Photos: Lars Blackmore
Text: Tammara Wood and Karin Curtis-Hill
On April 3rd, 2024 members of the Center for Quantitative Biology (CQB) gathered at the Hanover Inn to share their updates, accomplishments, and plans, with the CQB community, meet with their External Advisory Committee (EAC), and enjoy some good company and good food!
EAC Members:
Dr. Kelley Thomas, University of New Hampshire
Dr. Cathy Wu, University of Delaware
Dr. Paul Robson, Jackson Laboratory
Introduction and Updates
The meeting kicked off with a brief center overview from our director, Dr. Michael Whitfield, highlighting the successes from Phase 1.
He discussed how Dr. Zhao is awaiting her NOA due July 2024, opening a slot for a new project leader in Phase 2. Also highlighted was our new research project lead, Dr. Jennifer Hong, the recruitment of two new faculty members; Drs. Ken Hoehn and Lauren Walker, and ongoing searches in the Department of Biomedical Data Science, the Center for Technology and Behavioral Health, and the Center for Precision Health and Artificial Intelligence.
Both Single Cell Genomics and Genomic Data Science Cores have been extremely busy with investments in instruments and infrastructure, providing pilot grants for new users and/or novel projects. More than $2.5M in COBRE Supplements were funded in Year 5, including Team Science and Cloud Computing awards. A Women’s Health Supplement will be funded soon.
Project Summaries
“Predicting TCR and BCR specificity to microbiomes by massively mining RNA-seq samples”
Project Lead: Li Song
Dr. Li Song presented a brief overview of his background before discussing why T Cell Receptors (TCRs) and B Cell Receptors (BCRs) are important. He explained how researchers have developed many different experimental approaches to discover the antigen-specific TCRs or BCRs and how these experimental platforms are usually low-throughput and the computational approach can only inspect a limited number of receptors, antigens, or species, usually with little information for BCRs. His lab has developed computational methods to extract both biologically meaningful microbiome and immune repertoire information from RNA-seq data.
His group applied their TRUST4 algorithm to TCGA and cancer immunotherapy samples to study the immune repertoire in the tumor microenvironment. Although methods like TRUST4 and T1K can infer the immune-related information from the data, including TCR, BCR and HLA genotypes for MHC, they still do not know the origin of these antigens, including those from microbes. To get at this information his group plans to map the reads to the microbial genome database to identify taxonomy information for each read, but memory usage was a major concern. A common approach to combat this is to use memory-efficient data structures, such as those adopted in the method Centrifuge; however, this too is doomed to be a bottleneck of the memory usage in data analysis as the database grows. Dr. Song’s solution was to develop a lossless compression of microbial genomes for efficient taxonomic classification called Centrifuger, a paradigm similar to the method Centrifuge but with significantly lower memory requirement and higher sensitivity and precision.
Dr. Song’s future work will focus on immune receptor analysis, extending it to more sequencing platforms; microbiome analysis to improve accuracy, pangenome, translated search, adaptive sampling, and quantification; and to connect the immune repertoire and microbiome information from a large number of RNA-seq data.
“Mapping the impact of sex hormones on macrophage fates and functions”
Project Lead: Britt Goods
Dr. Britt Goods’ work addresses unmet needs in reproductive health and immunology by applying and developing systems biology tools across biological scales. Her lab aims to solve problems surrounding macrophage fates and functions, non-hormonal contraceptives and identifying drivers of health and disease. Her presentation focused on macrophages and the impact of sex hormones impacting their function. Her data showed, after exposure to estrogen, a pronounced alteration of the global transcriptome for differentiated macrophages with M1-like pro-inflammatory macrophages both time and dose dependent and M2-like anti-inflammatory macrophages only time dependent. She also showed how treatment with progesterone impacts M1-like macrophages that are distinct from those of estrogen.
In conclusion, Dr. Goods showed that her group can generate polarized inflammatory and anti-inflammatory macrophages. They also found that estrogen and progesterone exposure alters the global transcriptome of human macrophages with M1 macs impacted more than M2 macs. She showed how genes and pathways related to immune responses were impacted and provided data on cytokine measurements that suggest E2 increases secretion of VEGF and CCL2. Her future work will focus on understanding the impact of estrogen and progesterone on macrophage differentiation and expand to testosterone and luteinizing hormone.
“Gene regulation and dynamical efficacy in antibiotic responses”
Project Leader: Daniel Schultz
Dr. Daniel Schultz’ lab is interested in the dynamics of cell processes, with a focus on antibiotic responses in bacteria. His lab combines experimental and computational approaches using microfluidics, experimental evolution, mathematical modeling and bioinformatics. He provided an overview of how antibiotic responses evolve to adapt to new complex environments, such as in clinical settings. His lab developed a specialized microfluidic device to study structured biofilm-like microcolonies instead of just single cells, that more traditional microfluidic devices track.
He showed how regulation of the E. coli tetracycline resistance tet operon can be lost when evolved in fast-changing drug regimens. He presented data on how induction of the wild type mexXYZ multidrug resistance mechanism in P. aeruginosa is slow in natural environments, but once in the human lung it acquires a similar loss of regulation to speed up the response. He also showed how understanding the effect of regulatory pathways in the resistance phenotypes of microbes allows treatment planning that addresses specific drug-resistance profiles.
“Computational approaches to studying somatic mutations in cancer”
Project Leader: Siming Zhao
Dr. Siming Zhao began her presentation with the central question in human genetics, ‘What are the disease-causing variants and how do they cause disease?’ She explained how GWAS, although a powerful computational approach, has significant challenges. Her group’s solution is to integrate GWAS with functional genomics data. Her recent publication, Adjusting for genetic confounders in transcriptome-wide association studies improves discovery of risk genes of complex traits, in January 2024, describes how her lab’s new method, causal TWAS (cTWAS), provides a robust statistical framework for gene discovery.
Moving forward, Dr. Zhao has three areas of proposed work:
- Developing new methods and analysis to map genetic variants with context dependent regulatory effect
- Identifying the cellular context for disease-causing genetic variants
- Inference of disease relevance using single cell omics data
“Understanding brain extracellular matrix in the tumor microenvironment”
Project Lead: Jennifer Hong
Dr. Jennifer Hong began by presenting images of brains with tumors, asking the group which patient had a seizure. Seizures are often the first presentation of brain tumors, with the reappearance or worsening of seizures indicative of tumor progression, yet there are striking differences in the rate of seizures in these patients that are unexplained. Seizures are considered the most important risk factor for long- term disability in brain tumor patients, impacting both mental and physical fitness and thus independence. Her work focuses on the unmet clinical need by understanding the tole of the tumor microenvironment in initiating seizures in patients with brain tumors.
“Revealing the impact of tryptophan metabolism on host-microbe and microbe-microbe interactions in the gut”
Pilot Project Leader: Ben Ross
Dr. Ben Ross provided an update on his project where his group has successfully established SGM consortium in gnototiobic mice, successfully detected and quantified tryptophan metabolites, how sex has a significant impact on SGM composition, and how possibly his group has not successfully eliminated indole production.
Dr. Ross plans to finish analysis of banked samples, initiate SGM 2.0 experiments, and prepare a manuscript of his work.
“Spatial transcriptomic dissection of the vertebrate urinary development program using zebrafish”
Pilot Project Leader: Duncan Morhardt
Dr. Duncan Morhardt discussed the pros and cons of working with zebrafish as a means of understanding the conserved, critical mechanisms of external urethral development. His project proposes to catalogue the expression landscape of urethral development in zebrafish using RNA-seq to inform probes in the Xenium platform. He provided his group’s initial anatomic studies of zebrafish urinary structures and urinary morphology over time. He explained how his lab is making headway on transcriptomic characterization, optimizing experimental conditions, and leveraging (quantitative) advantages of the zebrafish. His next step is use of the Xenium platform and analysis of early and late bladder development of zebrafish.
Team Science – “Multi-omics modeling of bacterial metabolism and effects on immune physiology”
Leads: Anne Hoen, Benjamin Ross, Li Song, and Mark Sundrud
The team presented their current work on using novel multi-omics approaches to investigate the form and function of key microbiota-derived metabolites on host gene expression in the gut. They began with their key questions:
- What is the size and complexity of intestinal bile acid and tryptophan metabolite pools?
- How and where are they absorbed to interface with host immune and epithelial cells?
- How do they influence host gene expression?
- What are the similarities and differences between these pools in mice with intact vs. minimal microbiomes?
They then walked the group through their new approach for tracking the production and metabolism of microbe-derived gut metabolites in vivo, and in turn, how this information can be used to infer rates and routes of intestinal absorption. They discussed combining their multi-omics approaches with gnotobiotic methods to interogate microbial biosynthetic mechanisms underlying the production of discrete intestinal metabolite species. They ended their presentation with a variety of computational workflows that have been developed for meta-transcriptomics analysis, as well as differential and correlation network analyses.
Team Science – “Defining the pathogenic role of myeloid cell populations in glomerulonephritis using Spatial Transcriptomics and DNA Methylation”
Leads: Sladjana Skopelja-Gardner and Lucas Salas Diaz
Dr. Skopelja-Gardner discussed the role of neutrophils in lupus nephritis (LN) pathogenesis and how myeloid cells mediate glomerulonephritis. Their group was able to confirm neutrophil presence in the glomeruli using spatial transcriptomic analyses of LN tissues. They determined Low Density Neutrophils and High Density Neutrophils infiltrate LN kidneys and that CITEseq reveals distinct neutrophil gene signatures in healthy vs. lupus. They confirmed neutrophils are elevated in the urine of LN patients with active disease and that urine DNA methylation deconvolution analysis can be used to non-invasively quantify neutrophils in relation to clinical parameters.
Core Updates
Genomic Data Science Core Single Cell Genomics Core
Core Co-Directors: Shannon Soucy & Owen Wilkins
Dr. Shannon Soucy provided an overview of the progress made by the Genomic Data Science Core over the last year. She presented the group with core usage numbers broken down by service categories that included epigenetics, gene expression, single cell and spatial. She then presented a graph on GDSC Training Workshop attendance, providing a of breakdown of users by CQB affiliation. Dr. Soucy also provided an update on GDSC Interns and their work, mentioning the core is now accepting 2024 internship applications from the QBS MS program. GDSC infrastructure includes analysis portfolio pipelines/workflows, large scale parallelization and genomic references on DartFS/Discovery. This segued into the feasibility of leveraging GCP Cloud Computing, with Dr. Soucy discussing the Cloud Computing supplement, advantages/disadvantages and data storage optimization.
Single Cell Genomics Core
Core Director: Fred Kolling
Dr. Fred Kolling provided an overview on how SCGC provides end-to-end workflow support for single cell and spatial transcriptomics studies, while integrating with GDSC for analysis. His talk focused on how SCGC will focus on the needs of the research community during Phase 2, with emphasis on expanding capabilities in Translational Research, Single Cell Multiomics, and Spatial Transcriptomics. The future directions of the core are to spread awareness of translational capabilities with clinical partners, continue to build relationships with other INBRE institutions to serve as a regional resource, validate post-Xenium workflows for IHC, multiplex-IF and other modalities – integration with microscopy shared resource, and incorporate Visium HD into spatial portfolio.
Poster Session
The day concluded with a poster session and reception with hors d’oeuvres and beverages. This was a chance for everyone to socialize and students to discuss their projects. We were joined by attendees of the AI Symposium next door, resulting in a large and lively crowd.
