The metabolic marvels of the human brain

Madeline Andrews is researching innovative ways to treat neurological disorders by studying brain development

The World Health Organization reports that one in three people are affected by neurological conditions. This high prevalence makes neurological issues the leading cause of illness and disability worldwide.

Madeline Andrews, an assistant professor of biomedical engineering in the Ira A. Fulton Schools of Engineering at Arizona State University, is revolutionizing neurological disease research with her work on stem cell-based model systems. By developing sophisticated tools to model the human brain, she hopes to unlock new insights into the complexities of neurological disorders.

Her approach focuses on directing stem cells — unspecialized cells that have the distinct ability to develop into various specialized cell types — to become brain cells,  providing an unprecedented platform for studying brain development, function and disease. The stem cells used in her studies are collected from a patient’s skin and blood to enable the analysis of neurological diseases.

Glucose is the brain’s primary energy source, fueling the complex processes that support cognition, memory and overall neurological function. Humans require glucose to maintain both mental and physical activities effectively.

During brain development, glucose enters brain cells, and it is broken down by metabolic pathways like glycolysis and oxidative phosphorylation to produce the energy necessary to support rapid cell division, growth and differentiation. The brain is highly metabolically active, consuming about 25% of the body’s energy intake from food. The remaining 75% supports bodily functions.

These energy-intensive processes drive the transformation of neural stem cells into specialized cells such as neurons and glial cells, which build the brain’s intricate structure and networks. Without sufficient glucose and oxygen or efficient metabolism, the brain cannot sustain these critical developmental stages, leading to disruptions in its growth and function.

Andrews’ work using patient–derived cells promises to transform our understanding of brain bioenergetics and pave the way for new therapeutic strategies to mitigate metabolic changes caused by neurological disease.

Madeline Andrews in her lab. Photographer: Erika Gronek/ASU

In a recent conversation, Andrews discussed her research and its potential impact.

Q: How has your background in neuroscience helped you in the field of biomedical engineering?

A: My background in neuroscience has been instrumental in working within biomedical engineering. My training as a developmental molecular biologist provides a critical lens to determine what is accurate and effective when developing models and tools to study human brain development and disease.

Q: What is the biggest challenge for researchers while studying glucose inside brain cells?

A: The ultimate goal is understanding how cell interactions, circuits and functional activity drive healthy brain tissue function and how these functions change in the presence of disease. However, research scientists have yet to thoroughly examine the brain using functional tools to measure its metabolic brain cellular behavior. It is extremely challenging to look at metabolic changes within individual, live cells — particularly within an intact brain. In my lab, we use cell culture models as a proxy to study these metabolic programs within relevant cell types. Depending on the neurological disorder, we look for changes that could drive disease or exacerbate it.

A low magnification image of organoids derived from patient blood or skin cells reprogrammed into cell cultures. Photograph courtesy of Madeline Andrews

Q: What types of cell cultures are you interested in examining for signs of a neurological disorder and how do you study them in your research?

A: We use complex cell culture systems called organoids. Organoids are derived from patient blood or skin cells that are reprogrammed into stem cells, then cultured in 3D spheres that contain cell types and resemble organizational features of the brain.

One method we use to study organoids involves using microscopes to examine the ratio of metabolites within a cell or how different cell types change when exposed to various nutrients. We can compare different environmental conditions of metabolic activity in control cells with those of patients with a particular neurological disorder.

For example, we can evaluate the ratios of two different metabolites, such as NAD and NADH, which are essential for energy production in the body, via its main form of energy currency, called adenosine triphosphate, or ATP. From this ratio, we can understand how energy is used and produced in different cell types throughout instances of balanced health and disease.

A tool we use in collaboration with Scott Beeman, a fellow Fulton Schools assistant professor of biomedical engineering, is nuclear magnetic resonance, or NMR, to study how certain metabolites interact when exposed to an external magnetic field. For example, we use glucose labeled with a detectable marker, and NMR helps us understand how the glucose is processed and used within cells. This technique provides another way to analyze metabolic pathway activity in the cells.

Q: What kind of metabolic cellular behavior are you looking for in the brain?

A: In my lab, we study how neurons maintain themselves to understand what aspects cause abnormalities which ultimately cause neurological diseases. We collect the cell culture medium and analyze metabolic readouts. Various microscopy techniques allow us to observe the abundance of glucose signals within the cells.

Historically, most cell culture methods were optimized for cancer cell lines, which were co-opted to develop other cell culture models. As a result, in vitro systems often have glucose levels five to 10 times higher than in the brain. This highlights the current limitations of cell culture systems that we aim to improve to make them more accurate. We strive to better understand human-specific cell population requirements by functionally affecting and measuring different metabolites.

Q: What would be the impact of improving the quality of your brain cell cultures?

A: These models are rooted in cancer research. We need to develop options that are tailored to the cells we are using so we can answer these questions. Improving the quality of brain cell cultures would result in models that more accurately reflect the complexities of the brain.

This would entail developing better protocols to simulate brain-like conditions more effectively. With these more accurate models, we can use them to study how neurological disorders develop and screen potential therapeutics.

Q: What significant findings have you discovered from studying glucose in brain cell models?

A: Our research on glucose in brain cell models, particularly developmental models, has revealed that cells in cultures are not switching to different programs as clearly as in the body. We theorize that improving the quality of our cell cultures’ metabolism will result in models that more accurately reflect the complexities of the brain.