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Deep Learning (DL) has recently enabled unprecedented advances in one of the grand challenges in computational biology: the half-century-old problem of protein structure prediction. In this paper we discuss recent advances, limitations, and future perspectives of DL on five broad areas: protein structure prediction, protein function prediction, genome engineering, systems biology and data integration, and phylogenetic inference. We discuss each application area and cover the main bottlenecks of DL approaches, such as training data, problem scope, and the ability to leverage existing DL architectures in new contexts. To conclude, we provide a summary of the subject-specific and general challenges for DL across the biosciences. Deep learning has enabled advances in understanding biology. In this review, the authors outline advances, and limitations of deep learning in five broad areas and the future challenges for the biosciences.

The development of decision support systems for pathology and their deployment in clinical practice have been hindered by the need for large manually annotated datasets. To overcome this problem, we present a multiple instance learning-based deep learning system that uses only the reported diagnoses as labels for training, thereby avoiding expensive and time-consuming pixel-wise manual annotations. We evaluated this framework at scale on a dataset of 44,732 whole slide images from 15,187 patients without any form of data curation. Tests on prostate cancer, basal cell carcinoma and breast cancer metastases to axillary lymph nodes resulted in areas under the curve above 0.98 for all cancer types. Its clinical application would allow pathologists to exclude 65–75% of slides while retaining 100% sensitivity. Our results show that this system has the ability to train accurate classification models at unprecedented scale, laying the foundation for the deployment of computational decision support systems in clinical practice. A deep learning model trained on real-world digital pathology data achieves clinical performance in cancer diagnosis.

RNA sequencing (RNA-seq) is the leading technology for genome-wide transcript quantification. However, publicly available RNA-seq data is currently provided mostly in raw form, a significant barrier for global and integrative retrospective analyses. ARCHS4 is a web resource that makes the majority of published RNA-seq data from human and mouse available at the gene and transcript levels. For developing ARCHS4, available FASTQ files from RNA-seq experiments from the Gene Expression Omnibus (GEO) were aligned using a cloud-based infrastructure. In total 187,946 samples are accessible through ARCHS4 with 103,083 mouse and 84,863 human. Additionally, the ARCHS4 web interface provides intuitive exploration of the processed data through querying tools, interactive visualization, and gene pages that provide average expression across cell lines and tissues, top co-expressed genes for each gene, and predicted biological functions and protein–protein interactions for each gene based on prior knowledge combined with co-expression. Publicly available RNA-seq data is provided mostly in raw form, resulting in a barrier for integrative analyses. Here, Lachmann et al. develop a high-throughput processing infrastructure and search database (ARCHS4) that provides processed RNA-seq data for 187,946 publicly available mouse and human samples to support exploration and reuse.

Computational methods for analyzing single-cell data are uncovering new ways of defining cells. Single-cell genomics has now made it possible to create a comprehensive atlas of human cells. At the same time, it has reopened definitions of a cell's identity and of the ways in which identity is regulated by the cell's molecular circuitry. Emerging computational analysis methods, especially in single-cell RNA sequencing (scRNA-seq), have already begun to reveal, in a data-driven way, the diverse simultaneous facets of a cell's identity, from discrete cell types to continuous dynamic transitions and spatial locations. These developments will eventually allow a cell to be represented as a superposition of 'basis vectors', each determining a different (but possibly dependent) aspect of cellular organization and function. However, computational methods must also overcome considerable challenges—from handling technical noise and data scale to forming new abstractions of biology. As the scale of single-cell experiments continues to increase, new computational approaches will be essential for constructing and characterizing a reference map of cell identities.

Spatial transcriptomics enables the simultaneous measurement of morphological features and transcriptional profiles of the same cells or regions in tissues. Here we present multi-modal structured embedding (MUSE), an approach to characterize cells and tissue regions by integrating morphological and spatially resolved transcriptional data. We demonstrate that MUSE can discover tissue subpopulations missed by either modality as well as compensate for modality-specific noise. We apply MUSE to diverse datasets containing spatial transcriptomics (seqFISH+, STARmap or Visium) and imaging (hematoxylin and eosin or fluorescence microscopy) modalities. MUSE identified biologically meaningful tissue subpopulations and stereotyped spatial patterning in healthy brain cortex and intestinal tissues. In diseased tissues, MUSE revealed gene biomarkers for proximity to tumor region and heterogeneity of amyloid precursor protein processing across Alzheimer brain regions. MUSE enables the integration of multi-modal data to provide insights into the states, functions and organization of cells in complex biological tissues. Deep learning analysis of microscopy and spatial transcriptomics data characterizes cell types and states.

Breast cancer (BC) is spreading more and more every day. Therefore, a patient's life can be saved by its early discovery. Mammography is frequently used to diagnose BC. The classification of mammography region of interest (ROI) patches (i.e., normal, malignant, or benign) is the most crucial phase in this process since it helps medical professionals to identify BC. In this paper, a hybrid technique that carries out a quick and precise classification that is appropriate for the BC diagnosis system is proposed and tested. Three different Deep Learning (DL) Convolution Neural Network (CNN) models—namely, Inception-V3, ResNet50, and AlexNet—are used in the current study as feature extractors. To extract useful features from each CNN model, our suggested method uses the Term Variance (TV) feature selection algorithm. The TV-selected features from each CNN model are combined and a further selection is performed to obtain the most useful features which are sent later to the multiclass support vector machine (MSVM) classifier. The Mammographic Image Analysis Society (MIAS) image database was used to test the effectiveness of the suggested method for classification. The mammogram's ROI is retrieved, and image patches are assigned to it. Based on the results of testing several TV feature subsets, the 600-feature subset with the highest classification performance was discovered. Higher classification accuracy (CA) is attained when compared to previously published work. The average CA for 70% of training is 97.81%, for 80% of training, it is 98%, and for 90% of training, it reaches its optimal value. Finally, the ablation analysis is performed to emphasize the role of the proposed network’s key parameters.

Multiplexed RNA sequencing in individual cells is transforming basic and clinical life sciences 1 – 4 . Often, however, tissues must first be dissociated, and crucial information about spatial relationships and communication between cells is thus lost. Existing approaches to reconstruct tissues assign spatial positions to each cell, independently of other cells, by using spatial patterns of expression of marker genes 5 , 6 —which often do not exist. Here we reconstruct spatial positions with little or no prior knowledge, by searching for spatial arrangements of sequenced cells in which nearby cells have transcriptional profiles that are often (but not always) more similar than cells that are farther apart. We formulate this task as a generalized optimal-transport problem for probabilistic embedding and derive an efficient iterative algorithm to solve it. We reconstruct the spatial expression of genes in mammalian liver and intestinal epithelium, fly and zebrafish embryos, sections from the mammalian cerebellum and whole kidney, and use the reconstructed tissues to identify genes that are spatially informative. Thus, we identify an organization principle for the spatial expression of genes in animal tissues, which can be exploited to infer meaningful probabilities of spatial position for individual cells. Our framework (‘novoSpaRc’) can incorporate prior spatial information and is compatible with any single-cell technology. Additional principles that underlie the cartography of gene expression can be tested using our approach. A new computational framework, novoSpaRc, leverages single-cell data to reconstruct spatial context for cells and spatial expression across tissues and organisms, on the basis of an organization principle for gene expression.

Cells interact with their environment, communicate among themselves, track time and make decisions through functions controlled by natural regulatory genetic circuits consisting of interacting biological components. Synthetic programmable circuits used in therapeutics and other applications can be automatically designed by computer-aided tools. The Cello software designs the DNA sequences for programmable circuits based on a high-level software description and a library of characterized DNA parts representing Boolean logic gates. This process allows for design specification reuse, modular DNA part library curation and formalized circuit transformations based on experimental data. This protocol describes Cello 2.0, a freely available cross-platform software written in Java. Cello 2.0 enables flexible descriptions of the logic gates’ structure and their mathematical models representing dynamic behavior, new formal rules for describing the placement of gates in a genome, a new graphical user interface, support for Verilog 2005 syntax and a connection to the SynBioHub parts repository software environment. Collectively, these features expand Cello’s capabilities beyond Escherichia coli plasmids to new organisms and broader genetic contexts, including the genome. Designing circuits with Cello 2.0 produces an abstract Boolean network from a Verilog file, assigns biological parts to each node in the Boolean network, constructs a DNA sequence and generates highly structured and annotated sequence representations suitable for downstream processing and fabrication, respectively. The result is a sequence implementing the specified Boolean function in the organism and predictions of circuit performance. Depending on the size of the design space and users’ expertise, jobs may take minutes or hours to complete. This protocol describes how to design genetic circuits using the web implementation of the Cello 2.0 software, which allows users to construct a DNA sequence for a genetic circuit composed of defined elements and predicts the circuit’s performance in new organisms and genetic contexts.

In common with other omics technologies, mass spectrometry (MS)-based proteomics produces ever-increasing amounts of raw data, making efficient analysis a principal challenge. A plethora of different computational tools can process the MS data to derive peptide and protein identification and quantification. However, during the last years there has been dramatic progress in computer science, including collaboration tools that have transformed research and industry. To leverage these advances, we develop AlphaPept, a Python-based open-source framework for efficient processing of large high-resolution MS data sets. Numba for just-in-time compilation on CPU and GPU achieves hundred-fold speed improvements. AlphaPept uses the Python scientific stack of highly optimized packages, reducing the code base to domain-specific tasks while accessing the latest advances. We provide an easy on-ramp for community contributions through the concept of literate programming, implemented in Jupyter Notebooks. Large datasets can rapidly be processed as shown by the analysis of hundreds of proteomes in minutes per file, many-fold faster than acquisition. AlphaPept can be used to build automated processing pipelines with web-serving functionality and compatibility with downstream analysis tools. It provides easy access via one-click installation, a modular Python library for advanced users, and via an open GitHub repository for developers. Mass spectrometry-based proteomics faces the challenge of processing vast data amounts. Here, the authors introduce AlphaPept, an open-source, Python-based framework that offers high speed analysis and easy integration for large-scale proteome analysis.

DNA is a promising candidate for long-term data storage due to its high density and endurance. The key challenge in DNA storage today is the cost of synthesis. In this work, we propose composite motifs , a framework that uses a mixture of prefabricated motifs as building blocks to reduce synthesis cost by scaling logical density. To write data, we introduce Bridge Oligonucleotide Assembly, an enzymatic ligation technique for synthesizing oligos based on composite motifs. To sequence data, we introduce Direct Oligonucleotide Sequencing, a nanopore-based technique to sequence short oligos, eliminating common preparatory steps like DNA assembly, amplification and end-prep. To decode data, we introduce Motif-Search, a novel consensus caller that provides accurate reconstruction despite synthesis and sequencing errors. Using the proposed methods, we present an end-to-end experiment where we store the text “HelloWorld” at a logical density of 84 bits/cycle (14–42× improvement over state-of-the-art).