By Scott Richards

PubMed is the number one source for medical and healthcare research. It is hosted at the National Institutes of Health (NIH) and provides bibliographic information including abstracts and links to the full text publisher websites for more than 35 million items. PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. The public database is maintained by the U.S. National Library of Medicine and the National Center for Biotechnology Information. PubMed is both the search platform provided by the National Center for Biotechnology information and the database. PubMed includes MEDLINE (records indexed with MeSH terms) but also material in process, older records from before the inception of MEDLINE, and material from journals not included in MEDLINE. EMBASE (Excerpta Medica Database) is a proprietary research database that also includes PubMed. It can also be accessed by other database providers such as Ovid. The Cochrane Library is best know for its systematic reviews. There are 53 review groups around the world that ensure that the published reviews are of high-quality and evidence based. Articles are updated over time to reflect new research. PubMed Central is the free, open access branch of PubMed. It includes full-text versions for all indexed papers. You might also want to check out its sister site Europe PMC. The National Library of Medicine (NLM) is the world’s largest biomedical library and a national resource for health professionals, scientists, and the public.

PubMed Citations

PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. As of 23 May 2023, PubMed has more than 35 million citations and abstracts dating back to 1966. Additionally, PubMed contains over 30 million citations and abstracts of peer-reviewed biomedical literature.

MEDLINE Journals Books

MEDLINE is a bibliographic database of life sciences and biomedical information, including bibliographic information for articles from academic journals covering medicine, nursing, pharmacy, dentistry, veterinary medicine, and health care. It also covers much of the literature in biology and biochemistry, as well as fields such as molecular evolution. MEDLINE is freely available on the Internet and searchable via PubMed and NLM’s National Center for Biotechnology Information’s Entrez system.

PubMed comprises more than 38 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full text content from PubMed Central and publisher web sites.

National Library of Medicine and NCI

The U.S. National Library of Medicine (NLM) is the world’s largest medical library and a branch of the National Institutes of Health (NIH). It is located in Bethesda, Maryland, and was established to collect and provide access to biomedical and health care materials. The NLM also oversees the National Center for Biotechnology Information (NCBI), which was created in 1988 through legislation sponsored by U.S. Congressman Claude Pepper. The NCBI is an intramural division within the NLM and is responsible for developing information systems for molecular biology, conducting research in computational biology, and creating public databases in biotechnology and biomedicine.

The NCBI houses several major databases, including GenBank for DNA sequences, PubMed for biomedical literature, and the NCBI Epigenomics database. These databases are accessible online through the Entrez search engine. The NCBI also provides bioinformatics tools such as BLAST, which is used for sequence similarity searching, and the Entrez system, which allows for the search and retrieval of data from multiple databases.

The NLM and NCBI work together to provide resources for biomedical research and health information. The NLM’s mission includes improving access to health information through programs like the National Network of Libraries of Medicine (NNLM), while the NCBI focuses on developing computational solutions for life and health science information needs. The NCBI also collaborates with other organizations to coordinate with sequence databases such as those of the European Molecular Biology Laboratory (EMBL) and the DNA Data Bank of Japan (DDBJ).

In addition to its databases and tools, the NLM and NCBI support research and education in biomedical informatics and data science. The NLM’s Intramural Research Program includes the Lister Hill National Center for Biomedical Communications and the NCBI’s Computational Biology Branch. The NCBI also maintains the Bookshelf, a collection of freely accessible biomedical books, and provides access to the PubMed Central (PMC) repository, which offers open access to biomedical and life sciences literature.

The NLM and NCBI continue to evolve, with recent updates to resources such as PubMed Central and the development of new tools for analyzing genomic data. The collaboration between these institutions plays a crucial role in advancing biomedical research and providing essential resources to the scientific community.

GenBank DNA Sequences

GenBank is a comprehensive database that contains publicly available DNA sequences for more than 165,000 named organisms, obtained primarily through submissions from individual laboratories and batch submissions from large-scale sequencing projects. It is part of the International Nucleotide Sequence Database Collaboration (INSDC), which includes the DNA DataBank of Japan (DDBJ) and the European Nucleotide Archive (ENA).

GenBank is accessible through the NCBI’s retrieval system, Entrez, which integrates data from the major DNA and protein sequence databases along with taxonomy, genome, mapping, protein structure and domain information, and the biomedical journal literature via PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases.

In October 2024, GenBank contained 34 trillion base pairs from over 4.7 billion nucleotide sequences and more than 580,000 formally described species. The database started in 1982 and has grown at an exponential rate, doubling roughly every 18 months.

GenBank is built by direct submissions from individual laboratories, as well as from bulk submissions from large-scale sequencing centers. Submissions are made using the web-based BankIt or standalone Sequin programs, and accession numbers are assigned by GenBank staff upon receipt. Daily data exchange with the EMBL Data Library and the DNA Data Bank of Japan helps ensure comprehensive worldwide coverage.

GenBank is accessible through the NCBI’s retrieval system, Entrez, which integrates data from the major DNA and protein sequence databases along with taxonomy, genome, mapping, protein structure and domain information, and the biomedical journal literature via PubMed. Complete bimonthly releases and daily updates of the GenBank database are available by FTP.

The GenBank sequence database is an open access, annotated collection of all publicly available nucleotide sequences and their protein translations. It is produced and maintained by the National Center for Biotechnology Information (NCBI; a part of the National Institutes of Health in the United States) as part of the International Nucleotide Sequence Database Collaboration (INSDC).

International Nucleotide Sequence Database Collaboration

The International Nucleotide Sequence Database Collaboration (INSDC) is a global collaboration of independent governmental or non-profit organizations that manage nucleotide sequence databases, capturing and preserving nucleotide sequence information and annotations to create a comprehensive collection that preserves the scientific record and enables broad sharing of such data. INSDC Members exchange data and make exchanged data freely accessible without restrictive licensing as part of the scientific record, including all corrections and updates.

The mission of INSDC is to support advancements in biomedical and life sciences, public health, research, innovation, discovery, education, capacity building, and bioeconomies by providing services to accept, preserve, and openly disseminate sequence data and metadata that are generated worldwide. INSDC is the premiere open access nucleotide sequence data sharing collaboration in the world, fostering access of nucleotide sequence data from all continents and regions, and providing broad recognition to those who generate and share sequence data.

INSDC is governed by two committees: the Executive Committee and the INSDC Implementation Committee. The Executive Committee establishes the strategic directions of INSDC, directs administrative activities such as organizing meetings and overseeing the INSDC website content, resolves disputes, and sets membership expectations. The INSDC Implementation Committee accepts INSDC-wide policies, protocols, and procedures; prepares for and responds to technology changes; approves modifications for infrastructure requirements, features, and schemas used to build INSDC-participating repositories and their services; trains, assesses, and approves new INSDC Members; and maintains website content and internal documentation.

The INSDC is a collaboration between the following member organizations: the Research Organization of Information and Systems (ROIS), National Institute of Genetics (NIG), the European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute (EBI), and the National Library of Medicine (NLM), National Center for Biotechnology Information (NCBI) at the National Institutes of Health.

INSDC has been the core infrastructure for collecting and providing nucleotide sequence data and metadata for over 30 years. Three partner organizations, the DNA Data Bank of Japan (DDBJ) at the National Institute of Genetics in Mishima, Japan; the European Nucleotide Archive (ENA) at the European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI) in Hinxton, UK; and GenBank at National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health in Bethesda, Maryland, USA have been collaboratively maintaining the INSDC for the benefit of not only science but all types of community worldwide.

The INSDC consists of three partners: the DNA Data Bank of Japan (DDBJ) at the National Institute for Genetics in Mishima, Japan; the European Nucleotide Archive (ENA) at the European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI) in Hinxton, UK; and GenBank at National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health in Bethesda, Maryland, USA.

The INSDC has grown significantly and contains 32 million next-generation sequence runs and 4.76 billion assembled sequences. The members of the International Nucleotide Sequence Database Collaboration (INSDC) have built systems to collect, archive, and disseminate sequence data for more than four decades. The three collaborating organizations, the National Library of Medicine, National Center for Biotechnology Information (NLM-NCBI) in the United States, Research Organization of Information and Systems, National Institute of Genetics (ROIS-NIG) in Japan; and the European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI) formalized their relationship through the adoption of an arrangement which documents their commitment to free and open access to genomic sequences.

EMBL-EBI Overview

The European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI) is a leading center for research and services in bioinformatics, part of the European Molecular Biology Laboratory (EMBL). It is located on the Wellcome Genome Campus in Hinxton, near Cambridge, UK. The EMBL-EBI provides freely available data and bioinformatics services to the scientific community, supporting research in various fields of life sciences.

EMBL-EBI was founded in 1994 and has grown significantly over the years. It employs over 600 full-time equivalent (FTE) staff and offers a wide range of services, including maintaining and indexing biological data in databases such as Ensembl, UniProt, and the Protein Data Bank. The institute also provides training programs to teach scientists the fundamentals of working with biological data and promotes the use of bioinformatic tools.

EMBL-EBI is one of six sites of the European Molecular Biology Laboratory (EMBL), Europe’s only intergovernmental life sciences organisation. It plays a crucial role in the development of science and innovation, as recognized by the European Strategy Forum on Research Infrastructures (ESFRI). The EMBL-EBI’s work is essential for researchers worldwide, enabling them to access publicly available databases of biological data and analytical tools.

The EMBL-EBI has also been involved in significant projects such as the Human and Mouse Genome Projects, the Human Cell Atlas, and the AlphaFold Protein Structure Database. It collaborates with various institutions and participates in international initiatives to ensure the provision of high-quality data and services to the scientific community.

In addition to its research and service activities, EMBL-EBI engages in industry interactions through its Industry Programme, helping companies leverage advances in bioinformatics. The institute also encourages spin-outs with the help of its technology transfer office, EMBLEM.

AlphaFold Protein Structure Database

The AlphaFold Protein Structure Database (AlphaFold DB) is an extensive and open-access resource that archives predicted protein structures generated by Google DeepMind’s AlphaFold AI system. It was developed in partnership with the European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI).

Key features

Massive Coverage: The database contains predictions for over 214 million protein structures, encompassing nearly all known proteins in the UniProt database.
High Accuracy: AlphaFold is recognized for its ability to predict protein structures with high accuracy, as demonstrated in the CASP14 benchmark.
Open Access: The predicted structures and associated data are freely available for both academic and commercial use under a Creative Commons Attribution 4.0 (CC-BY 4.0) license.
Data Availability: Users can access the data through various mechanisms, including bulk downloads via FTP, programmatic access via an API, and interactive visualization on protein-specific web pages.
Integration with Other Resources: AlphaFold DB has been integrated with other major biological data resources such as PDB, UniProt, Ensembl, InterPro, and MobiDB, enhancing its utility for research.
Confidence Metrics: Each predicted structure comes with confidence metrics, including pLDDT scores (per-residue confidence) and Predicted Aligned Errors (PAE), helping users assess the reliability of the predictions.

Accessing and interpreting the data

Users can search for proteins using gene names, protein names, UniProt accession numbers, or organism names through the AlphaFold DB website at https://alphafold.ebi.ac.uk/.
Protein-specific pages provide interactive 3D visualizations of the predicted structures, colored according to pLDDT scores, and interactive 2D plots of PAE values.
pLDDT scores range from 0 to 100, with higher values indicating higher confidence. Low pLDDT scores (below 50) may correspond to intrinsically disordered regions or genuinely poor predictions.
PAE plots visualize the confidence in the relative positions of different parts of the protein model (e.g., domains). Low PAE values indicate high confidence in relative domain positions, while high values suggest unreliable positioning.
Bulk downloads are available for complete proteomes of 48 organisms and for the Swiss-Prot subset of UniProt.

Limitations

Predictions in AlphaFold DB are currently limited to single protein chains, even for proteins that form multimers in nature.
The database does not predict the positions of non-protein components such as ligands, cofactors, metals, ions, or post-translational modifications.
AlphaFold is not validated for predicting the effects of mutations.
While AlphaFold can help identify intrinsically disordered regions, it only provides a single snapshot of their conformations, and these regions can be more accurately represented as conformational ensembles.

The AlphaFold Protein Structure Database represents a significant advance in structural biology, providing unprecedented access to a vast collection of predicted protein structures that can accelerate research in various fields, from understanding fundamental biological processes to drug discovery.

Key aspects of the Human Cell Atlas

Goals: To understand human health, and to diagnose, monitor, and treat diseases more effectively.
Approach: Leveraging cutting-edge technologies like single-cell RNA sequencing and spatial transcriptomics, researchers are building an unprecedented cellular blueprint of the human body. This involves cataloging cell types and subtypes, mapping cell lineages, and understanding how cells interact within tissues and organs.
Impact: The HCA promises to revolutionize medicine by enabling earlier disease detection, precise therapeutic interventions, and personalized health strategies. It is expected to lead to breakthroughs in understanding and treating various conditions, including cancer, COVID-19, cystic fibrosis, and inflammatory bowel disease. The project is also shedding light on organ development, immune function, and the effects of aging on human tissues.
Collaboration: The HCA is a global partnership, involving thousands of scientists from hundreds of institutions across over 100 countries. This collaborative effort includes biological networks focused on specific organs and tissues (e.g., lung, heart, liver, immune system), as well as regional networks across Asia, the Middle East, Africa, and Latin America.
Open Science and Ethics: The HCA emphasizes open data and collaboration, ensuring that research findings and tools are readily accessible to the scientific community worldwide. An Ethics Working Group has been established to address critical ethical considerations, including data privacy, informed consent, and equitable representation of diverse populations in the atlas. The aim is to maximize the benefit of the data while upholding patient rights and respecting diverse ethical and legal frameworks across different countries.
Data Portal: The HCA Data Portal provides a centralized platform for finding, storing, and analyzing community-generated, multi-omic, open data, particularly single-cell transcriptomic data.

The Human Cell Atlas is a massive undertaking, likened in scale to the Human Genome Project, with the potential to transform our understanding of human biology and disease.

The National Library of Medicine (NLM), part of the National Institutes of Health (NIH), is the world’s largest biomedical library. It is a leader in research in biomedical informatics and data science.

The NLM’s mission is to acquire, organize, preserve, and provide free online access to scholarly biomedical literature and data globally. It also supports access to health information across the U.S. and funds research and training in biomedical informatics and data science.

Key NLM resources include PubMed, a database for biomedical literature, and MedlinePlus, a public health information site. The National Center for Biotechnology Information (NCBI) also develops bioinformatics resources for protein structures and domains. NLM offers various grants and programs for training in biomedical informatics and data science.

NLM and the AlphaFold Protein Structure Database

The AlphaFold Protein Structure Database (AlphaFold DB), a collection of predicted protein structures, is a collaboration between EMBL-EBI and Google DeepMind. NLM-affiliated resources help disseminate this data. AlphaFold DB predictions are integrated into resources like PDB and UniProt, accessible through NLM resources. NCBI provides tools for viewing and analyzing protein structures, potentially including those from AlphaFold.

NLM and the Human Cell Atlas

The Human Cell Atlas (HCA) is a global effort to map all human cells. While not led by NLM, this initiative aligns with NLM’s mission of supporting biomedical research and data access. NLM funds research related to the Human BioMolecular Atlas Program (HuBMAP), an NIH initiative contributing to the HCA. NLM’s support for bioinformatics and data science is essential for analyzing datasets generated by projects like the HCA.