Scientists have reconstructed a previously unknown class of microbial metabolites from Neanderthal dental calculus. They named the compounds paleofurans. The work did not uncover a Neanderthal medicine or prove that anyone consumed these molecules. Instead, it showed that mineralized tooth plaque can preserve enough damaged microbial DNA to rebuild biosynthetic instructions and produce the resulting compounds in a modern laboratory host.
The 2023 Science study analyzed calculus from 12 Neanderthals and 52 anatomically modern humans spanning roughly 100,000 years to the present. From those samples, the team reconstructed 459 bacterial metagenome-assembled genomes (MAGs) and found a biosynthetic gene cluster shared by seven Middle and Upper Paleolithic individuals. Heterologous expression of the reconstructed pathway yielded paleofurans, demonstrating a practical route from archaeological DNA to testable natural products.
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What chemicals were reconstructed from Neanderthal dental calculus?
The named products are paleofurans, a previously unknown class of metabolites associated with a bacterial biosynthetic gene cluster. A biosynthetic gene cluster is a group of genes that work together to make a molecule or family of molecules. In this case, ancient sequence fragments pointed to a cluster that occurred in seven Middle and Upper Paleolithic individuals. Researchers reconstructed the damaged pathway and expressed it in a laboratory organism, which produced paleofurans.
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Fix the driver behind crashes, sound loss and screen glitchesFind Drivers →Clear out junk files and repair common Windows errorsFree Scan →Scan for outdated or missing drivers - takes under a minuteDriver Scan →The important distinction is between sequence-guided reconstruction and archaeological recovery of a finished chemical. No vial of paleofuran was extracted from a Neanderthal tooth. The compounds were made in a contemporary expression system using genetic instructions inferred from ancient DNA. Klapper and colleagues described the result this way: “We identified a biosynthetic gene cluster shared by seven Middle and Upper Paleolithic individuals that allows for the heterologous production of a class of previously unknown metabolites that we name ‘paleofurans.’”
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The available evidence establishes that the pathway encoded by the ancient sequence can direct metabolite production under laboratory conditions. It does not establish the precise role those molecules played in an ancient mouth, whether they benefited or harmed their hosts, or whether Neanderthals ever isolated, ingested, or therapeutically used them.
Why dental calculus preserves microbial DNA for so long
Dental calculus, also called mineralized plaque or tartar, forms when plaque hardens through mineral deposition. The resulting material is unusually durable compared with soft tissue. It can trap bacterial cells, extracellular DNA and chemical traces in a mineral matrix that persists after other biological material has disappeared.
That durability makes calculus a long-term record of oral microbial communities. A foundational Nature study reported evidence of an approximately 48,000-year-old Methanobrevibacter oralis genome in Neanderthal calculus. Its authors described DNA in calculus as a source of information about ancient hominin behavior and health and as a system for studying long-term microbial evolution.
Preservation is not perfect. Ancient DNA is generally short, chemically damaged and mixed with DNA from many organisms. Mineralized plaque can also acquire environmental or modern contamination during burial, excavation, handling and laboratory processing. Consequently, a sequence recovered from calculus is evidence that must be authenticated, assembled and interpreted with controls; it is not automatically an intact snapshot of a living ancient cell.
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How the paleofuran reconstruction worked
The workflow links archaeological sampling, metagenomics, computational assembly and synthetic biology. Each stage solves a different problem created by fragmented ancient DNA.
- Sample mineralized plaque. Researchers collected dental calculus from Neanderthals and anatomically modern humans covering about 100,000 years of human history. The study included 12 Neanderthals and 52 modern humans.
- Sequence DNA fragments. DNA extracted from the calculus was read as many short fragments. The reads contained a mixture of host, bacterial and other microbial DNA, along with any contaminants that survived processing.
- Assemble contigs. Overlapping reads were joined computationally into longer contiguous sequences, or contigs. Ancient damage and low coverage make this step harder than assembling DNA from a fresh isolate.
- Bin contigs into MAGs. Contigs with compatible sequence composition and coverage were grouped into metagenome-assembled genomes. The 2023 study reconstructed 459 bacterial MAGs, providing genome-scale context for the organisms represented in the calculus.
- Search for biosynthetic gene clusters. The assembled genomes were screened for linked genes that could encode enzymes for making specialized metabolites. These clusters are more informative than isolated genes because their arrangement can reveal a complete biochemical route.
- Repair or reconstruct damaged pathways. Where ancient sequences were incomplete or chemically altered, the investigators used the available evidence to infer workable pathway sequences. The reconstruction had to preserve the enzyme functions needed to test production while remaining grounded in the ancient sequence data.
- Express the pathway in a laboratory host. Selected genes were placed in a modern heterologous expression system. The host supplied the cellular machinery needed to transcribe and translate the pathway, allowing researchers to detect the resulting metabolites.
- Characterize the products. Chemical analysis of the expression products established that the pathway generated a previously unknown metabolite class, named paleofurans.
This approach turns an archaeological DNA archive into a natural-product-discovery system. It does not require recovering a living ancient microbe, which is usually impossible, and it avoids assuming that a damaged environmental genome can be cultured directly.
What the 2023 study actually sampled
| Study element | Reported value | What it means |
|---|---|---|
| Neanderthal calculus samples | 12 individuals | Provides an ancient hominin sample set for microbial genome reconstruction. |
| Anatomically modern human samples | 52 individuals | Adds comparative oral microbiome material across the same broad historical span. |
| Time span | About 100,000 years to the present | Places the microbial sequences in a deep evolutionary and archaeological context. |
| Bacterial MAGs | 459 | Represents genome-level reconstructions assembled from mixed calculus DNA. |
| Individuals sharing the paleofuran-associated cluster | Seven Middle and Upper Paleolithic individuals | Shows that the cluster was detected in multiple ancient individuals rather than a single sample. |
| Metabolite class | Paleofurans | A previously unknown class produced by heterologous expression of the reconstructed pathway. |
“Shared by seven individuals” describes a sequence-level observation. It does not mean all seven people had the same health condition, consumed the same plant or medicine, or produced identical quantities of the compounds. The study does not provide a clinical efficacy measurement for paleofurans.
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1Scan for outdated or missing drivers - takes under a minute2Clear out junk files and repair common Windows errors3Fix the driver behind crashes, sound loss and screen glitchesWhy a biosynthetic gene cluster matters more than a single gene
Microbes make many specialized chemicals through coordinated enzyme pathways. A single enzyme-like sequence can suggest a biochemical capability, but it rarely proves what final molecule was made. A cluster containing several neighboring genes provides stronger evidence because the genes may encode precursor formation, chemical modification, tailoring reactions and transport or regulation.
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Ancient assemblies are often incomplete, so researchers must distinguish a plausible pathway from a fully observed one. In the paleofuran work, the decisive test was functional: a reconstructed cluster was expressed in a laboratory host and yielded detectable products. That experiment supports the conclusion that the sequence information retained enough instruction to make metabolites, even though the ancient DNA itself was fragmented.
Functional expression also narrows the interpretation. It shows what the reconstructed genes can do in the chosen host under laboratory conditions. It does not recreate the exact chemistry of a Neanderthal mouth, where nutrient availability, neighboring microbes, temperature, immune factors and gene regulation would have differed.
Paleofurans versus the later actifensin findings
A 2025 Journal of the American Chemical Society study extended the same broad idea—using ancient and modern oral biofilms to find biologically active molecules—but it investigated a different product class. The study reported Actinomyces-derived defensin-like peptides called actifensins. Evolutionary analyses, structural modeling and experimental validation indicated that these peptides retained antimicrobial activity.
| Comparison axis | Paleofurans | Actifensins |
|---|---|---|
| Source material | Ancient dental calculus, including Neanderthal samples | Ancient and modern dental biofilms, including Neanderthal material |
| Publication | Klapper and colleagues, Science, 2023 | Journal of the American Chemical Society, 2025 |
| Computational approach | Metagenomic assembly, bacterial MAG reconstruction and biosynthetic-cluster identification | Metagenomics combined with structural modeling and evolutionary analysis |
| Product type | Previously unknown metabolite class | Actinomyces-derived defensin-like peptides |
| Functional test | Reconstructed pathway expressed heterologously to produce metabolites | Experimental validation reported maintained antimicrobial activity |
| What the result supports | Ancient oral DNA can encode reconstructable chemistry | Ancient oral-biofilm sequences can inform peptide and antimicrobial discovery |
These findings should not be merged into one claim. Paleofurans are the products of the 2023 reconstructed pathway; actifensins are a separate 2025 discovery with a different molecular class and validation path. Neither result demonstrates that Neanderthals used a compound as a medicine.
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Did Neanderthals use paleofurans as medicine?
There is no evidence that they did. The study found genetic instructions and then used a modern laboratory system to produce metabolites. It did not recover a prepared remedy, identify intentional dosing, demonstrate ingestion or show therapeutic effects in a Neanderthal.
Even if paleofurans eventually prove biologically active, activity alone would not establish ancient medical use. A molecule can be made by a resident oral bacterium without being noticed by its host. It might participate in microbial competition, alter neighboring organisms, protect a biofilm or have no meaningful effect on human cells. Establishing deliberate use would require independent archaeological, chemical and behavioral evidence beyond a biosynthetic sequence.
Independent reader supportYour contribution helps us test, update, and keep practical guides available for everyone.Could fossil microbes yield new drugs?
They could supply starting points, but discovery is only the first stage. Ancient-calculus sequences expand the chemical search space beyond compounds found in organisms that are easy to culture today. A pathway that disappeared from modern microbial communities may still be represented by fragments preserved in mineralized plaque.
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- A reproducible sequence-supported pathway rather than an isolated damaged read.
- Successful expression that produces a defined molecule or coherent family of molecules.
- Structural characterization sufficient to distinguish the product from known compounds.
- Evidence of a useful biological activity, such as selective antimicrobial action, in controlled assays.
- A route to scalable production and purification that does not depend on irreplaceable archaeological material.
- Safety, stability, selectivity and exposure data appropriate to the intended use.
What must happen after reconstruction
- Confirm the ancient sequence and rule out modern or environmental contamination.
- Repeat expression and chemical analysis to establish that production is reproducible.
- Determine molecular structures and identify pathway variants among individuals or time periods.
- Test activity against relevant organisms or targets while measuring toxicity to human cells.
- Optimize the pathway in a production host if yields are low or intermediates accumulate.
- Evaluate pharmacology, stability, resistance potential and manufacturing feasibility before any clinical claim.
Paleofurans have reached the pathway-expression and metabolite-discovery stage described above. The available account does not report a clinical efficacy number, approved use or therapeutic trial for them.
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Technical limits readers should keep in mind
Fragmentation and chemical damage
Ancient DNA breaks into short pieces and accumulates modifications over time. Short reads can leave gaps in genes, confuse closely related organisms and make it difficult to determine whether a pathway is complete. Reconstruction therefore involves uncertainty that must be tracked rather than hidden.
Contamination control
Modern human DNA, laboratory microbes and burial-environment organisms can enter a calculus sample. Ancient-DNA studies use clean handling, extraction controls, damage patterns, coverage patterns and comparative analyses to separate authentic ancient signal from contamination. A sequence that appears only once or lacks the expected damage and contextual support deserves particular caution.
Sequence similarity is not proof of function
A gene that resembles a known resistance determinant or biosynthetic enzyme may not retain the complete sequence, expression control or cellular context required for activity. The same caution applies to ancient antimicrobial-resistance claims: detecting a resistance-like sequence is not equivalent to proving that an intact, functional ancient resistance phenotype existed.
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Laboratory expression is a model
Heterologous production proves that a reconstructed pathway can work in the chosen host. It does not reproduce ancient ecology. The host may supply cofactors or regulation absent from the original organism, or fail to supply conditions that once changed the product profile. Results should therefore be described as laboratory production guided by ancient sequence evidence.
Why this changes the study of ancient microbes
Traditional paleomicrobiology often focuses on identifying organisms, reconstructing genomes or tracing disease. Biosynthetic reconstruction adds a chemical dimension: it asks what molecules ancient microbial communities were genetically equipped to make. Dental calculus is especially valuable because it records a structured biofilm and mineralizes around the time it forms, preserving a microbial archive that can outlast soft tissues.
The 459 bacterial MAGs from the 2023 study provide a resource for looking beyond one metabolite class. Other clusters may encode molecules that influence microbial competition, host interaction or environmental adaptation. Comparative sampling across Neanderthals and modern humans can also reveal which pathways persisted, disappeared or moved between microbial lineages.
The broader lesson is carefully bounded but significant: an archaeological specimen does not need to contain an intact ancient organism for its molecular information to remain experimentally useful. When authentication, assembly and functional testing are combined, mineralized plaque can connect deep microbial evolution with modern natural-product chemistry.
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Quick Recap
Key takeaways
- Paleofurans are a previously unknown metabolite class produced by expressing a biosynthetic gene cluster reconstructed from ancient dental-calculus DNA.
- The 2023 study examined 12 Neanderthals and 52 anatomically modern humans spanning about 100,000 years to the present and reconstructed 459 bacterial MAGs.
- The paleofuran-associated cluster was found in seven Middle and Upper Paleolithic individuals.
- The finding does not prove Neanderthals made, isolated, consumed or medically used paleofurans.
- A 2025 study reported distinct Actinomyces-derived actifensin peptides with maintained antimicrobial activity; that work should not be treated as additional evidence that paleofurans were medicines.
- Ancient oral biofilms can guide natural-product discovery, but contamination, DNA damage, incomplete assemblies and the limits of laboratory expression require cautious interpretation.
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