KEY CONCEPTS UNDERLYING OUR WORK
Life is a series of metabolic hurdles. Our health depends on our ability to surmount them.
Life is energy, or at least a quest for it. Function drives energy demand, while metabolism regulates supply. And yet, metabolism adheres to a strict budget. When demand exceeds supply, the system fails. These periodic surges in energy supply/demand can be conceptualized as metabolic “hurdles” that must be cleared to achieve the intended function. The metabolic hurdle scales almost infinitely in size and duration, from the microsecond, ATP-mediated opening of an ion channel to the decades-long development of a human brain.
The brains of children make extraordinary metabolic demands
The metabolic hurdle of childhood brain development constitutes what is arguably the most remarkable achievement of human evolution. While most mammals expend less than 5% of their energy output on brain function, the adult human brain consumes ~20% of total body energy. Yet, human neurometabolic demand reaches its peak around ages 3 - 5yo, when the brains of children command more than 60% of the body’s energy. The mechanisms underpinning this singular feat of metabolic resilience (and vulnerability) remain almost entirely unknown.
Childhood is a gauntlet of metabolic risk during which the volatile metabolic demands of the immune system must be accommodated
A number of human evolutionary adaptations appear to facilitate our enormous metabolic investment in our brains. Physical strength, growth, reproduction, and other metabolically demanding parameters have been deferred to the 2nd and 3rd decades of life. Immune defense, on the other hand, is crucial to childhood survival and must be accommodated despite its metabolically intensive and volatile nature. During periods of peak metabolic demand, this fragile energy balance can lead to a mismatch in energy supply and demand (i.e. metabolic failure), resulting in diseases that affect the brain, the immune system or both.
Well-characterized genetic diseases can highlight metabolic pathways relevant to human neurodevelopment
A growing number of severe childhood neurologic disorders have been defined by genetic mutations, shedding light on the biological pathways that are crucial (and perhaps unique) to human development. Characterizing and treating the pathway alterations in these rare genetic disorders is crucial to helping affecting children and families and should offer unique insights into more common human disorders.
ALD & MS offer complementary models for conceptualizing and unraveling the interactions between metabolism and immunity in the brain
We are dedicated to characterizing two childhood neuroimmunologic disorders: X-linked adrenoleukodystrophy & multiple sclerosis. Despite key differences, these disorders share a surprising number of similarities. Our lab compares and contrasts these disorders to generate complementary insights into neurometabolism and neuroinflammation.
The clinical trial as the master experiment
Because so much of human evolution has been centered on adaptations to the physical and metabolic architecture of the human brain and blood, these human systems are perhaps uniquely inaccessible via animal models. For example, the genetic model of ALD in mice do not manifest the cerebral inflammation that affects most individuals with ALD. To mitigate these and other pitfalls, our lab strives to curate definitive knowledge of human biology by employing innovative clinical research strategies to collect alternately deep and focused biological data. We subsequently apply computational methods and non-human models to iterate and refine our queries.