An Unexpected Journey Tracing Molecular Oxygen | Michael Pacold, MD, PhD | TEDxNYU Langone Health

Key Concepts

• Oxygen's Journey: The fundamental question of where inhaled oxygen goes within the body.
• Historical Discovery of Oxygen: Contributions of Carl Scheele, Joseph Priestley, Antoine Lavoisier.
• Respiration as "Slow Fire": Lavoisier's analogy for oxygen's role in energy production.
• Isotope Labeling (¹⁸O₂): A technique to trace molecules by using heavier isotopes.
• Mass Spectrometry: An instrument used to detect and measure the mass of molecules, enabling the identification of ¹⁸O₂.
• Coenzyme Q10 (CoQ10): A critical molecule essential for energy production, found in every cell.
• Pediatric Neurodegenerative Disease: A rare, lethal condition in children caused by the inability to synthesize CoQ10.
• Disease Symptoms: Seizures, spasticity, paralysis, and ultimately death.
• CoQ10 Precursors: The building blocks of CoQ10, identified as the molecule that takes up ¹⁸O₂.
• Treatment Challenges: CoQ10's poor absorption by the body.
• Disease Models: The use of mice to study and understand the disease.
• Therapeutic Breakthrough: Successful treatment of disease model mice using CoQ10 precursors.
• Clinical Trial: Approval and commencement of treatment for the first human patient.
• Scientific Method: The iterative process of observation, hypothesis, experimentation, and conclusion.

The Journey of Oxygen and a Rare Pediatric Disease

This video explores the fundamental scientific question of where inhaled oxygen goes within the body, a question that has intrigued scientists for centuries. This inquiry, initially posed by pioneers like Carl Scheele, Joseph Priestley, and Antoine Lavoisier, has unexpectedly led to the identification of a critical molecule and the development of a potential treatment for a rare and lethal pediatric neurological disease.

Historical Context: The Discovery of Oxygen

The journey begins approximately 300 years ago with the discovery of oxygen. Carl Scheele and Joseph Priestley were the first to isolate oxygen, demonstrating its presence in our atmosphere. Antoine Lavoisier further elucidated its importance, establishing that oxygen is crucial for both combustion and respiration. Lavoisier famously proposed that respiration is akin to a "slow fire," a concept that has been validated by modern science. He observed that a living organism (like a guinea pig) and a fire consumed the same amount of oxygen to produce a comparable amount of heat, indicating that oxygen fuels life processes. Despite their groundbreaking work, these early scientists lacked the tools to definitively trace the path of oxygen within a living organism.

Modern Investigation: Tracing Oxygen with ¹⁸O₂

Centuries later, the speaker's lab revisited the question: "Where does the oxygen go?" To answer this, they employed a sophisticated technique: isotope labeling. By treating cells with gaseous heavy oxygen, specifically ¹⁸O₂, they introduced a traceable marker. ¹⁸O₂ atoms are two neutrons heavier than the ¹⁶O₂ that we normally breathe. While this mass difference is minuscule (a billionth of a billionth of a billionth of a kilogram), it is detectable by an instrument called a mass spectrometer. This technology allowed the researchers to follow the ¹⁸O₂ as it was processed by the cells.

Uncovering a Critical Molecule: CoQ10 Precursors

The ¹⁸O labeling experiments revealed a critical molecule that incorporated ¹⁸O more than any other. This molecule turned out to be a previously identified, but somewhat overlooked, precursor in the synthesis of Coenzyme Q10 (CoQ10). CoQ10 is a vital molecule found in every cell of the human body, playing a crucial role in energy production.

The Link to a Lethal Pediatric Disease

The significance of this discovery became starkly apparent when considering children who cannot synthesize CoQ10. These children develop a rare and lethal pediatric neurodegenerative disease. The symptoms are severe and include seizures, spasticity (tense, tight, paralyzed muscles), and ultimately, death, often by the age of eight or nine. The brain, being highly energy-dependent, is particularly vulnerable to CoQ10 deficiency, leading to these devastating neurological symptoms. This highlighted a profound realization: we breathe oxygen not just to survive, but to construct the very molecules that enable our survival.

The Challenge of CoQ10 Supplementation

Many may recognize CoQ10 as a common dietary supplement available in pharmacies. However, direct supplementation with CoQ10 has proven ineffective for these children. Despite very high doses, the body does not absorb CoQ10 well, rendering this approach futile.

Developing a Disease Model and a Novel Treatment

Recognizing the limitations of direct CoQ10 treatment, the lab shifted focus to the identified precursors. To understand and develop effective treatments, creating accurate disease models was essential. They aimed to develop a mouse model that mimicked the human disease, specifically a mouse unable to build the CoQ10 precursors. Following the principles of the scientific method, they successfully obtained mice that could not synthesize these building blocks.

These mice exhibited the same severe symptoms as the human patients: seizures and spasticity, and tragically, none survived beyond two weeks. Initial attempts to treat these mice with CoQ10 yielded no improvement. However, when treated with the CoQ10 building blocks that the lab had discovered, a remarkable transformation occurred. Within two days, the mice began to stand and walk, and after a month, they were moving normally. This was described as a "miracle," and subsequent experiments with larger cohorts of mice confirmed the efficacy of this treatment, with treated mice now living full lifespans for their species.

A Beacon of Hope: Clinical Trial and Future Prospects

The success in animal models has paved the way for human treatment. The speaker is thrilled to announce that they have received approval to treat the first patient with this rare, lethal neurologic disease using the discovered CoQ10 building blocks. Treatment is currently underway, and the team is "very, very hopeful about the results." More importantly, this prospective treatment has brought much-needed hope to the patient and their family.

Conclusion: The Power of Fundamental Science

The speaker concludes by emphasizing that life-changing medical discoveries often emerge from pursuing fundamental scientific questions, even when the path is uncertain and leads outside one's comfort zone. Understanding biology at a fundamental level is crucial for advancing patient care. The discovery that led to this potential treatment originated from a question posed 300 years ago by scientists driven by a passion for understanding the natural world. This historical inquiry, coupled with modern scientific tools and methodologies, has now culminated in a prospective treatment for a devastating disease, demonstrating the profound and often unexpected impact of basic scientific research.