REVIEW ARTICLE –
Reprogramming Cancer Cells Toward Normalcy: The BENEIN Framework and Gene-Switch Targets in Colorectal Cancer
By Dr. Gholam Mujtaba, MD, Ed.D.
Dr. Athar Mujtaba, DNP, MD.
Dr. Assad Mujtaba, DNP, MD
Abstract
Recent breakthroughs in cancer therapy suggest two distinct yet potentially complementary paradigms: (1) a systems?biology?based “cancer reversion” approach, BENEIN (Boolean Network Inference and Control), that endeavors to coax colorectal cancer (CRC) cells back to a normal, differentiated state; and (2) Rice University’s innovative non?invasive near?infrared (NIR) nanophysical technique—molecular jackhammers—capable of mechanically destroying tumor cells with ultrafast vibronic action. Here, I synthesize foundational findings from both streams, examine translational opportunities and challenges, and propose integrative future strategies that may drive next-generation, safer, and more effective cancer therapies.
Introduction
Traditional cancer treatments focus on eradicating malignant cells via surgery, radiation, and cytotoxic or targeted drugs. However, the emergence of cell-state reprogramming strategies reframes the therapeutic goal: rather than kill, can we coax cancer cells into benign, differentiated phenotypes? The BENEIN framework, developed by researchers at KAIST, pioneers this concept in colorectal cancer by modeling gene-regulatory networks (GRNs) at single-cell resolution and identifying minimal combinatorial “master-switch” targets to redirect malignant attractor states toward normal enterocyte lineages.
Meanwhile, Rice University chemists have engineered a molecular mechanism—“molecular jackhammers”—a non-invasive NIR-activated mechanical assault on cancer cell membranes using vibronic-driven action (VDA), representing a radically different physical modality of tumor eradication.
Bringing these two lines of innovation into a single strategic lens underscores the potential of combining reprogramming and nano-mechanical targeting to achieve precision, efficacy, and reduced toxicity in future oncologic interventions.
BENEIN Methodology Overview
• Network inference: BENEIN reconstructs a Boolean GRN from single-cell RNA-seq datasets across colorectal differentiation trajectories, distinguishing pre- and post-transition states and inferring regulatory logic.
• Control target search: The pipeline identifies perturbation sets capable of shifting the network’s attractor landscape from malignant toward normal epithelial states.
• Application: Using human large intestine single-cell data, BENEIN nominated potential switch sets for CRC reversion.
Key Findings from KAIST (BENEIN Study)
1 Master?switch set: Simultaneous inhibition of MYB, HDAC2, and FOXA2 was predicted to drive CRC cells toward enterocyte-like differentiation and suppress oncogenic programs.
2 In vitro reprogramming: Coordinated knockdowns shifted malignant CRC cells’ transcriptomes toward normal colon profiles, upregulated differentiation markers, and downregulated pathways like MYC/WNT.
3 In vivo tumor suppression: In mouse xenograft models, this triple inhibition reduced tumor growth, demonstrating functional reversion beyond culture systems.
4 Systems?level corroboration: Independent attractor?landscape analyses further validated a reversion switch along the normal?to?cancer transition in CRC, reinforcing BENEIN’s conceptual underpinnings (KAIST systems biology lab).
Together, these findings inaugurate a novel paradigm—cancer reversion via coordinated transcriptional and epigenetic control—distinct from cytotoxicity and akin to differentiation therapy in APL, but empowered by computational network inference.
Therapeutic Promise & Translational Challenges
Advantages:
• Reduced toxicity: Reprogramming avoids indiscriminate cytotoxic damage.
• Resistance mitigation: Restoring differentiation programs may circumvent typical resistance pathways.
Challenges:
• Delivery: Achieving simultaneous, tumor-selective inhibition (e.g., via RNAi, CRISPRi, or degrader cocktails) remains technologically tricky.
• Tumor heterogeneity: CRCs exhibit mosaic heterogeneity; different clones might require variant control sets.
• Durability: It’s unclear whether reprogrammed states persist after treatment cessation.
• Safety: MYB, HDAC2, FOXA2 have normal physiologic roles; off?target toxicity must be addressed preclinically.
These challenges define a roadmap for IND-enabling studies, including pharmacokinetics, biodistribution, toxicology, and lineage conversion biomarkers.
Rice University’s Molecular Jackhammer Therapy (NIR-Driven)
Rice researchers, led by James Tour with lead author Ciceron Ayala?Orozco, discovered that aminocyanine molecules—dyes traditionally used in imaging—can be activated by near?infrared light to undergo vibronic-driven action (VDA), resulting in ultrafast, concerted whole?molecule vibrations (“molecular jackhammers”) that rupture cancer cell membranes.
• Mechanism: The aminocyanines form molecular plasmons under NIR light and vibrate at sub-picosecond frequencies, mechanically ripping cell membranes. The process is distinct from photodynamic or photothermal methods.
• Efficacy: Achieved ~99% cell-kill rates in vitro (human melanoma cultures) and 50% complete remission in mouse melanoma models
The Rice Thresher (https://www.ricethresher.org/article/2024/01/molecular-jackhammers-present-novel-method-of-eradicating-cancer?utm_source=chatgpt.com)College of Engineering+8PubMed+8Rice News+8 (https://pubmed.ncbi.nlm.nih.gov/38114816/?utm_source=chatgpt.com)Optics.org (https://optics.org/news/15/1/10?utm_source=chatgpt.com)Rice News+3Healthcare in Europe+3College of Engineering+3 (https://healthcare-in-europe.com/en/news/cancer-jackhammer-approach.html?utm_source=chatgpt.com).
• Depth advantage: NIR penetrates up to ~10?cm, versus ~0.2?cm for visible light
Rice News+2Dark Daily+2 (https://news.rice.edu/news/2023/molecular-jackhammers-good-vibrations-eradicate-cancer-cells?utm_source=chatgpt.com).
• Resistance profile: Likely minimal development of resistance due to the mechanical nature of killing
Healthcare in Europe (https://healthcare-in-europe.com/en/news/cancer-jackhammer-approach.html?utm_source=chatgpt.com)PubMed (https://pubmed.ncbi.nlm.nih.gov/38114816/?utm_source=chatgpt.com).
This modality introduces a non?invasive, targeted, physical kill mechanism complementary to genetic or pharmacologic reprogramming strategies.
Integrative Perspective & Future Directions
Bringing together BENEIN reprogramming and NIR molecular jackhammers opens exciting translational synergy:
1 Sequential or combination strategies: Use BENEIN-guided reprogramming to force differentiation in partial clones, then apply NIR jackhammers to eliminate reversion-resistant or undifferentiated populations.
2 Tagged jackhammer delivery: Engineer aminocyanine conjugates that preferentially bind malignant CRC clones (e.g., via surface markers), enabling selective mechanical disruption.
3 Monitoring reversion / destruction: Leverage transcriptomic assays to confirm reprogramming, then imaging co-localized NIR response to zero residual malignant clones.
4 Patient?derived models: Test both modalities in CRC organoids/PDX from diverse subtypes to assess combinatorial efficacy, resistance patterns, and off-target effects.
5 Safety and biodistribution: Investigate effects of receptor?targeted jackhammer therapy and control-switch inhibitor delivery on normal tissues, especially in combination.
These integrative approaches could yield a novel multi-modal orthogonal therapy: reprogram malignancy, then physically remove remaining threats with high precision and low toxicity.
Conclusion
KAIST’s BENEIN framework and Rice University’s molecular jackhammer technology embody two forward?looking strategies in oncology: one reprograms malignancy via systems?biology control, the other obliterates cancer cells with non?invasive mechanical force. Individually, each offers transformative potential; together, they could form a powerful, synergistic arsenal against tumor persistence, heterogeneity, and recurrence. Translating these advances will require innovative delivery, rigorous safety profiling, and concerted efforts to model combinatorial modalities—but the promise of reshaping cancer therapy toward precision, fewer side effects, and therapeutic resilience justifies rapid pursuit.
References
1 Gong?J?R, Lee?C?K, Kim?H?M, et al. Control of Cellular Differentiation Trajectories for Cancer Reversion. Advanced Science. 2025;12(3):e2402132. doi:10.1002/advs.202402132. Epub 2024?12?11.
2 KAIST News Center. Groundbreaking technology converts cancer cells into normal cells without killing them. News release, 2024?12?23.
3 Shin?D, et al. Attractor La
ndscape Analysis Reveals a Reversion Switch in the Transition of Colorectal Cancer. KAIST Systems Biology & Bioengineering Lab, 2025.
4
Advanced Science News. Computer system helps scientists understand how cancer could be reversed. 2025?01?31.
5
Ayala?Orozco?C, et al. Molecular Jackhammers Eradicate Cancer Cells by Vibronic?Driven Action.
Nature Chemistry
(2023); also PubMed PMID: 38114816
Rice News+4Healthcare in Europe+4College of Engineering+4 (https://healthcare-in-europe.com/en/news/cancer-jackhammer-approach.html?utm_source=chatgpt.com)Healthcare in Europe+9PubMed+9Rice News+9 (https://pubmed.ncbi.nlm.nih.gov/38114816/?utm_source=chatgpt.com)
.
6
Additional reporting: ScienceAlert (Dec 25, 2024)
utmb.edu+3ScienceAlert+3The Rice Thresher+3 (https://www.sciencealert.com/scientists-destroy-99-of-cancer-cells-in-lab-using-vibrating-molecules?utm_source=chatgpt.com)
; Rice News / various media
en.wikipedia.org (https://en.wikipedia.org/wiki/Naomi_Halas?utm_source=chatgpt.com)
