Introduction to Immuno-Bioinformatics

Posted from Discovering Biology in a Digital World by Todd Smith on Wed May 30, 2018
Overview of the Immuno-Bioinformatics Course

In recent posts, I discussed container technology with an emphasis on Docker and Singularity. The motivation being that Digital World Biology is designing an immuno-bioinformatics class that will be taught at Shoreline Community College (Shoreline). This class will be part of Shoreline’s immuno-biotechnology certificate [1] that is currently under development.

Why is an Immuno-Biotechnology Certificate needed?

Immuno-biotechnology is one of the fastest growing areas in the field of biotechnology. The ability to produce and manufacture specialized immune system proteins, such as antibodies, has long been an important component of biotechnology. In fact, many of the current array of biotechnology-produced drugs are derived from antibodies. But, there is more. New technologies like immune-profiling, where expressed gene segments from antibody and T cell receptors are massively sequenced, and targeted cancer therapies, where researchers create, engineer, and grow modified T cells to attack tumors, are leading to job growth and demands for new skills and knowledge in biomanufacturing, quality systems, informatics, and cancer biology. Indeed over 700 of the more than 6400 companies listed Biotech-Careers.org has a company core activity associated with immunology-based research and development. In some states, like Washington, immunology-related biotechnology businesses comprise almost 30% of the biotechnology industry. 

What does an Immuno-bioinfomatics include?

Shoreline’s Immuno-bioinformatics will be a five-week hands on computer class that will demonstrate ways in which immunologists use bioinformatics. Topics will include receptor profiling, vaccine development, and reagent / drug development as described below. 

Receptor Profiling - Receptor Profiling, made possible by high-throughput, massively parallel, DNA sequencing is used to study the immune response in disease and to antigens and vaccines. Common methods involve sequencing RNA from immune cells in blood and other tissues. After RNA is converted to cDNA, synthetic DNA primers that flank the common regions of V-gene and J-gene segments are used to amplify DNA molecules containing antibody (BCR; B-cell receptor) or T-cell receptor (TCR) sequences. As each molecule is sequenced independently, the collection of sequences obtained from an experiment, or assay, measures the ensemble of receptor sequences that were present in a sample. Bioinformatics tools are then used to determine the frequency of sequences as a way to measure if specific sequences from the receptors are being selected for as part of an immune response. 

Vaccine Development - BCRs and TCRs bind to specific regions of molecules, commonly proteins. These regions, called epitopes, can be use to stimulate the immune system in short and long-term ways to create vaccines that protect us from disease and fight cancer. The biotechnology industry is deeply interested in developing new kinds of vaccines for viral and other diseases including cancer. In vaccine development, bioinformatics is used to predict epitopes from protein sequences and population responses to potential vaccines made from those epitopes. 

Reagent / Drug Development - For many years, antibodies have been developed to be used as reagents in many kinds of assays. Due to the specificity of the antibody / antigen interaction, antibodies can be excellent detection reagents. In biotechnology, antibodies are developed for diagnostic and research applications. As noted above, they and TCRs are also developed into drugs. In cancer, antibodies can be used to bind to cancer cells to simulate a tumor destroying immune response. Antibodies can also block interactions between cells that help cancers grow. Hybrids of antibodies and TCRs (CAR-T technology) are also used direct immune cells to tumors in highly targeted ways. The bioinformatics related to developing diagnostics and reagents can use receptor profiling, epitope analysis, and other methods. In diagnostic and reagent development, statistical analyses are also important because data from many tests need to be analyzed overtime to ensure assay reproducibility and validity. 

General Concepts about Immunology

To understand the uses of immuno-bioinformatics and how different bioinformatics methods work, we need to understand general immunological concepts. From several hundred BCR and TCR genes, a diverse repertoire of many many millions of specific receptors are possible. Combinatorial recombination of genes, combined with insertion, or deletion of nucleotides during the recombination process creates an immense diversity of receptor molecules. In the case of BCRs, additional variation is introduced through mutation (somatic hyper mutation) of the gene sequences to further refine an antibody's specificity and affinity for its target antigen. 

Vaccine development requires an understanding of the commonalities and differences between BCRs and TCRs. While both kinds of receptors bind epitopes in antigens, the way each receptor does this very different. BCRs can bind to linear epitopes, or epitopes that are made up of amino acids are in close proximity in a protein’s three dimensional structure. These, discontinuous, epitopes can span large regions of a protein’s sequence. TCR epitopes, on the other hand, are linear peptides that are processed from proteins and are bound to MHC (major histocompatibility complex) proteins. And, because there are two kinds of MHC proteins, there are two kinds of TCR epitopes. 

Hands on Experience

Bioinformatics is only fun, when you work with data. Thus, most of the class time will be spent working with data and reviewing how the results of analyses measure the immune system and reinforce immunology concepts. In short, the data show the biology. Authentic data sets from scientific publications will be used in conjunction with web-based software systems that are used by scientists in industry and academia for receptor profiling and vaccine development. Such systems utilize many kinds of bioinformatics tools that perform specific data manipulations and analyses. Using the tools in organized systems makes it possible to learn how a tool its used to explore an aspect of the science without the distraction of how to set up the tool for use. 

Core Bioinformatics

While the first part of the hands on experience focuses on the scientific end points of immuno-bioinformatics, it does not provide a full appreciation of all of the steps needed to understand the data and how data collection and quality can impact the results. In the case of receptor profiling this is particularity important as the process for collecting the data involves many steps that can produce artifacts if they are not performed well, or if the data are not processed with this understanding in mind. Hence, in the last part of the course will utilize cloud computing and command line tools to conduct the initial steps of a profiling experiment.

Through the class experience students will be exposed to several aspects of bioinformatics from data analysis to data processing to gain a deep appreciation of the power and richness of the immune system.  

Reference

National Science Foundation funds pioneering immuno-biotechnology coursework for college and high school students 

Acknowledgment of Support: This material is based in part on work supported by the National Science Foundation under Grant Number DUE 1700441. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.