Life Science Applications of the Bottom-Up Approach

Bottom-up approach to modelling and simulation in the life sciences

  • Human tissue-specific modelling by detailing and recreating functional components of whole tissue. The smaller subunits of biological processes that make up the whole can form a simulation of a tissue and organ under various conditions through mathematical reconstruction alone.
  • HepatoNet1, a reconstruction of the liver is an example of the bottom-up approach to human tissue-specific modelling. Integrating details, such as cholesterol formation and ammonia detoxification, mean that the effects caused by a change in condition can be simulated for the liver as a whole.
  • The bottom-up approach has also been applied to drug safety assessment. A mechanistic insight into drug function is produced by integrating in vitro input data. The model produced can simulate the drug exposure response at an individual and population level.
  • Important development for reducing clinical trial times and expense of drug development.

Genome building with the bottom-up approach can develop influenza vaccines at speed. Credit: Komsan Loonprom/ Shutterstock.com

Bottom-up approach to genome building

  • The ability to efficiently design and construct genomes is an important step in the development of synthetic vaccines. A bottom-up approach to genome building is speeding up the process.
  • By developing a full gene sequence from smaller segments, error is reduced as each section of the sequence can be easily verified.
  • The overlapping oligonucleotide segments are then assembled through cycles of recombination and amplification until the whole genome is formed.
  • This methodology has important implications for influenza vaccines, where mutations mean annual vaccines do not provide protection for all strains of the virus. The bottom-up approach to genome building can be employed to developing synthetic viruses for vaccines quickly, keeping pace with the rate of mutation.

Bottom-up approach to proteomics

  • Proteomics is the large-scale study of the proteins produced in a biological system or organism.
  • The field has been aided by a bottom-up approach where proteins are characterised by the sub unit peptide components within the protein.
  • This type of protein analysis is often performed through mass spectrometry.
  • The peptides are first derived from the proteolytic digestion of intact proteins before introduction to the mass spectrometer. Peptide identification is produced from the mass spectra and the original protein is inferred by assignation of the peptide sequence.
  • Proteins that share the same type of peptide are often grouped together.
  • Peptide analysis provides the advantage of simple ionization and fragmentation procedures. The bottom-up approach to proteomics supplies a high throughput method of large-scale protein analysis.
  • The methodology has been applied to the study of interactions between proteins and the complexes formed between proteins and other biomolecules. Purified protein complexes can be analysed by bottom-up mass spectrometry allowing for the identification of both direct and indirect interactors.
  • Knowledge of protein interactions will further the potential for targeted protein drug delivery and the development of new disease biomarkers, through increased understanding of the biological pathways that are suitable for targeting as well as the multiple interactions that define and early disease stage.

Reviewed by Afsaneh Khetrapal Bsc (Hons)

Sources:

  1. Gille, C. et al. 2010. HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology, Molecular Systems Biology, 6, e.411. https://www.ncbi.nlm.nih.gov/pubmed/20823849
  2. Tylutki, Z. et al. 2016. Top-down, Bottom-up and Middle-out Strategies for Drug Cardiac Safety Assessment via Modeling and Simulations, Current Pharmacology Reports, 2, pp. 171-177. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929154/
  3. Gibson, D.G. et al. 2010. Chemical synthesis of the mouse mitochondrial genome, Nature Methods, 7, pp. 901-903. https://www.nature.com/articles/nmeth.1515
  4. Zhang, Y. et al. 2013. Protein Analysis by Shotgun/Bottom-up Proteomics, Chemical Reviews, 113, pp. 2343-2394. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751594/

Further Reading

Further Reading

Last Updated: Feb 7, 2018

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