Addressing Concerns About the Proteolipid Code
Meaningful dialogue on the proteolipid code has so far been limited, as researchers who could offer valuable perspectives avoid debating me. This is possibly to avoid giving the proteolipid code a platform since it contradicts their work. Nonetheless, below are responses to some possible questions and critiques.
— Troy Kervin
Why does membrane biology need a unifying model?
Membrane biology is rich in data yet fragmented in theory. A coherent, unifying model is needed to guide experiments and inspire the next generation of technologies. Much of the field still revolves around the lipid raft framework. The proteolipid code provides an alternative foundation that is mechanistic and testable.
Unlike other grandiose frameworks such as string theory or the free energy principle in neuroscience, the proteolipid code is not ad hoc, unfalsifiable, or obscured by confusion or vagueness. I am a philosophy of science informed theorist. Indeed, I am trying to supersede the lipid raft theory, which originally made bold, falsifiable predictions but then became nebulous and arguably pseudoscientific in response to contradictory evidence.
The value of a scientific framework, model, or theory is tied to its relationship with other ideas. The proteolipid code was introduced to move beyond lipid rafts and to provide a more realistic description of membrane zonation. Over time, it should evolve toward greater specificity, predictive power, and practical application.
Many recent articles continue to use older lipid raft-centric concepts without addressing the implications of the proteolipid code. Examples include:
Rappoport A. A Lipid-Raft Theory of Alzheimer’s Disease. Annu Rev Biochem. 2025;94(1):387-416.
Mukhamedova N. et al. Targeting the ARF6-dependent recycling pathway to alter lipid rafts and reduce inflammation. 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.
Such works demonstrate that much of the field remains anchored to pre-code assumptions, often overlooking alternative interpretations that integrate proteins and lipids as co-determinants of membrane structure.
“The proteolipid code is too simple to be useful”
The flagship proteolipid code paper outlines the “hard core” of the framework, and although it is framed at a low resolution, it is sufficient to challenge previously proposed models and theories. Rather than drowning readers in mathematical complexity, our flagship paper conveys a simple, clear message that reflects the proteolipid code’s broad importance. The proteolipid code is the membrane model based on lipid fingerprints, and establishes a framework of first principles. It will become more specific with time.
How can the proteolipid code be falsified?
The proteolipid code can be falsified in at least two ways:
- Demonstrate stable, selfsame membrane subregions formed by lipid self-clustering that subsequently recruit proteins.
This would support a “lipid-only” or “lipid-first” code, contradicting the co-deterministic foundation of the proteolipid framework. - Discredit the lipid fingerprint theory (ACS Cent Sci. 2018).
For instance, if proteins were shown to lack unique, composition-dependent lipid distributions, the core premise of proteolipid zoning would fail.
Other ideas associated with the proteolipid code can be viewed as auxiliary hypotheses in the Lakatosian sense: important, but not essential to the survival of the framework.