Closed-loop control of cellular functions using combinatory drugs guided by a stochastic search algorithm

Pak Kin Wong, Fuqu Yu, Arash Shahangian, Genhong Cheng, Ren Sun, Chih Ming Ho

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

A mixture of drugs is often more effective than using a single effector. However, it is extremely challenging to identify potent drug combinations by trial and error because of the large number of possible combinations and the inherent complexity of the underlying biological network. With a closed-loop optimization modality, we experimentally demonstrate effective searching for potent drug combinations for controlling cellular functions through a large parametric space. Only tens of iterations out of one hundred thousand possible trials were needed to determine a potent combination of drugs for inhibiting vesicular stomatitis virus infection of NIH 3T3 fibroblasts. In addition, the drug combination reduced the required dosage by ≈10-fold compared with individual drugs. In another example, a potent mixture was identified in thirty iterations out of a possible million combinations of six cytokines that regulate the activity of nuclear factor kappa B in 293T cells. The closed-loop optimization approach possesses the potential of being an effective approach for manipulating a wide class of biological systems.

Original languageEnglish (US)
Pages (from-to)5105-5110
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number13
DOIs
StatePublished - Apr 1 2008

Fingerprint

Drug Combinations
Pharmaceutical Preparations
Vesicular Stomatitis
NF-kappa B
HEK293 Cells
Virus Diseases
Fibroblasts
Cytokines

Keywords

  • Combinatory drug therapy
  • Drug cocktail
  • Drug resistance
  • Feedback control
  • Viral infection

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Closed-loop control of cellular functions using combinatory drugs guided by a stochastic search algorithm. / Wong, Pak Kin; Yu, Fuqu; Shahangian, Arash; Cheng, Genhong; Sun, Ren; Ho, Chih Ming.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 13, 01.04.2008, p. 5105-5110.

Research output: Contribution to journalArticle

@article{d5911aa8da6b4bcf825f45dcbb6d8a0e,
title = "Closed-loop control of cellular functions using combinatory drugs guided by a stochastic search algorithm",
abstract = "A mixture of drugs is often more effective than using a single effector. However, it is extremely challenging to identify potent drug combinations by trial and error because of the large number of possible combinations and the inherent complexity of the underlying biological network. With a closed-loop optimization modality, we experimentally demonstrate effective searching for potent drug combinations for controlling cellular functions through a large parametric space. Only tens of iterations out of one hundred thousand possible trials were needed to determine a potent combination of drugs for inhibiting vesicular stomatitis virus infection of NIH 3T3 fibroblasts. In addition, the drug combination reduced the required dosage by ≈10-fold compared with individual drugs. In another example, a potent mixture was identified in thirty iterations out of a possible million combinations of six cytokines that regulate the activity of nuclear factor kappa B in 293T cells. The closed-loop optimization approach possesses the potential of being an effective approach for manipulating a wide class of biological systems.",
keywords = "Combinatory drug therapy, Drug cocktail, Drug resistance, Feedback control, Viral infection",
author = "Wong, {Pak Kin} and Fuqu Yu and Arash Shahangian and Genhong Cheng and Ren Sun and Ho, {Chih Ming}",
year = "2008",
month = "4",
day = "1",
doi = "10.1073/pnas.0800823105",
language = "English (US)",
volume = "105",
pages = "5105--5110",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "13",

}

TY - JOUR

T1 - Closed-loop control of cellular functions using combinatory drugs guided by a stochastic search algorithm

AU - Wong, Pak Kin

AU - Yu, Fuqu

AU - Shahangian, Arash

AU - Cheng, Genhong

AU - Sun, Ren

AU - Ho, Chih Ming

PY - 2008/4/1

Y1 - 2008/4/1

N2 - A mixture of drugs is often more effective than using a single effector. However, it is extremely challenging to identify potent drug combinations by trial and error because of the large number of possible combinations and the inherent complexity of the underlying biological network. With a closed-loop optimization modality, we experimentally demonstrate effective searching for potent drug combinations for controlling cellular functions through a large parametric space. Only tens of iterations out of one hundred thousand possible trials were needed to determine a potent combination of drugs for inhibiting vesicular stomatitis virus infection of NIH 3T3 fibroblasts. In addition, the drug combination reduced the required dosage by ≈10-fold compared with individual drugs. In another example, a potent mixture was identified in thirty iterations out of a possible million combinations of six cytokines that regulate the activity of nuclear factor kappa B in 293T cells. The closed-loop optimization approach possesses the potential of being an effective approach for manipulating a wide class of biological systems.

AB - A mixture of drugs is often more effective than using a single effector. However, it is extremely challenging to identify potent drug combinations by trial and error because of the large number of possible combinations and the inherent complexity of the underlying biological network. With a closed-loop optimization modality, we experimentally demonstrate effective searching for potent drug combinations for controlling cellular functions through a large parametric space. Only tens of iterations out of one hundred thousand possible trials were needed to determine a potent combination of drugs for inhibiting vesicular stomatitis virus infection of NIH 3T3 fibroblasts. In addition, the drug combination reduced the required dosage by ≈10-fold compared with individual drugs. In another example, a potent mixture was identified in thirty iterations out of a possible million combinations of six cytokines that regulate the activity of nuclear factor kappa B in 293T cells. The closed-loop optimization approach possesses the potential of being an effective approach for manipulating a wide class of biological systems.

KW - Combinatory drug therapy

KW - Drug cocktail

KW - Drug resistance

KW - Feedback control

KW - Viral infection

UR - http://www.scopus.com/inward/record.url?scp=42449099889&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42449099889&partnerID=8YFLogxK

U2 - 10.1073/pnas.0800823105

DO - 10.1073/pnas.0800823105

M3 - Article

C2 - 18356295

AN - SCOPUS:42449099889

VL - 105

SP - 5105

EP - 5110

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 13

ER -