Sergio E Baranzini

UCSF University of California, San Francisco | UCSF · Department of Neurology

Objective The relationship between multiple sclerosis and the gut microbiome has been supported by animal models in which commensal microbes are required for the development of experimental autoimmune encephalomyelitis. However, observational study findings in humans have only occasionally converged when comparing multiple sclerosis cases and contr...

Knowledge graphs have become a common approach for knowledge representation. Yet, the application of graph methodology is elusive due to the sheer number and complexity of knowledge sources. In addition, semantic incompatibilities hinder efforts to harmonize and integrate across these diverse sources. As part of The Biomedical Translator Consortium...

Background/Objectives: Serum proteomic analysis of deeply-phenotyped samples, biological pathway modeling and network analysis were performed to elucidate the inflammatory and neurodegenerative processes of multiple sclerosis (MS) and identify sensitive biomarkers of MS disease activity (DA). Methods: Over 1100 serum proteins were evaluated in >600...

Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic),...

Introduction Early diagnosis of Parkinson’s disease (PD) is important to identify treatments to slow neurodegeneration. People who develop PD often have symptoms before the disease manifests and may be coded as diagnoses in the electronic health record (EHR). Methods To predict PD diagnosis, we embedded EHR data of patients onto a biomedical knowl...

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. Here, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subs...

Genome-wide association studies (GWAS) successfully identified multiple sclerosis (MS) susceptibility variants. Despite this notable progress, understanding the biological context of these associations remains challenging, due in part to the complexity of linking GWAS results to causative genes and cell types. Here, we aimed to address this gap by...

Space biology research aims to understand fundamental spaceflight effects on organisms, develop foundational knowledge to support deep space exploration and, ultimately, bioengineer spacecraft and habitats to stabilize the ecosystem of plants, crops, microbes, animals and humans for sustained multi-planetary life. To advance these aims, the field l...

Human exploration of deep space will involve missions of substantial distance and duration. To effectively mitigate health hazards, paradigm shifts in astronaut health systems are necessary to enable Earth-independent healthcare, rather than Earth-reliant. Here we present a summary of decadal recommendations from a workshop organized by NASA on art...

Early identification of Alzheimer's Disease (AD) risk can aid in interventions before disease progression. We demonstrate that electronic health records (EHRs) combined with heterogeneous knowledge networks (e.g., SPOKE) allow for (1) prediction of AD onset and (2) generation of biological hypotheses linking phenotypes with AD. We trained random fo...

Motivation: Knowledge graphs (KG) are being adopted in industry, commerce, and academia. Biomedical KG present a challenge due to the complexity, size, and heterogeneity of the underlying information. Results: In this work we present the Scalable Precision Medicine Open Knowledge Engine (SPOKE), a biomedical KG connecting millions of concepts vi...

Meaningful representations of clinical data using embedding vectors is a pivotal step to invoke any machine learning (ML) algorithm for data inference. In this article, we propose a time-aware embedding approach of electronic health records onto a biomedical knowledge graph for creating machine readable patient representations. This approach not on...

Changes in gut microbiota have been associated with several diseases. Here, the International Multiple Sclerosis Microbiome Study (iMSMS) studied the gut microbiome of 576 MS patients (36% untreated) and genetically unrelated household healthy controls (1,152 total subjects). We observed a significantly increased proportion of Akkermansia muciniphi...

During the past decade, research has revealed that the vast community of micro-organisms that inhabit the gut - known as the gut microbiota - is intricately linked to human health and disease, partly as a result of its influence on systemic immune responses. Accumulating evidence demonstrates that these effects on immune function are important in n...

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults. To provide insight into the mechanisms determining progression, we conducted a genome-wide association study of...

Purpose Multiple sclerosis (MS) is an immune-mediated, neuroinflammatory disease of the central nervous system and in industrialised countries is the most common cause of progressive neurological disability in working age persons. While treatable, there is substantial interindividual heterogeneity in disease activity and response to treatment. Curr...

Knowledge representation and reasoning (KR&R) has been successfully implemented in many fields to enable computers to solve complex problems with AI methods. However, its application to biomedicine has been lagging in part due to the daunting complexity of molecular and cellular pathways that govern human physiology and pathology. In this article,...

Knowledge representation and reasoning (KR&R) has been successfully implemented in many fields to enable computers to solve complex problems with AI methods. However, its application to biomedicine has been lagging in part due to the daunting complexity of molecular and cellular pathways that govern human physiology and pathology. In this article,...

Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the central nervous system. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both disease status and severity in cohorts of European descent. The largest genome-wide associati...

Human space exploration beyond low Earth orbit will involve missions of significant distance and duration. To effectively mitigate myriad space health hazards, paradigm shifts in data and space health systems are necessary to enable Earth-independence, rather than Earth-reliance. Promising developments in the fields of artificial intelligence and m...

Space biology research aims to understand fundamental effects of spaceflight on organisms, develop foundational knowledge to support deep space exploration, and ultimately bioengineer spacecraft and habitats to stabilize the ecosystem of plants, crops, microbes, animals, and humans for sustained multi-planetary life. To advance these aims, the fiel...

Objective Early identification of chronic diseases is a pillar of precision medicine as it can lead to improved outcomes, reduction of disease burden, and lower healthcare costs. Predictions of a patient’s health trajectory have been improved through the application of machine learning approaches to electronic health records (EHRs). However, these...

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single-molec...

Neurodegeneration mediates neurological disability in inflammatory demyelinating diseases of the CNS. The role of innate immune cells in mediating this damage has remained controversial with evidence for destructive and protective effects. This has complicated efforts to develop treatment. The time sequence and dynamic evolution of the opposing fun...

Neurodegeneration mediates neurological disability in inflammatory demyelinating diseases of the CNS. The role of innate immune cells in mediating this damage has remained controversial with evidence for destructive and protective effects. This has complicated efforts to develop treatment. The time sequence and dynamic evolution of the opposing fun...

Although cerebrospinal fluid (CSF) analysis routinely enables diagnosis of neurological diseases, it is mainly used for gross distinction between infectious, autoimmune inflammatory, and degenerative central nervous system (CNS) disorders. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis...

Background Higher childhood body mass index (BMI) has been associated with an increased risk of multiple sclerosis (MS). Objective To evaluate whether childhood BMI has a causal influence on MS, and whether this putative effect is independent from early adult obesity and pubertal timing. Methods We performed Mendelian randomization (MR) using sum...

Background: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear. Objective: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS. Methods: We performed Mendelian randomi...

There has long been an interest in understanding how the hazards from spaceflight may trigger or exacerbate human diseases. With the goal of advancing our knowledge on physiological changes during space travel, NASA GeneLab provides an open-source repository of multi-omics data from real and simulated spaceflight studies. Alone, this data enables i...

Objective To examine whether lifelong genetically increased serum urate levels, a potent antioxidant, contribute to MS susceptibility using Mendelian randomization (MR). Methods This 2-sample MR study included 25 independent genetic variants strongly associated with serum urate levels in a genome-wide association study meta-analysis of 140,949 ind...

Multiple sclerosis is an autoimmune disease of the CNS in which both genetic and environmental factors are involved. Genome-wide association studies revealed more than 200 risk loci, most of which harbour genes primarily expressed in immune cells. However, whether genetic differences are translated into cell-specific gene expression profiles and to...

Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA ⁺ cells have in neuroinflammation a...

Objective: To determine the levels of brain-derived neurotrophic factor (BDNF) in the serum of patients suffering from multiple sclerosis (MS) to evaluate the potential of serum BDNF as a biomarker for MS. Methods: Using a recently validated enzyme-linked immunoassay (ELISA) we measured BDNF in patients with MS (pwMS), diagnosed according to the...

Significance B cells serve as a key weapon against infectious diseases. They also contribute to multiple autoimmune diseases, including multiple sclerosis (MS) where depletion of B cells is a highly effective therapy. We describe a comprehensive profile of central nervous system (CNS)-specific transcriptional B cell phenotypes in MS at single-cell...

Background: Severe coronavirus disease 2019 (COVID-19) is associated with multiple comorbidities and is characterized by an auto-aggressive inflammatory state leading to massive collateral damage. To identify preventive and therapeutic strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to ascertain the...

Objective To evaluate the value of serum immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies reactive with phosphatidylcholine (PC) and lactosylceramide (LC) as biomarkers in MS. Methods We developed an ultrasensitive ELISA technique to analyze serum IgG and IgM antibodies to LC and PC, which we used to analyze samples from 362 patients w...

Background Evidence for a role of human gut microbiota in multiple sclerosis (MS) risk is mounting, yet large variability is seen across studies. This is, in part, due to the lack of standardization of study protocols, sample collection methods, and sequencing approaches. Objective This study aims to address the effect of a household experimental...

Vitamin D deficiency is a major environmental risk factor for the development of multiple sclerosis. The major circulating metabolite of vitamin D (25-hydroxyvitamin D) is converted to the active form (calcitriol) by the hydroxylase enzyme CYP27B1 In multiple sclerosis lesions, the tyrosine kinase MerTK expressed by myeloid cells regulates phagocyt...

The SARS-Cov-2 virus, which causes COVID 19, uses the cell surface protein ACE2 as receptor for entry into cells. Critically ill COVID-19 patients often require prolonged mechanical ventilation which can cause mechanical stress to lung tissue. In vitro studies have shown that expression of ACE2 in alveolar cells is increased following mechanical st...

Vitamin D deficiency is a major environmental risk factor for the development of multiple sclerosis (MS). The major circulating metabolite of vitamin D (25OHD) is converted to the active form (calcitriol) by the hydroxylase enzyme CYP27B1. In MS lesions the tyrosine kinase MerTK expressed by microglia and macrophages regulates phagocytosis of myeli...

New DNA sequencing technologies have uncovered non-coding RNA (ncRNA) as a major player in regulating cellular processes and can no longer be dismissed as “junk” or “dark” RNA. Among the ncRNA, microRNA (miRNA) is arguably the most extensively characterized category and a number of studies have implicated them in regulating critical functions that...

Multiple sclerosis (MS) has a complex etiology involving both genetic and environmental factors. New therapeutic strategies have shown to modulate, and in some cases, completely abrogate disease activity in relapsing MS. Substantial advances have also been made on the dissection of the fundamental genetic etiology underlying MS risk. While the most...

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a c...

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of met...

Objective: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS). Methods: Adults with MS/CIS in the UCSF-EPIC cohort study were included. LTL was measured on DNA samples by quantitative PCR and expressed as telomere to somatic DNA...

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabol...

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabol...

In order to advance precision medicine, detailed clinical features ought to be described in a way that leverages current knowledge. Although data collected from biomedical research is expanding at an almost exponential rate, our ability to transform that information into patient care has not kept at pace. A major barrier preventing this transformat...

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have bee...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Disruption of the blood–brain barrier (BBB) is critical to initiation and perpetuation of disease in multiple sclerosis (MS). We report an interaction between oligodendroglia and vasculature in MS that distinguishes human white matter injury from normal rodent demyelinating injury. We find perivascular clustering of oligodendrocyte precursor cells...

Supplementary Table S1a: Comparison of pyramidal, cerebellar and bowel/bladder functional scales at baseline between the silent progression sub‐group versus the other sub‐groups Supplementary Table S1b: Comparison of pyramidal, cerebellar and bowel/bladder functional scales at long‐term follow‐up between the silent progression sub‐group versus the...

Supplementary Table S5: Analysis of the influence of age‐adjusted baseline brain volumes on short term, one year confirmed and long‐term disability in participants with and without clinical relapses

Supplementary Table S3: Analysis of the influence of age‐adjusted baseline brain volume on long‐term disability.

Supplementary Table S7a Sensitivity analysis of the correlations of relapses with disability and radiographic findings excluding participants who remained CIS at last observation Supplementary Table S7b: Multivariate regression model of relative brain volume over time, excluding stable CIS subjects

Supplementary Table S2a: Multivariate regression of platform therapies on relative brain volume over time Supplementary Table S2b: Multivariate regression of escalation therapy on relative brain volume over time Supplementary Table S2c: Comparison of relative brain loss by treatment tier

Supplementary Table S4: Analysis of the influence of age‐adjusted baseline brain volumes on silent progression

Supplementary Table S6a: Analysis of the impact of brain MRI activity on long‐term disability in treated and untreated participants Supplementary Table S6b: Analysis of the impact of brain MRI activity on brain atrophy in treated and untreated participants

(Cell 176, 610–624.e1–e18; January 24, 2019) We have identified four minor errors in the originally published version of this article: (1) We inadvertently left out the contributions of Leslie Y.T. Leung in the Author Contributions section. This has now been added.(2) Table S2 lists clinical and epidemiological data of MS patients. In Table S2, we...

Objective Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pre‐treatment era. Nonetheless, in our recently reported prospective cohort more than half of patients with relapsing MS accumulated significant new disabili...

Consortia are large, multidisciplinary research efforts that carry the power of numbers. In addition, they enable the sharing of protocols and strategies, ultimately resulting in credible, reproducible, and groundbreaking discoveries. Several consortia are currently investigating the role of bacteria in health and disease, including the Internation...

In order to advance precision medicine, detailed clinical features ought to be described in a way that leverages current knowledge. Although data collected from biomedical research is expanding at an almost exponential rate, our ability to transform that information into patient care has not kept at pace. A major barrier preventing this transformat...

Several efforts identifying differential bacterial prevalence in the gut of multiple sclerosis (MS) patients have been reported and many more are underway. While these are critical first steps in determining the involvement of gut microbes in MS pathogenesis, functional assays (both in vitro and in vivo) are needed to explore the mechanisms underly...

A significant unmet need for patients with multiple sclerosis (MS) is the lack of U.S. Food and Drug Administration (FDA)-approved remyelinating therapies. We have identified a compelling remyelinating agent, bazedoxifene (BZA), a European Medicines Agency (EMA)-approved (and FDA-approved in combination with conjugated estrogens) selective estrogen...

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during E...

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune enceph- alomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during...

The computational analysis of microbiome samples is a highly specialized task, requiring powerful hardware and deep know-how not only in informatics and statistics but also in ecology and taxonomy. Different approaches must be followed based on the sequencing method (16S or shotgun) and while these can provide partially overlapping information, the...

Objective To determine the effects of the disease-modifying therapies, glatiramer acetate (GA) and dimethyl fumarate (DMF), on the gut microbiota in patients with MS. Methods Participants with relapsing MS who were either treatment-naive or treated with GA or DMF were recruited. Peripheral blood mononuclear cells were immunophenotyped. Bacterial D...

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by adaptive and innate immune system dysregulation. Recent work has revealed moderate alteration of gut microbial communities in subjects with MS and in experimental, induced models. However, a mechanistic understanding linking the observed changes in the m...

Objective The neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD. Methods We used recently developed analytical te...

Conducting a robust experiment is not trivial in microbiome research, and as with any study, experimental methods, environmental factors, and analysis methods can affect results. Standards for data collection and analysis are still emerging in the field, and notably, many of the most fundamental issues that concern microbiome studies arise from sta...