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Greedy scheduling of cellular self-replication leads to optimal doubling times with a log-Frechet distribution.

ABSTRACT: Bacterial self-replication is a complex process composed of many de novo synthesis steps catalyzed by a myriad of molecular processing units, e.g., the transcription-translation machinery, metabolic enzymes, and the replisome. Successful completion of all production tasks requires a schedule-a temporal assignment of each of the production tasks to its respective processing units that respects ordering and resource constraints. Most intracellular growth processes are well characterized. However, the manner in which they are coordinated under the control of a scheduling policy is not well understood. When fast replication is favored, a schedule that minimizes the completion time is desirable. However, if resources are scarce, it is typically computationally hard to find such a schedule, in the worst case. Here, we show that optimal scheduling naturally emerges in cellular self-replication. Optimal doubling time is obtained by maintaining a sufficiently large inventory of intermediate metabolites and processing units required for self-replication and additionally requiring that these processing units be "greedy," i.e., not idle if they can perform a production task. We calculate the distribution of doubling times of such optimally scheduled self-replicating factories, and find it has a universal form-log-Frechet, not sensitive to many microscopic details. Analyzing two recent datasets of Escherichia coli growing in a stationary medium, we find excellent agreement between the observed doubling-time distribution and the predicted universal distribution, suggesting E. coli is optimally scheduling its replication. Greedy scheduling appears as a simple generic route to optimal scheduling when speed is the optimization criterion. Other criteria such as efficiency require more elaborate scheduling policies and tighter regulation.

SUBMITTER: Pugatch R

PROVIDER: S-EPMC4345593 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Greedy scheduling of cellular self-replication leads to optimal doubling times with a log-Frechet distribution.

Pugatch Rami R

Proceedings of the National Academy of Sciences of the United States of America 20150209 8

Bacterial self-replication is a complex process composed of many de novo synthesis steps catalyzed by a myriad of molecular processing units, e.g., the transcription-translation machinery, metabolic enzymes, and the replisome. Successful completion of all production tasks requires a schedule-a temporal assignment of each of the production tasks to its respective processing units that respects ordering and resource constraints. Most intracellular growth processes are well characterized. However, ...[more]

PMID: 25675498

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Project description:In Chronic Myeloid Leukemia (CML), successful treatment requires accurate molecular monitoring to evaluate disease response and provide timely interventions for patients failing to achieve the desired outcomes. We wanted to determine whether measuring BCR-ABL1 mRNA doubling-times (DTs) could distinguish inconsequential rises in the oncogene's expression from resistance to tyrosine kinase inhibitors (TKIs). Thus, we retrospectively examined BCR-ABL1 evolution in 305 chronic-phase CML patients receiving imatinib mesylate (IM) as a first line treatment. Patients were subdivided in two groups: those with a confirmed rise in BCR-ABL1 transcripts without MR3.0 loss and those failing IM. We found that the DTs of the former patients were significantly longer than those of patients developing IM resistance (57.80 vs. 41.45 days, p = 0.0114). Interestingly, the DT values of individuals failing second-generation (2G) TKIs after developing IM resistance were considerably shorter than those observed at the time of IM failure (27.20 vs. 41.45 days; p = 0.0035). We next wanted to establish if decreases in BCR-ABL1 transcripts would identify subjects likely to obtain deep molecular responses. We therefore analyzed the BCR-ABL1 halving-times (HTs) of a different cohort comprising 174 individuals receiving IM in first line and observed that, regardless of the time point selected for our analyses (6, 12, or 18 months), HTs were significantly shorter in subjects achieving superior molecular responses (p = 0.002 at 6 months; p < 0.001 at 12 months; p = 0.0099 at 18 months). Moreover, 50 patients receiving 2G TKIs as first line therapy and obtaining an MR3.0 (after 6 months; p = 0.003) or an MR4.0 (after 12 months; p = 0.019) displayed significantly shorter HTs than individuals lacking these molecular responses. Our findings suggest that BCR-ABL1 DTs and HTs are reliable tools to, respectively, identify subjects in MR3.0 that are failing their assigned TKI or to recognize patients likely to achieve deep molecular responses that should be considered for treatment discontinuation.

Dataset Information

Greedy scheduling of cellular self-replication leads to optimal doubling times with a log-Frechet distribution.

Publications

Greedy scheduling of cellular self-replication leads to optimal doubling times with a log-Frechet distribution.

Similar Datasets

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