CCR5 and Biological Complexity: The Need for Data Integration and Educational Materials to Address Genetic/Biological Reductionism at the Interface of Ethical, Legal, and Social Implications.

Jacob Bauss,Michele Morris,Joshua Mills,Joseph W Zagorski,Rosemary Olivero,Rama Shankar,Jeremy W Prokop,Bin Chen,Cynthia L Stenger,Leah N Buck,Alexandra Eby,John Huss,Joseph A Carcillo,Surender Rajasekaran,Sara Cline,Nicholas L Hartog,Caitlin Smith,David Hinds,Caleb P Bupp

doi:10.3389/fimmu.2021.790041

Abstract

In the age of genomics, public understanding of complex scientific knowledge is critical. To combat reductionistic views, it is necessary to generate and organize educational material and data that keep pace with advances in genomics. The view that CCR5 is solely the receptor for HIV gave rise to demand to remove the gene in patients to create host HIV resistance, underestimating the broader roles and complex genetic inheritance of CCR5. A program aimed at providing research projects to undergraduates, known as CODE, has been expanded to build educational material for genes such as CCR5 in a rapid approach, exposing students and trainees to large bioinformatics databases and previous experiments for broader data to challenge commitment to biological reductionism. Our students organize expression databases, query environmental responses, assess genetic factors, generate protein models/dynamics, and profile evolutionary insights into a protein such as CCR5. The knowledgebase generated in the initiative opens the door for public educational information and tools (molecular videos, 3D printed models, and handouts), classroom materials, and strategy for future genetic ideas that can be distributed in formal, semiformal, and informal educational environments. This work highlights that many factors are missing from the reductionist view of CCR5, including the role of missense variants or expression of CCR5 with neurological phenotypes and the role of CCR5 and the delta32 variant in complex critical care patients with sepsis. When connected to genomic stories in the news, these tools offer critically needed Ethical, Legal, and Social Implication (ELSI) education to combat biological reductionism.

Highlights

Chemokine Receptor Type 5 (CCR5) is a member of the G-protein coupled receptor (GPCR) superfamily
Phylogenetic reconstruction of these 100 GPCR human proteins shows that CCR5 clusters next to CCR2 and near CCR1, CCR3, CCRL2, CCR4, CCR8, CX3CR1, XCR1, and ACKR2 (Figure 1A)
A total of 186 amino acids (52.8%) are conserved >90% in CCR5 orthologs. These conserved amino acids at the GPCR, top 16, and CCR5 ortholog levels mapped onto a model of the CCR5 structure reveal a broad GPCR conservation in the core, 16 most similar conservation in several clusters, and broad CCR5 conservation of the transmembrane, intracellular, and extracellular residues (Figure 1B)

Summary

Introduction

Hypothesis-driven research in genomics can often result in overly simplified views of genes that result in reductionism when not balanced with a full view of the biological complexity. To combat these reductionistic views in genomics, it is critical to look more broadly, often non-hypothesis driven and based on the larger data analysis. It is the responsibility of the genetics community to build tools that combat misunderstanding and reductionism [1], when Ethical, Legal and Social Implications (ELSI) are involved. The big data community often is embraced to move beyond gene to single-function insights to broaden our view of how genetics contributes to biology

Methods

Results

Conclusion