomenal that we have the support and backing of the Zuckerman Program to pursue it. While financial support is important, the Zuckerman Program also created a great community of scholars.  I am also looking forward to establishing collaborations with colleagues at the Zuckerman Brain Institute at Columbia University – it would be amazing to work on joint projects with them. We recently held a joint symposium which was really exciting!  We are optimistic based on connections generated by the symposium, and look forward to future opportunities to collaborate on joint projects with our colleagues in the US.

Where do you hope your research will have the greatest impact? 

All the research I’ve done so far has been very disease relevant, even though at its core, my research is basic, but not clinical research, and demonstrates just how important basic research is for better diagnostics and therapeutics. During my master’s research I discovered genes that years later were found to be mutated in autistic patients. Similarly, during my PhD, the genes I discovered, and the function of genes later turned out to be mutated in peripheral neuropathies. It was my basic research that helped form specific hypotheses about the etiology of these disorders.

While disease is constantly on my mind, it’s not the goal. I want there to be a basic understanding of the brain and how it works.  If we understand how the brain works normally, it will help us understand how the brain works when all is not normal, in psychiatric disorders, for example.

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