Biomedical subjects

Fabian J Theis

Publications and source records attributed to Fabian J Theis.

6 recordsLinked to original sources

PubMed2026

Creating bottom-up RNA transfer vehicles from synthetic protein assemblies.

Evolution guides biological systems to populate ecological niches, with viruses among the most successful examples of this principle. Viruses evolved over billions of years to efficiently transfer genetic information. Although viruses are highly diverse, most have converged towards remarkable similarity in the size and shape of their capsids1,2. By contrast, generative models for protein design enable the creation of protein architectures that are absent from nature3-5. Here we investigate whether protein assemblies designed by artificial intelligence can be functionalized to construct nucleic acid transport vehicles that are independent of evolutionary trajectories. By combining natural protein domains with synthetic protein assemblies, we create more than 100 bottom-up RNA transfer vehicles with unique sizes and shapes. These vehicles surpass the RNA transfer efficiency of widely used delivery vehicles by several orders of magnitude. In addition, we demonstrate that their tropism can be programmed by incorporation of computationally designed peptide binders and use them to deliver therapeutically relevant cargo RNAs into a wide range of cellular models. We show the in vivo biodistribution of one of these vehicles in a mouse at near-single-cell resolution, confirm its safety, and use it to perform a gene-editing treatment strategy for Duchenne muscular dystrophy in patient-derived cells and a pig. Our work demonstrates how proteins created by generative artificial intelligence can be harnessed for the rational engineering of RNA transport systems with the desired properties by overcoming the limitations of natural protein diversity.

Journal Article↗

PubMed2026

Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer's disease.

Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer's disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a disease-associated microglial subtype, characterized by elevated GPNMB expression and enriched for polygenic AD risk, expands with AD pathology and shows increased phagocytic activity. We identify MITF as an upstream regulator required to maintain this microglial state. Cell-cell interaction analyses prioritize APOE-SORL1 and APOE-TREM2 signaling pairs associated with disease progression. Using human and mouse models, we demonstrate that the neuroprotective effects of this microglial subtype depend on TREM2. These findings provide mechanistic insights into myeloid cell function in aging and AD, aiding therapeutic discovery.

Humans↗

PubMed2025

scooby: Modeling multi-modal genomic profiles from DNA sequence at single-cell resolution.

Understanding how regulatory DNA elements shape gene expression across individual cells is a fundamental challenge in genomics. Joint RNA-seq and epigenomic profiling provides opportunities to build unifying models of gene regulation capturing sequence determinants across steps of gene expression. However, current models, developed primarily for bulk omics data, fail to capture the cellular heterogeneity and dynamic processes revealed by single-cell multi-modal technologies. Here, we introduce scooby, the first framework to model scRNA-seq coverage and scATAC-seq insertion profiles along the genome from sequence at single-cell resolution. For this, we leverage the pre-trained multi-omics profile predictor Borzoi as a foundation model, equip it with a cell-specific decoder, and fine-tune its sequence embeddings. Specifically, we condition the decoder on the cell position in a precomputed single-cell embedding resulting in strong generalization capability. Applied to a hematopoiesis dataset, scooby recapitulates cell-specific expression levels of held-out genes, and identifies regulators and their putative target genes through in silico motif deletion. Moreover, accurate variant effect prediction with scooby allows for breaking down bulk eQTL effects into single-cell effects and delineating their impact on chromatin accessibility and gene expression. We anticipate scooby to aid unraveling the complexities of gene regulation at the resolution of individual cells.

Journal Article↗

PubMed2024

Plasticity of Human Microglia and Brain Perivascular Macrophages in Aging and Alzheimer's Disease.

The complex roles of myeloid cells, including microglia and perivascular macrophages, are central to the neurobiology of Alzheimer's disease (AD), yet they remain incompletely understood. Here, we profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 unique donors covering the human lifespan and varying degrees of AD neuropathology. We delineated 13 transcriptionally distinct myeloid subtypes organized into 6 subclasses and identified AD-associated adaptive changes in myeloid cells over aging and disease progression. The GPNMB subtype, linked to phagocytosis, increased significantly with AD burden and correlated with polygenic AD risk scores. By organizing AD-risk genes into a regulatory hierarchy, we identified and validated MITF as an upstream transcriptional activator of GPNMB, critical for maintaining phagocytosis. Through cell-to-cell interaction networks, we prioritized APOE-SORL1 and APOE-TREM2 ligand-receptor pairs, associated with AD progression. In both human and mouse models, TREM2 deficiency disrupted GPNMB expansion and reduced phagocytic function, suggesting that GPNMB's role in neuroprotection was TREM2-dependent. Our findings clarify myeloid subtypes implicated in aging and AD, advancing the mechanistic understanding of their role in AD and aiding therapeutic discovery.

Journal Article↗

PubMed2004

A new concept for separability problems in blind source separation.

The goal of blind source separation (BSS) lies in recovering the original independent sources of a mixed random vector without knowing the mixing structure. A key ingredient for performing BSS successfully is to know the indeterminacies of the problem-that is, to know how the separating model relates to the original mixing model (separability). For linear BSS, Comon (1994) showed using the Darmois-Skitovitch theorem that the linear mixing matrix can be found except for permutation and scaling. In this work, a much simpler, direct proof for linear separability is given. The idea is based on the fact that a random vector is independent if and only if the Hessian of its logarithmic density (resp. characteristic function) is diagonal everywhere. This property is then exploited to propose a new algorithm for performing BSS. Furthermore, first ideas of how to generalize separability results based on Hessian diagonalization to more complicated nonlinear models are studied in the setting of postnonlinear BSS.

Algorithms↗

PubMed2003

Linear geometric ICA: fundamentals and algorithms.

Geometric algorithms for linear independent component analysis (ICA) have recently received some attention due to their pictorial description and their relative ease of implementation. The geometric approach to ICA was proposed first by Puntonet and Prieto (1995). We will reconsider geometric ICA in a theoretic framework showing that fixed points of geometric ICA fulfill a geometric convergence condition (GCC), which the mixed images of the unit vectors satisfy too. This leads to a conjecture claiming that in the nongaussian unimodal symmetric case, there is only one stable fixed point, implying the uniqueness of geometric ICA after convergence. Guided by the principles of ordinary geometric ICA, we then present a new approach to linear geometric ICA based on histograms observing a considerable improvement in separation quality of different distributions and a sizable reduction in computational cost, by a factor of 100, compared to the ordinary geometric approach. Furthermore, we explore the accuracy of the algorithm depending on the number of samples and the choice of the mixing matrix, and compare geometric algorithms with classical ICA algorithms, namely, Extended Infomax and FastICA. Finally, we discuss the problem of high-dimensional data sets within the realm of geometrical ICA algorithms.

Algorithms↗