Reply to Chaïbi and Tandjaoui-Lambiotte and to Young and Scott

From the Authors:

We thank the authors for their thoughtful commentary on our article (1). Chaïbi and Tandjaoui-Lambiotte highlight the complex interrelationship of anatomy, biology, and epidemiology applied during eons in helping us understand the phenomenon of “resilient lungs to smoke.” A framing of genetically conferred protection, first seen in early chronic obstructive pulmonary disease (COPD) research and later validated by large-scale studies such as COPDGene (Genetic Epidemiology of COPD), mostly aligns with our core idea: that human lungs may have developed unique mechanisms to cope with smoke exposure (2, 3). Focusing on resilience rather than just vulnerability is essential if we are to push the field forward. Because we also enjoy engaging in philosophical thought, we agree that biological evolution does not follow a specific goal. That’s why we made an effort to use precise, nonteleological language that avoids implying any purpose or direction. Before falling into the common traps of Panglossian thinking, such as assuming everything in evolution has an ideal function or drawing flawed, purpose-driven conclusions, which have both faced recent criticism (4), it is important to look at comparative research. Studying human lungs alongside those of animals (which are far less exposed to smoke, especially cigarette smoke) might offer valuable insights. Any resemblance to World War II British airplanes could be considered overstretched or even accidental.

Young and Scott make a compelling case for connecting genetic markers of preserved lung function with broader evolutionary themes, something we discussed in depth. We are especially on the same page when it comes to the promise of protective genetic variants in revealing new biological pathways that could have therapeutic value. The discussion around nicotinic acetylcholine receptor gene variants and how these relate to risks for both COPD and lung cancer is a great example of how genetics can intersect with addiction, immune response, and cancer development (5). But genetics tell only part of the story. Early-life events, such as prenatal exposure to smoke, nutrition, or childhood respiratory infections, can shape lung health for a lifetime (6).

Overall, we believe resilience needs to be understood from a systems-level perspective. The lungs’ ability to bounce back from smoke damage depends on more than just immune cells or epithelial layers. Factors such as tissue regeneration, metabolic balance, the microbiome, and neuroimmune pathways all play a role and point toward a more integrated approach to understanding resilience. Figuring out why certain individuals remain healthy despite heavy smoke exposure means looking at how all the layers, including genes, biology, environment, and time, interact. We strongly advocate for trials and comparative biology that investigate how these multiple layers impact lung health. By studying what protects the resilient, we may uncover new paths for prevention and treatment of COPD, lung cancer, and other smoke-related conditions.