Meaningful dialogue on the proteolipid code has been limited so far, in part because the framework is still new and its implications span several areas of membrane biology. Many researchers who could offer valuable perspectives may be cautious about engaging publicly with emerging models that differ from established approaches. Nonetheless, thoughtful questions and critiques are welcome, and some anticipated ones are addressed below.
— Troy Kervin
Why consider a unifying model for membrane biology?
Membrane biology is exceptionally rich in data but remains theoretically fragmented. A coherent, mechanistic framework can help integrate diverse findings, guide experimental design, and inspire new technologies. Much of the field still relies on concepts derived from the lipid-raft paradigm. The proteolipid code is proposed as an alternative foundation—one that is mechanistic, testable, and designed to evolve with accumulating evidence.
The proteolipid code is informed by philosophy of science, aiming for clarity, falsifiability, and explanatory power. It seeks to provide a more realistic description of membrane zonation by integrating both protein and lipid determinants. While the original lipid raft hypothesis made bold predictions, its scope and definitions broadened over time, making empirical assessment challenging. The proteolipid code is intended as a constructive next step, offering a pathway toward increased specificity and predictive utility.
Scientific frameworks are valuable not in isolation but in how they relate to and refine existing ideas. The proteolipid code was introduced to move beyond raft-centric models and to stimulate new lines of investigation into membrane organization.
Many recent articles continue to operate within pre-code assumptions, for example:
- Rappoport A. A Lipid-Raft Theory of Alzheimer’s Disease. Annu Rev Biochem. 2025.
- Mukhamedova N. et al. Targeting the ARF6-dependent recycling pathway to alter lipid rafts. J Lipid Res. 2025.
- Juarez-Contreras I. et al. Structural dissection of ergosterol metabolism reveals a pathway optimized for membrane phase separation. Sci Adv. 2025.
These works demonstrate the continued influence of older conceptual frameworks, and highlight the need for discussions that include alternative interpretations incorporating both lipid and protein contributions.
“The proteolipid code is too simple to be useful.”
The flagship paper presents the essential core of the framework at an intentionally accessible level. The aim was to articulate first principles clearly rather than introduce a prematurely complex model. As with any scientific theory, the framework is expected to grow more specific, quantitatively detailed, and experimentally grounded over time. The foundational idea, that membrane organization reflects protein-specific lipid fingerprints, provides a starting point for such refinement.
How can the proteolipid code be falsified?
The framework is empirically testable and could be falsified in several ways, including:
- Show that lipids self-assemble into submembrane platforms that recruit proteins after such platforms have formed.
Such a finding would support a “lipid-only” or “lipids-first” mechanism and contradict the co-deterministic premise of the proteolipid code. - Discredit the lipid fingerprint concept (ACS Cent Sci. 2018).
If proteins were shown not to exhibit unique, heterogeneous lipid distributions, the central organizing principle of proteolipid zoning would not hold.
Other ideas associated with the framework function as auxiliary hypotheses: they may guide research and interpretation, but the framework’s viability ultimately depends on the testable core claims above.