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TwinCell Blueprint: Foundation for AI-Assisted Cell Reprogramming

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PROGRAM OVERVIEW

Heilmeier Questions

Effort Problem Statement / Goals

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What is your approach?

  • We couple our automated cellular reprogramming and sensing platform (iReprogram Inc.) with a new LLM-guided model and predictive control methodology to accelerate the discovery of new reprogramming protocols in a closed hypothesis and validation loop
  • We will develop a composite model of fine-tuned LLMs (e.g. scBERT, AI Pontryagin, Graph-BERT)

What data/compelling evidence do you seek to get?

  • High-fidelity, time-series genome folding and gene expression (topological language of the genome), leading to a high-impact reprogramming demonstration

How will the effort inform a new start and map to office strategy?

  • The effort couples composite LLMs with a high-throughput data generation platform as a compelling exemplar of AI-accelerated scientific discovery

Funding / Acquisition Strategy

LOCATION:

What problem are you tackling?

  • The quest to reprogram cells from one cell type to another, (e.g. Weintraub 1986, Yamanaka 2007), remains a holy grail, with transformational potential in cancer research and interventions, organ and tissue repair, drug discovery, and personalized medicine
  • Current methodologies are slow and inefficient, and require first going through the intermediate step of producing induced pluripotent stem cells (iPSCs)

What is your main objective/What are you trying to learn?

  • We propose to couple our automated in vitro cellular reprogramming platform with a new compositional, multimodal AI/LLM modeling and control approach to demonstrate Direct Reprogramming of human fibroblasts to hematopoietic stem cells at 10X efficiency vs. reprogramming via iPSC

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CUI

Distribution Statement F: Further Dissemination only as directed by (Director, DARPA, 5/2/2023) or higher DoD authority.

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SELECT ONE: 6.1/6.2/6.3

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TwinCell Blueprint: Foundation for AI-Assisted Cell Reprogramming

SELECT ONE: 6.1/6.2/6.3

Automated Experimentation

Folding

Expression

State-Space Representation

(Reduced)

Predicted TFs

Status Quo: Our Lab

Proposed: AI Accelerated Discovery

Automated Experimentation

Folding

Expression

State-Space Representation

(Expanded)

Predicted TFs

GeneFormer

HiCFoundation

Our Hi-C

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Ronquist S, Patterson G, Muir LA, Lindsly S, Chen H, Brown M, Wicha MS, Bloch A, Brockett R, Rajapakse I. "Algorithm for cellular reprogramming." PNAS 2017 Nov 7;114(45):11832-7. Supporting Information

Chen H, Chen J, Muir LA, Ronquist S, Meixner W, Ljungman M, Ried T, Smale S, Rajapakse I. "Functional Organization of the Human 4D Nucleome. " PNAS 112.26 (2015): 8002-8007. Supporting Information