# Central Dogma Transformer III: Interpretable AI Across DNA, RNA, and Protein

arXiv: https://arxiv.org/abs/2603.23361 · HTML: https://mlsanity.com/paper/2603.23361/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 4 of its 34 references that are in the map.
- First posted on arXiv 24 Mar 2026.

## Builds on (most cited first, 4 of 4)

- [Attention is not Explanation](https://mlsanity.com/paper/1902.10186/) (2019)
- [Attention is not not Explanation](https://mlsanity.com/paper/1908.04626/) (2019)
- [Multi-Task Learning with Deep Neural Networks: A Survey](https://mlsanity.com/paper/2009.09796/) (2020)
- [STRAND: Sequence-Conditioned Transport for Single-Cell Perturbations](https://mlsanity.com/paper/2602.10156/) (2026)

## Abstract (arXiv)

Biological AI models increasingly predict complex cellular responses, yet their learned representations remain disconnected from the molecular processes they aim to capture. We present CDT-III, which extends mechanism-oriented AI across the full central dogma: DNA, RNA, and protein. Its two-stage Virtual Cell Embedder architecture mirrors the spatial compartmentalization of the cell: VCE-N models transcription in the nucleus and VCE-C models translation in the cytosol. On five held-out genes, CDT-III achieves per-gene RNA r=0.843 and protein r=0.969. Adding protein prediction improves RNA performance (r=0.804 to 0.843), demonstrating that downstream tasks regularize upstream representations. Protein supervision sharpens DNA-level interpretability, increasing CTCF enrichment by 30%. Analysis of experimentally measured mRNA and protein responses reveals that the majority of genes with observable mRNA changes show opposite protein-level changes (66.7% at |log2FC|>0.01, rising to 87.5% at |log2FC|>0.02), exposing a fundamental limitation of RNA-only perturbation models. Despite this pervasive direction discordance, CDT-III correctly predicts both mRNA and protein responses. Applied to in silico CD52 knockdown approximating Alemtuzumab, the model predicts 29/29 protein changes correctly and rediscovers 5 of 7 known clinical side effects without clinical data. Gradient-based side effect profiling requires only unperturbed baseline data (r=0.939), enabling screening of all 2,361 genes without new experiments.