Who is using proximity ligation assays, and what for?

Proximity ligation assays — a class of techniques that turn a protein–protein interaction into a fluorescent or sequenceable signal by joining two oligonucleotide-tagged antibodies — were invented in 2002 by Ulf Landegren's group at Uppsala University. Two decades on, the field has spread from a single methods paper into a standard piece of the biology toolkit, used everywhere from cancer signalling to virus diagnostics to in-situ sequencing.

This article looks at who is actually using PLA today, and for what, from 9,765 open-access publications spanning 1995–2026. The corpus is built from 3 keyword searches on Europe PMC's full-text index and deduplicated on PMCID.

The shape of the field

Adoption was slow at first — fewer than 10 PLA papers a year between 2005 and 2009. The technique reached real momentum around 2013 and has been climbing steadily since. Output in 2025 was about 1.7× the volume of 2020. 2025 alone saw 1,343 papers (in this corpus) using the technique. The dashed segment in the chart projects 2026 to roughly match 2025's 1,343 papers — 377 papers in the first 134 days are tracking in line with the volume needed, and several months of PMC indexing lag means the YTD figure is somewhat understated. Output looks set to remain at 2025 levels. PLA is no longer a specialist methodology; it is everywhere.

Who is leading the field

The most-cited authors within the corpus are dominated by methodology veterans, application-area leaders, and biosensor groups. Below are the top researchers ranked by how many times their work is cited by other PLA papers in this corpus — a sharper signal of within-field influence than raw citation counts.

Explore the co-authorship network

Top researchers in the corpus and their co-authorship connections. Each cluster is a lab or collaborating group; edges are weighted by how many papers they share. Search by name in the top-left box.

What people are using PLA for

Mapping the corpus' keywords onto biological themes gives a clear answer to “what for”. Cancer and oncology dominate — about 831 papers sit in this bucket, ranging from breast and colorectal tumour signalling to metastatic-niche characterisation to circulating-tumour-cell assays. Cell biology mechanisms are next: roughly 507 papers use PLA to dissect organelle–organelle contacts, autophagy, ER stress, and mitochondrial quality control. Neurodegeneration — Alzheimer's, Parkinson's, ALS, prion-like spread of α-synuclein — accounts for about 270 papers on its own. Beyond those: signal transduction and post-translational modifications, immunology and inflammation, DNA damage and repair, stem-cell biology, metabolism.

A paper can sit in multiple buckets — a breast-cancer signalling study counts for both Cancer and Signal transduction. The chart below is therefore an intentional overlap, designed for recognition coverage rather than partitioning.

The methods variants

PLA appears under many names. The original “proximity ligation assay” sits alongside the brand name Duolink (Sigma's commercial reagent kit), the in situ spatial variants, and the rolling-circle-amplification (RCA) signal mechanism that powers the readout. Adjacent technologies that share antibody–oligonucleotide chemistry — proximity extension assays (Olink's commercial platform), DNA-PAINT super-resolution, CITE-seq for single-cell — appear when researchers crossover.

Self-tagging in JATS keywords is sparse (only ~38% of papers expose kwd-group), so the chart below is a sample, not a census. Useful for relative shape, not absolute counts. For a step-by-step bench protocol covering the canonical in-situ-PLA workflow, see our PLA protocol guide.

Where they are

PLA-using research is global. US and the United States lead in volume, but the European footprint is striking — Italy, France, Germany, the United Kingdom, Spain, Sweden all have hundreds of researchers each. Sweden punches well above its weight, a quiet legacy of the Karolinska / Uppsala / SciLifeLab lineage that includes both PLA's invention (Landegren) and its evolution into in-situ sequencing (Nilsson, Cartana, ultimately 10x Genomics).

The lineage

Ulf Landegren's lab at Uppsala invented PLA in 2002 (Söderberg et al., Nature Methods, 2006 being the canonical methods paper). Mats Nilsson, also at Uppsala / SciLifeLab, took the rolling-circle signal idea in a different direction — toward in-situ sequencing — and co-founded Cartana, later acquired by 10x Genomics.

Seminal works — entry points for newcomers

The papers most cited by other papers in this corpus. These are the references everyone else points back to — useful starting reads for understanding the modern PLA literature.

Top journals

Where this work tends to appear:

Methodology — what this is and isn't

What this analysis covers. Open-access publications indexed by Europe PMC, retrieved via 3 full-text searches. Papers found by more than one search are deduplicated on PMCID and tagged with every query that retrieved them.

Adjacent-technique filter. 2,461 papers were excluded from the counts above as adjacent-but-not-PLA. The phrase “proximity ligation” is shared between antibody-PLA (Söderberg/Landegren) and DNA-DNA Hi-C / ChIA-PET / chromatin-conformation work — same wording, very different methodology. Hi-C tooling papers also tend to be cited heavily, so leaving them in distorts the seminal list and the citation graph. Papers reachable only via the rolling-circle-amplification query (RCA-only diagnostics that don't use PLA proper) are excluded for the same reason.

What it doesn't cover. Closed-access publications; preprints not indexed by Europe PMC; PLA work in fields not yet swept by our seed keywords (e.g. plant biology, agricultural pathology). Author identity is resolved at the byline level — researchers whose papers don't list a contact in the front matter aren't represented as nodes in the graphs, so connectivity is a subset of the full collaboration network. The “what for” analysis is at topic-cluster level (cancer, neurodegen, etc.) rather than per-paper.