At Work: Developmental Biologist Julia Kaltschmidt

Pictured: Julia Kaltschmidt

Developmental biologist Julia Kaltschmidt studies neuronal circuits in mice and the factors that can cause the developmental process to go awry. We spoke with her in 2008, soon after she arrived to establish her laboratory at the Sloan Kettering Institute.

I was born in Berlin but spent much of my early life in Lüneburg, a small medieval town in the northern part of Germany. Growing up, I was fortunate to travel and explore different parts of the world, including the wilderness of Alaska and the monasteries of Tibet.

At home, I breathed both art and science. I painted a lot and found inspiration in artists’ studios, at exhibitions, and in the underground vaults of the Hamburg harbor, where sailors from all over the world sell their goods. At the same time I became absorbed in science. My father conducted research on ribosomal proteins in a Berlin Max Planck laboratory for a decade before going into medicine.

That period of research figured very prominently in our household, making science an essential part of our lives. The first serious writing in English I ever held in my hands was The Double Helix by James Watson. I think it was these first encounters, along with my passion for exploring the unknown, that sparked my scientific interest.

In Germany, you choose two majors to focus on during the last two years of high school, so I picked biology and chemistry. It was my continued interest in these fields, combined with a curiosity about the United States, that led me to choose undergraduate studies in science at the University of Wisconsin-Madison.

I came to Madison in 1993 and had a fantastic experience, completing a double major in biochemistry and molecular biology. I had a great mentor in Lawrence Dahl, the professor of my first chemistry class. We would go for lunch together and discuss chemistry and his life as a scientist. These conversations were very influential in determining my career path.

An Interest in Development

During college, I spent my summers at the Max Planck Institute for Developmental Biology in Tübingen, Germany, in the laboratory of Nobel Laureate Christiane Nüsslein-Volhard. It was there that I received my first hands-on training in molecular and developmental biology, participating in ongoing studies of the patterning of the dorso-ventral axis in the zebrafish embryo.

My interest in developmental biology led me to pursue a PhD in Andrea Brand’s lab at The Wellcome/CRC Institute [now called The Gurdon Institute] in Cambridge, England, where I focused on how neural precursor cells divide to give rise to various nerve-cell types during embryonic development in Drosophila fruit flies.

Ideally, we would like to understand how individual neurons assemble into circuits, and how these circuits are embedded within the brain to produce specific behaviors.
Julia Kaltschmidt Developmental Biologist

By using green-fluorescent-protein (GFP) labeling techniques — in which a transgenically expressed fluorescent protein acts as a marker in living cells — I was able to show how the mitotic spindle of neural precursor cells rotates its axis in the moments leading up to cell division. The finding clarified the process by which these cells divide and differentiate as the embryo develops. These experiments reaffirmed for me the importance of studying cell biology in a developmental context and the relevance of using new imaging tools in understanding cellular function.

After completing my PhD, I spent a brief but very fruitful period in the lab of Alfonso Martinez Arias within the Department of Genetics at the University of Cambridge. There I used similar GFP and imaging methods to look at developmental dynamics in the Drosophila epidermis. Throughout my time in Cambridge I existed in what I call the “graduate student bubble,” because the college system allows you to get immersed in life as a student. I essentially did science nonstop for 15 hours a day.

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Vertebrate Circuitry

Although I was fascinated by the Drosophila central nervous system, I wanted to explore a vertebrate model in my postdoctoral research. In 2001, I joined the lab of Thomas Jessell in the Department of Biochemistry and Molecular Biophysics at Columbia University in New York to study the development of neuronal circuits.

Our brain contains billions of neurons that are interconnected through a specific network of synapses. I conducted research into the mechanisms of synaptic specificity in the mammalian spinal cord, seeking to understand the process by which appropriate connections between neurons are formed while inappropriate ones are avoided. Or more plainly, how does an organism such as a mouse or human wire itself during development?

In 2008, I came to the Sloan Kettering Institute to set up my own lab so I could further investigate synaptic specificity and circuit formation. In order for neuronal circuits to organize and function properly, it is important that neurons select their appropriate targets. My lab investigates this process in mice in the context of the spinal stretch reflex circuit, a core unit of neuronal organization in the spinal cord.

This circuit is dedicated to proprioceptive control, the sensing of position and movement of the limbs. Proprioception is something like a sixth sense: vital, but hidden — it constantly conveys to the brain the position of the limbs and allows us to walk without having to think about each individual step.

To use a familiar example, when a doctor does the classic “knee-jerk” reflex test by tapping below the kneecap, stretch sensory receptors are activated and generate an impulse, which is transmitted into the spinal cord via proprioceptive sensory afferent fibers. The sensory neurons connect directly with motor neurons, which transmit the impulse to the periphery and cause muscle contraction. However, additional regulatory circuit components are important to retain and control motor output.

Anatomical and physiological studies have shown that inhibitory interneurons in the spinal cord coordinate sensory-motor transformations. For example, one class of GABAergic interneurons ensures coordinated flexion/relaxation of functionally antagonistic muscle groups.

My lab is interested in asking, “What are cellular and molecular mechanisms responsible for generating sensory-motor specificity? Further, how do local circuit interneurons filter and process sensory-motor information and generate coordinate motor output?” In order to address these questions we use methods for visualizing synapse formation that allow us to both study their morphology and organization and to identify their precise targeting within neuronal networks.

As I mentioned earlier, one of the key issues during the generation of such functional circuits is the specificity and selectivity with which neurons choose their synaptic partners. By understanding of the mechanisms underlying the specificity of the different synaptic connections, we hope to develop genetic tools for specifically disrupting synapse formation. We can then analyze the consequences of such disruptions on the organization of neuronal circuits and the emergence of behavior.

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A Look into the Future

Ideally, what we would really like to do is to find the link between the properties of individual neurons, the way they assemble into circuits, and how these circuits are embedded within the brain to produce specific behaviors.

The Sloan Kettering Institute is an ideal setting in which to investigate these questions. It is a premier research institution that combines an interest in different disciplines and has close links to clinical research. I have fantastic colleagues, and the expertise of the Sloan Kettering core facilities is outstanding.

Additionally I have started to collaborate with a lab at Weill Cornell Medical College and maintain a very active relationship with labs at Columbia University. I am excited about the things we will achieve in this stimulating scientific environment situated in the heart of New York City.

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