February ABC Seminar: Vitalii Kleshchevnikov, PhD – Wellcome Sanger Institute – “Probabilistic models to resolve cell identity and tissue architecture”

February ABC Seminar: Vitalii Kleshchevnikov, PhD – Wellcome Sanger Institute – “Probabilistic models to resolve cell identity and tissue architecture”

Cell identity drives cell-cell communication and tissue architecture and is in return regulated by cell-extrinsic cues. Cell identity is determined by the combination of intrinsic developmentally established transcription factor use (TF) and constitutive as well as cell communication-dependent TF activities. Presented work shows two probabilistic models that we developed to advance the understanding of these processes using single-cell and spatial genomic data.

Spatial transcriptomic technologies promise to resolve cellular wiring diagrams of tissues in health and disease, but comprehensive mapping of cell types in situ remains a challenge. Here we present cell2location, a Bayesian model that can resolve fine-grained cell types in spatial transcriptomic data and create comprehensive cellular maps of diverse tissues. Cell2location accounts for technical sources of variation and borrows statistical strength across locations, thereby enabling the integration of single cell and spatial transcriptomics with higher sensitivity and resolution than existing tools. We assess cell2location in three different tissues and demonstrate improved mapping of fine-grained cell types. In the mouse brain, we discover fine regional astrocyte subtypes across the thalamus and hypothalamus. In the human lymph node, we spatially map a rare pre-germinal center B cell population. In the human gut, we resolve fine immune cell populations in lymphoid follicles. Collectively our results present cell2location as a versatile analysis tool for mapping tissue architectures in a comprehensive manner.

Python package is provided here:  https://github.com/BayraktarLab/cell2location.

Cell identity and plasticity is regulated by a combinatorial code mediated by transcription factors and the cell communication environment. Systematically dissecting how the regulatory code robustly defines the vast complexity of cell populations across tissues is a long-standing challenge. Measured using the assay for transposase-accessible chromatin with sequencing (ATAC-seq), DNA accessibility provides a readout of intermediate gene regulation steps at single-cell resolution, with technologies measuring both RNA and ATAC providing the necessary evidence to build mechanistic models of regulation. Existing methods address one or several subproblems of modelling DNA accessibility. For example, the DNA sequence-based deep learning models represent combinatorial interactions and in-vivo TF-DNA recognition preferences. In contrast, GRN models use TF abundance profiles across cells and in-vitro-derived TF-DNA recognition preferences, optionally incorporating ATAC-seq data as a filter. All models learn cell-type specific weights and properties and don’t generalize to new TF abundance states such as new cell types. Therefore, we are missing an end-to-end mechanistic model that represents all steps of the biological process, that generalizes to both new DNA sequences and TF abundance combinations and can simultaneously characterize hundreds to thousands of cell states observed in single-cell genomics atlases. Here, we formulated cell2state, a mechanistic end-to-end probabilistic model of TF recruitment to a chromatin locus and downstream TF effect on DNA accessibility. Cell2state is designed to achieve the generalization of regulatory predictions to unseen cell types. Cell2state A) estimates TF nuclear protein abundance and models B) how TFs recognize DNA, C) how TF sites in DNA lead to TF recruitment to a chromatin locus, D) how the activity of DNA-associated TFs affects chromatin accessibility. To evaluate generalization, we defined the computational problem and developed a workflow for predicting the scATAC-seq readout for previously unseen chromosomes and cell types. We show that cell2state outperforms the state-of-the-art deep learning models (ChromDragoNN) at explaining DNA accessibility differences across cells. Finally, to look at cell state plasticity, we developed ways to use cell2state to simulate the possible chromatin states given TF abundance of source cell types.

Speaker:  Vitalii Kleshchevnikov, PhD
Affiliation:  Wellcome Sanger Institute
Position:  Bioinformatician @ Bayraktar, Stegle, Teichmann group
Host: Daniel MacDonald, Gibson Lab

Date: Monday February 26, 2024
Time: 10:00AM-11:00AM ET
Zoom: https://partners.zoom.us/j/82163676866
Meeting ID: 821 6367 6866

Vitalii Kleshchevnikov is driven by a deep interest in three key areas: i) understanding the regulatory code which allows a single genome to specify the full diversity of cell populations and their interaction, ii) formalizing the biology of these processes into mechanistic AI/ML models, and iii) accelerating the therapy development to address ageing alterations in these processes. Vitalii did his PhD jointly supervised by Dr Omer Bayraktar, Dr Oliver Stegle, Dr Sarah Teichmann at Wellcome Sanger Institute (2018-2023) and will present the published and ongoing work. Prior to PhD, Vitalii worked on the role of peptide motifs (SLiMs) in intracellular signaling (Dr Evangelia Petsalaki, EMBL-EBI), predicting CRISR KO mutational outcomes (Dr Leopold Parts, Wellcome Sanger Institute) and profiling protein interactions in accelerated ageing (A*STAR) – while completing MSc and BSc in Kyiv, Ukraine.

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January ABC Seminar: Efrat Muller – Tel Aviv University – “Methods for integrating metagenomics and metabolomics data”

January ABC Seminar: Efrat Muller – Tel Aviv University – “Methods for integrating metagenomics and metabolomics data”

The human gut microbiome, and its metabolic activity in particular, have been implicated in a wide range of disease states, including metabolic disorders, inflammatory bowel diseases, and colorectal cancer. This growing appreciation for the impact of the gut microbiome’s metabolism on human health has given rise to studies that generate both microbiome and metabolome high-throughput data from human gut microbiome samples. Truly integrated analysis of both omic datasets, however, remains a challenging task. My research aims to develop new frameworks for analyzing and integrating these datasets using a combination of machine learning, metabolic modeling, and network analysis. I’ll specifically present two projects: the first evaluates the robustness of microbiome-metabolome associations using machine learning and meta-analysis models; the second aims to identify “multi-omic modules” that capture both cross-omic associations and associations with disease simultaneously. Taken together, these frameworks can enhance our understanding of microbiome-metabolome connections and equip the microbiome research community with novel methods for such integrated data analysis.

Speaker: Efrat Muller
Affiliation: Prof. Elhanan Borenstein Lab, Tel Aviv University
Position: Doctoral Candidate
Hosted by: Jennifer Dawkins, Gerber Lab

Date: Monday January 22, 2024
Time: 10:00AM-11:00AM ET
Zoom: https://partners.zoom.us/j/82163676866
Meeting ID: 821 6367 6866

Links:
Google Scholar
Linkedin

Efrat Muller is a Computer Science PhD student studying computational methods for human microbiome research, under the supervision of Professor Elhanan Borenstein at Tel Aviv University. Prior to her PhD, she worked in product management and data analysis positions at Medial EarlySign(a startup in the digital health industry) and at Intel Corporation’s Big Data and Machine Learning group. Efrat completed a B.Sc. and M.Sc. in computer science with honors from Ben-Gurion University. She is generally enthusiastic about any intersection of computer science, machine learning, healthcare and well-being.

Efrat received the EMEA Google Generation Scholarship (2022), Edmond J. Safra Center Excellent Research Student Prize (2022), Naamat scholarship for female PhD students (2022), and prizes for excellence in teaching (Discrete Math course for CS students, 2019-2021).

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Postdoctoral Fellow, Microbiome-Host Immune System Interactions – Gerber Lab

The Gerber Lab (http://gerber.bwh.harvard.edu) is a multidisciplinary group at Brigham and Women’s Hospital/Harvard Medical School that develops novel computational models and high-throughput experimental systems to understand the role of the microbiota in human diseases, and applies these findings to develop new diagnostic tests and therapies. The director of the lab, Dr. Georg Gerber, MD, PhD, MPH, uses his unique expertise, combining advanced machine learning method development, medical microbiology, and human pathology, to leverage cutting-edge technologies to tackle scientifically and clinically important problems.

We are looking for an exceptional researcher who will play a major role in a new initiative in the lab to investigate systematically how commensal microorganisms interact with the host immune system. Although host-bacterial interactions have been extensively characterized for some pathogens, much less is known about how commensal bacteria in the microbiome interact with us. The lab will use both experimental systems (e.g., gnotobiotic animals and cell culture) and computational approaches to study various aspects of immune host system-microbiome interactions, including influence on infection/inflammation and immune repertoire development/diversity.

The successful candidate will be highly motivated and creative, taking a lead role in experimental design, execution of experiments, and interpretation of results. This position is a fantastic opportunity for an individual with strong experimental skills to learn about and apply computational techniques, enriched by extensive collaborations with top computational researchers.

Qualifications:

  • PhD in Immunology, Microbiology, or related discipline.
  • Excellent publication track record.
  • Proficiency in cell and molecular techniques including cell culture, flow cytometry, qPCR, and ELISA assays.
  • Proficiency in mouse studies including animal handling, blood collection, necropsy and cell isolation.
  • Superior communication skills and ability to work on multidisciplinary teams.
  • Experience in cellular immunology, including immune cell proliferation is highly desirable.
  • Experience in microbiology, including culture of anaerobic bacteria is highly desirable.
  • Experience with next-generation sequencing library preparation and data analysis is highly desirable.

Environment:  the Gerber Lab is located in the Division of Computational Pathology (http://comp-path.bwh.harvard.edu), which Dr. Gerber heads, at Brigham and Women’s Hospital (BWH) at Harvard Medical School (HMS), and the Massachusetts Host-Microbiome Center (MHMC) (http://metagenomics.partners.org), which Dr. Gerber co-directs. BWH, an HMS affiliated teaching hospital is adjacent to the HMS main quad and is the second largest non-university recipient of NIH research funding. The Division is situated within the BWH Department of Pathology, which houses over 40+ established investigators, 50+ postdoctoral research fellows, and 100+ research support staff. The MHMC has extensive facilities to support microbiome research, including the largest not-for-profit gnotobiotic mouse facility in New England, a microbiology unit with advanced anaerobic culturing systems, and a molecular unit with next generation sequencers and robotic liquid handlers. BWH is part of the greater Longwood Medical Area in Boston, a rich, stimulating environment conducive to intellectual development and research collaborations, which includes HMS, Harvard School of Public Health and Boston Children’s Hospital.

To apply: email a single PDF including cover letter, CV, brief research statement and a list of at least three references to Dr. Georg Gerber (ggerber@bwh.harvard.edu). In your CV, indicate whether you are a U.S. citizen/permanent resident or visa holder (and list visa type). Incomplete applications will be considered non-responsive and unfortunately cannot be considered.

We are an equal opportunity employer and all qualified applicants will receive consideration for employment without regard to race, color, religion, sex, national origin, disability status, protected veteran status, gender identity, sexual orientation, pregnancy and pregnancy-related conditions or any other characteristic protected by law.

Harris H. Wang, PhD Columbia University-“Spatial metagenomics, culturomics, and engineering of human and environmental microbiomes”

Harris H. Wang, PhD Columbia University-“Spatial metagenomics, culturomics, and engineering of human and environmental microbiomes”

BWH Computational Pathology Special Seminar

Harris H. Wang, PhD
Associate Professor of Systems Biology
Interim Chair, Department of Systems Biology, Columbia University

Microbes that colonize the gastrointestinal tract play important roles in host metabolism, immunity, and homeostasis. Microbes that live in soil are responsible for a variety of key decomposition and remediation activities in the biosphere. Better tools to study and alter these microbiomes are essential for unlocking their vast potential to improve human health and combat climate change. This talk will describe our recent efforts to develop next-generation tools to study and modify microbial communities. Specifically, I will discuss new advances in spatial metagenomics, AI-enabled culturomics, and precision microbiome editing to program different microbiomes with new traits. These capabilities provide a foundation to accelerate the development of microbiome-based products and therapies.

Research Links:  http://wanglab.c2b2.columbia.edu/

Harris Wang is an Associate Professor of Systems Biology and serves as the Interim Chair of the Department of Systems Biology at Columbia University, Vagelos College of Physicians and Surgeons. He is also jointly appointed the Department of Pathology and Cell Biology. Dr. Wang received his B.S. degrees in Mathematics and Physics from MIT and his Ph.D. in Biophysics from Harvard University. His research group mainly develops enabling genomic technologies to characterize the mammalian gut microbiome and to engineer these microbes with the capacity to monitor and improve human health. Dr. Wang is an Investigator of the Burroughs Wellcome Fund and the recipient of numerous awards, including the Vilcek Prize for Creative Promise in Biomedical Science, Blavatnik National Award Finalist, NSF CAREER, Sloan Research Fellowship, and the Presidential Early Career Award for Scientists and Engineers (PECASE).

Date: Friday October 27, 2023
Time:  2:00-3:00pm ET
In Person: Wolf Conference Center, Hale BTM 02006B, 60 Fenwood Rd Boston 02115
Online: https://partners.zoom.us/j/89199829402
Meeting ID: 891 9982 9402

Gerber Lab awarded $3.1 Million Five Year NIH-NIGMS R35 Grant “Probabilistic deep learning models and integrated biological experiments for analyzing dynamic and heterogeneous microbiomes”

Gerber Lab awarded $3.1 Million Five Year NIH-NIGMS R35 Grant “Probabilistic deep learning models and integrated biological experiments for analyzing dynamic and heterogeneous microbiomes”

This work will leverage deep learning technologies to advance the microbiome field beyond finding associations in data, to accurately predicting the effects of perturbations on microbiota, elucidating mechanisms through which the microbiota affects the host, and improving bacteriotherapies to enable their success in the clinic. New deep learning models will be developed that address specific challenges for the microbiome, including noisy/small datasets, highly heterogenous human microbiomes, the need for direct interpretability of model outputs, complex multi-modal datasets, and constraints imposed by biological principles. Computational models and biological experiments will be directly coupled through reinforcing cycles of predicting, testing predictions with new experiments, and improving models. An important objective will also be to make computational tools widely available to the research community, through release of quality open-source software.

RePORTER Link

 

Vitalii Kleshchevnikov, PhD – Wellcome Sanger Institute – “Probabilistic models to resolve cell identity and tissue architecture”

Vitalii Kleshchevnikov, PhD – Wellcome Sanger Institute – “Probabilistic models to resolve cell identity and tissue architecture”

Speaker:  Vitalii Kleshchevnikov, PhD
Affiliation:  Wellcome Sanger Institute
Position:  Bioinformatician @ Bayraktar, Stegle, Teichmann group
Host: Daniel MacDonald, Gibson Lab

Abstract:  Cell identity drives cell-cell communication and tissue architecture and is in return regulated by cell-extrinsic cues. Cell identity is determined by the combination of intrinsic developmentally established transcription factor use (TF) and constitutive as well as cell communication-dependent TF activities. Presented work shows two probabilistic models that we developed to advance the understanding of these processes using single-cell and spatial genomic data.

Spatial transcriptomic technologies promise to resolve cellular wiring diagrams of tissues in health and disease, but comprehensive mapping of cell types in situ remains a challenge. Here we present cell2location, a Bayesian model that can resolve fine-grained cell types in spatial transcriptomic data and create comprehensive cellular maps of diverse tissues. Cell2location accounts for technical sources of variation and borrows statistical strength across locations, thereby enabling the integration of single cell and spatial transcriptomics with higher sensitivity and resolution than existing tools. We assess cell2location in three different tissues and demonstrate improved mapping of fine-grained cell types. In the mouse brain, we discover fine regional astrocyte subtypes across the thalamus and hypothalamus. In the human lymph node, we spatially map a rare pre-germinal centre B cell population. In the human gut, we resolve fine immune cell populations in lymphoid follicles. Collectively our results present cell2location as a versatile analysis tool for mapping tissue architectures in a comprehensive manner.

Python package is provided here:  https://github.com/BayraktarLab/cell2location.

Cell identity and plasticity is regulated by a combinatorial code mediated by transcription factors and the cell communication environment. Systematically dissecting how the regulatory code robustly defines the vast complexity of cell populations across tissues is a long-standing challenge. Measured using the assay for transposase-accessible chromatin with sequencing (ATAC-seq), DNA accessibility provides a readout of intermediate gene regulation steps at single-cell resolution, with technologies measuring both RNA and ATAC providing the necessary evidence to build mechanistic models of regulation. Existing methods address one or several subproblems of modelling DNA accessibility. For example, the DNA sequence-based deep learning models represent combinatorial interactions and in-vivo TF-DNA recognition preferences. In contrast, GRN models use TF abundance profiles across cells and in-vitro-derived TF-DNA recognition preferences, optionally incorporating ATAC-seq data as a filter. All models learn cell-type specific weights and properties and don’t generalize to new TF abundance states such as new cell types. Therefore, we are missing an end-to-end mechanistic model that represents all steps of the biological process, that generalizes to both new DNA sequences and TF abundance combinations and can simultaneously characterize hundreds to thousands of cell states observed in single-cell genomics atlases. Here, we formulated cell2state, a mechanistic end-to-end probabilistic model of TF recruitment to a chromatin locus and downstream TF effect on DNA accessibility. Cell2state is designed to achieve the generalization of regulatory predictions to unseen cell types. Cell2state A) estimates TF nuclear protein abundance and models B) how TFs recognize DNA, C) how TF sites in DNA lead to TF recruitment to a chromatin locus, D) how the activity of DNA-associated TFs affects chromatin accessibility. To evaluate generalization, we defined the computational problem and developed a workflow for predicting the scATAC-seq readout for previously unseen chromosomes and cell types. We show that cell2state outperforms the state-of-the-art deep learning models (ChromDragoNN) at explaining DNA accessibility differences across cells. Finally, to look at cell state plasticity, we developed ways to use cell2state to simulate the possible chromatin states given TF abundance of source cell types.

Vitalii Kleshchevnikov is driven by a deep interest in three key areas: i) understanding the regulatory code which allows a single genome to specify the full diversity of cell populations and their interaction, ii) formalizing the biology of these processes into mechanistic AI/ML models, and iii) accelerating the therapy development to address ageing alterations in these processes. Vitalii did his PhD jointly supervised by Dr Omer Bayraktar, Dr Oliver Stegle, Dr Sarah Teichmann at Wellcome Sanger Institute (2018-2023) and will present the published and ongoing work. Prior to PhD, Vitalii worked on the role of peptide motifs (SLiMs) in intracellular signaling (Dr Evangelia Petsalaki, EMBL-EBI), predicting CRISR KO mutational outcomes (Dr Leopold Parts, Wellcome Sanger Institute) and profiling protein interactions in accelerated ageing (A*STAR) – while completing MSc and BSc in Kyiv, Ukraine.

Click here to be added to our mail list.

Efrat Muller, Tel Aviv University – “Methods for integrating metagenomics and metabolomics data”

Efrat Muller, Tel Aviv University – “Methods for integrating metagenomics and metabolomics data”

Speaker Name: Efrat Muller
Affiliation: Prof. Elhanan Borenstein Lab, Tel Aviv University
Position: Doctoral Candidate
Hosted by: Jennifer Dawkins, Gerber Lab

The human gut microbiome, and its metabolic activity in particular, have been implicated in a wide range of disease states, including metabolic disorders, inflammatory bowel diseases, and colorectal cancer. This growing appreciation for the impact of the gut microbiome’s metabolism on human health has given rise to studies that generate both microbiome and metabolome high-throughput data from human gut microbiome samples. Truly integrated analysis of both omic datasets, however, remains a challenging task. My research aims to develop new frameworks for analyzing and integrating these datasets using a combination of machine learning, metabolic modeling, and network analysis. I’ll specifically present two projects: the first evaluates the robustness of microbiome-metabolome associations using machine learning and meta-analysis models; the second aims to identify “multi-omic modules” that capture both cross-omic associations and associations with disease simultaneously. Taken together, these frameworks can enhance our understanding of microbiome-metabolome connections and equip the microbiome research community with novel methods for such integrated data analysis.

Links
Google Scholar
Linkedin

Efrat Muller is a Computer Science PhD student studying computational methods for human microbiome research, under the supervision of Professor Elhanan Borenstein at Tel Aviv University.  Prior to her PhD, she worked in product management and data analysis positions at Medial EarlySign(a startup in the digital health industry) and at Intel Corporation’s Big Data and Machine Learning group.  Efrat completed a B.Sc. and M.Sc. in computer science with honors from Ben-Gurion University.  She is generally enthusiastic about any intersection of computer science, machine learning, healthcare and well-being.

Efrat received the EMEA Google Generation Scholarship (2022), Edmond J. Safra Center Excellent Research Student Prize (2022), Naamat scholarship for female PhD students (2022), and prizes for excellence in teaching (Discrete Math course for CS students, 2019-2021).

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Tal Korem PhD, Columbia – “Contamination and genomic variability in microbiome data”

Microbiome studies hold tremendous potential along with substantial computational challenges. I will present two computational approaches for microbiome data analysis. First, I will present SCRuB, a new method for in silico removal of contamination from microbiome data. We show that modeling the taxonomic composition of contamination sources, rather than trying to infer whether specific taxa are categorically contaminant, allows for more robust decontamination and improves downstream phenotypic prediction. Second, I will present copangraph, a new graph-based approach for representing genomic variability within and across microbiomes. We demonstrate a hybrid co-assembly approach that yields high-quality representation of the microbiome.

Tal Korem’s research program focuses on the development of computational methods that identify and interpret host-microbiome interactions in various clinical setting. The ultimate goal of his research is to translate microbiome findings to clinical care, with microbiome-based therapeutics and microbiome-informed clinical practices. He has developed several approaches for microbiome data analysis, inferring microbial growth rates, structural variants, and microbiome-metabolite interactions; and has applied these methods in diverse clinical and biological investigations, most notably for personalization of dietary treatment and predicting preterm birth. He is a member of Columbia’s Program for Mathematical Genomics (PMG), an Assistant Professor in the Departments of Systems Biology and Obstetrics & Gynecology, and was previously a CIFAR-Azrieli global scholar by the Canadian Institute for Advanced Research.

All Welcome! Note this event will take place on Zoom: https://partners.zoom.us/j/84799112738

To be added to the ABC seminar email list, please email tarnoldmages@bwh.harvard.edu