The review, led by Emma U. Hammarlund of Lund University together with Per Malmberg, Julhash U. Kazi, Nicole R. Posth and Kenneth J. Pienta of Johns Hopkins, traces the intellectual journey of stable isotope science from its origins in early twentieth-century physics to its potential future at the bedside. The central claim is bold but carefully argued: the same fractionation principles that allow geologists to reconstruct ancient climates from seashells could allow clinicians to read altered physiology directly from blood, urine, and tumor tissue, without administering any labelled substance at all.

The story begins with puzzling discrepancies in atomic weights noticed by chemists in the late nineteenth century. Ernest Rutherford and Frederick Soddy showed in a burst of papers between 1902 and 1903 that radioactive atoms transform into new forms of matter and eventually into stable atoms. Soddy went further, concluding that chemical identity depends on nuclear charge rather than atomic weight, and in a short 1913 letter to Nature he introduced the term isotope, meaning same place, a word suggested to him by Dr. Margaret Todd. That same year, J. J. Thomson recorded faint traces of a mass-22 neon isotope on a photographic plate, and in 1914 Stefanie Horovitz, working at the Radium Institute in Vienna, used painstaking gravimetric analyses to confirm Soddy’s prediction that lead derived from uranium was slightly lighter than ordinary lead. Francis William Aston’s mass spectrograph, which earned him the 1922 Nobel Prize, then revealed that many elements are mixtures of isotopes, laying the groundwork for isotope analysis with steadily increasing precision.

Human physiology was the first field to put stable isotopes to work. In the 1930s, Rudolf Schoenheimer and David Rittenberg used newly described heavy isotopes of hydrogen and water to trace metabolism in rats and mice, detecting the labels through simple density measurements before mass spectrometers were even widely available. Their work revealed that the body’s fats and proteins are in a continuous dynamic state of synthesis and breakdown, and it established isotope tracer biochemistry in medicine, a paradigm that still dominates clinical applications today in fields from gastroenterology to metabolic research.

The deeper power of isotopes emerged once scientists understood that physical and biological processes fractionate them in predictable ways. In the late 1940s, Harold Urey showed that small mass differences alter bond vibrational energies, causing heavier isotopes to concentrate in the phases where they are most strongly bound. Because this equilibrium fractionation is temperature dependent, Urey proposed that oxygen isotopes in calcium carbonate shells could reconstruct past temperatures, the first paleothermometer. In parallel, Jacob Bigeleisen formulated the quantitative theory of kinetic isotope effects, showing that lighter isotopes react faster, diffuse more easily, and can be preferentially removed in one-directional processes. Together, these two frameworks turned isotope ratios into narratives of source, transformation, and constraint.

What made the method truly robust, the authors emphasize, was not just instrumentation but a globally shared reference system. Absolute isotope ratios are notoriously hard to measure accurately, so the community built common scales anchored in standards such as PDB for carbon, Standard Mean Ocean Water for water isotopes, and Canyon Diablo Troilite for sulfur. From the 1960s onward, the International Atomic Energy Agency, NIST, and the US Geological Survey established replacement standards and distributed them worldwide, and laboratories adopted two-point or multipoint normalization to correct for instrument bias. Few analytical methods achieve this degree of comparability across laboratories and decades, with pH and temperature among the closest parallels. It is this ecosystem of shared references that allowed isotope data to travel, and it is precisely what medicine has only partly adopted.

The applications across the natural sciences illustrate the principle. Rare sulfur isotopes in sedimentary rock record the rise of Earth’s ozone layer, because ultraviolet-driven photolysis produced a mass-independent signature that vanished once the ozone shield formed. Carbon isotopes connect biological carbon fixation to the sedimentary record and distinguish C3 from C4 plant consumption in diets. In biology, archaeology, and forensics, isotope ratios in feathers, bones, and hair reveal provenance and movement: hydrogen isotopes in feathers link migratory birds to their breeding regions, strontium and oxygen isotopes trace prehistoric human migration, and hydrogen and oxygen in scalp hair reflect local drinking water averaged over weeks to months, mapped through geographic isoscapes. In epidemiology, carbon, nitrogen, and sulfur isotopes can distinguish food sources and dietary patterns more objectively than self-report, and lead isotopes can identify whether exposure came from paint or pipes.

Medicine, the authors argue, is not an outlier to this story but its next logical step. The clinical use of stable isotopes has largely remained within the tracer paradigm, from the 13C-urea breath test, in which urease-positive Helicobacter pylori hydrolyses labelled urea to release detectable 13CO2 in exhaled breath, to 13C-labelled substrates tracing metabolic flux through glycolysis and the TCA cycle, and hyperpolarized 13C-MRI and deuterium metabolic imaging mapping tumor metabolism without radiation burden. But fractionation related to disease offers something tracers cannot: a read-out of altered physiology without any administered label. Although isotope effects are small at the level of individual reactions, they accumulate across metabolic networks and become detectable in metabolites, tissues, and excreted products.

The clinical examples already span several isotope systems and tumor types. Serum calcium isotope fractionation tracks bone mineral balance: bone mineralization preferentially incorporates the lighter calcium isotope into the crystal lattice, leaving blood enriched in the heavier isotope, so when osteolytic resorption exceeds formation in active multiple myeloma, isotopically light calcium is released back into circulation. Serum values are accordingly lower in patients with active myeloma, around minus 0.75 per mille versus minus 0.66 per mille in remission, tracking disease activity earlier than bone-density imaging. In hepatocellular carcinoma, blood copper and sulfur isotope compositions differ from controls, and laser-ablation multicollector ICP-MS can now map copper isotope variation across tumor regions. Breast tumors are enriched in light zinc isotopes, with metallothionein-linked zinc sequestration proposed as a mechanism, and bladder cancer studies combining plasma copper isotope composition with machine learning have achieved high classification performance. These signals are modest, typically a few tenths of a per mille, but they exceed the roughly 0.05 to 0.1 per mille precision of some mass spectrometry instruments, and their magnitude is comparable to fractionation within the human body itself.

The challenges are real, and the review does not shy away from them. Natural-abundance isotope ratios integrate diet, geography, age, sex, renal and hepatic function, inflammation, medications, and microbiome composition, so clinical claims will require matched disease controls, longitudinal sampling, paired concentration measurements, and explicit metadata capture. Operational barriers include instrument cost, acid digestion, chromatographic isolation of analytes, and limited throughput. Nor are isotope ratios likely to replace circulating tumor DNA, methylation assays, or conventional metabolomics as stand-alone screens; their more realistic niche is mechanism-linked adjunct information integrated with multiomics and machine learning. Yet the authors see the balance shifting. High-throughput workflows, from LC/GC-IRMS to ICP-MS and Orbitrap-based isotopologue analysis, may not need the maximal precision of geochemistry if predictive performance comes from multidimensional isotope features fused with clinical and genomic data. Combined with exposomics and whole genome sequencing, they suggest, isotope signals could even seed a new field of carcinogenomics linking genetic susceptibility to environmental exposure. If medicine learns to read isotopes the way Earth scientists do, a blood sample may one day report not just what is present, but which processes are shifting in disease.

Subject of Research: Stable isotope fractionation as mechanistic biomarkers in medical oncology

Article Title: Stable isotopes from Earth science to bedside medicine: beyond tracers and toward mechanistic biomarkers in medical oncology

Article References: Hammarlund, E. U., Malmberg, P., Kazi, J. U., Posth, N. R., & Pienta, K. J. (2026). Stable isotopes from Earth science to bedside medicine: beyond tracers and toward mechanistic biomarkers in medical oncology. Medical Oncology, 43(11), Article 332. https://doi.org/10.1007/s12032-026-03436-x

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03436-x

Keywords: stable isotopes, isotope fractionation, mechanistic biomarkers, medical oncology, mass spectrometry, cancer detection, multiple myeloma, calcium isotopes, machine learning, liquid biopsy, reference materials, exposomics