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Register a new userEmerging whole-cell modeling principles and methods
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Whole-cell computational models aim to predict cellular phenotypes from genotype by representing the entire genome, the structure and concentration of each molecular species, each molecular interaction, and the extracellular environment. Whole-cell models have great potential to transform bioscience, bioengineering, and medicine. However, numerous challenges remain to achieve whole-cell models. Nevertheless, researchers are beginning to leverage recent progress in measurement technology, bioinformatics, data sharing, rule-based modeling, and multi-algorithmic simulation to build the first whole-cell models. We anticipate that ongoing efforts to develop scalable whole-cell modeling tools will enable dramatically more comprehensive and more accurate models, including models of human cells.
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Despite substantial potential to transform bioscience, medicine, and bioengineering, whole-cell models remain elusive. One of the biggest challenges to whole-cell models is assembling the large and diverse array of data needed to model an entire cell. Thanks to rapid advances in experimentation, much of the necessary data is becoming available. Furthermore, investigators are increasingly sharing their data due to increased emphasis on reproducibility. However, the scattered organization of this data continues to hamper modeling. Toward more predictive models, we highlight the challenges to assembling the data needed for whole-cell modeling and outline how we can overcome these challenges by working together to build a central data warehouse.
Branching in vascular networks and in overall organismic form is one of the most common and ancient features of multicellular plants, fungi, and animals. By combining machine-learning techniques with new theory that relates vascular form to metabolic function, we enable novel classification of diverse branching networks--mouse lung, human head and torso, angiosperm and gymnosperm plants. We find that ratios of limb radii--which dictate essential biologic functions related to resource transport and supply--are best at distinguishing branching networks. We also show how variation in vascular and branching geometry persists despite observing a convergent relationship across organisms for how metabolic rate depends on body mass.
Population pharmacokinetic (PK) modeling methods can be statistically classified as either parametric or nonparametric (NP). Each classification can be divided into maximum likelihood (ML) or Bayesian (B) approaches. In this paper we discuss the nonparametric case using both maximum likelihood and Bayesian approaches. We present two nonparametric methods for estimating the unknown joint population distribution of model parameter values in a pharmacokinetic/pharmacodynamic (PK/PD) dataset. The first method is the NP Adaptive Grid (NPAG). The second is the NP Bayesian (NPB) algorithm with a stick-breaking process to construct a Dirichlet prior. Our objective is to compare the performance of these two methods using a simulated PK/PD dataset. Our results showed excellent performance of NPAG and NPB in a realistically simulated PK study. This simulation allowed us to have benchmarks in the form of the true population parameters to compare with the estimates produced by the two methods, while incorporating challenges like unbalanced sample times and sample numbers as well as the ability to include the covariate of patient weight. We conclude that both NPML and NPB can be used in realistic PK/PD population analysis problems. The advantages of one versus the other are discussed in the paper. NPAG and NPB are implemented in R and freely available for download within the Pmetrics package from www.lapk.org.
Across the tree of life, populations have evolved the capacity to contend with suboptimal conditions by engaging in dormancy, whereby individuals enter a reversible state of reduced metabolic activity. The resulting seed banks are complex, storing information and imparting memory that gives rise to multi-scale structures and networks spanning collections of cells to entire ecosystems. We outline the fundamental attributes and emergent phenomena associated with dormancy and seed banks, with the vision for a unifying and mathematically based framework that can address problems in the life sciences, ranging from global change to cancer biology.
Understanding the relationship between genomic variation and variation in phenotypes for quantitative traits such as physiology, yield, fitness or behavior, will provide important insights for both predicting adaptive evolution and for breeding schemes. A particular question is whether the genetic variation that influences quantitative phenotypes is typically the result of one or two mutations of large effect, or multiple mutations of small effect. In this paper we explore this issue using the wild model legume Medicago truncatula. We show that phenotypes, such as quantitative disease resistance, can be well-predicted using genome-wide patterns of admixture, from which it follows that there must be many mutations of small effect. Our findings prove the potential of our novel whole-genome modeling -WhoGEM- method and experimentally validate, for the first time, the infinitesimal model as a mechanism for adaptation of quantitative phenotypes in plants. This insight can accelerate breeding and biomedicine research programs.
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