Across the globe, pollution is quietly reshaping the chemistry of our bodies. Toxic metals such as cadmium and mercury contaminate soils, water, and food, exposing millions of people to low but persistent doses over their lifetimes. These pollutants do not simply ‘sit’ in the bloodstream – they interact with proteins, enzymes, and cells in ways that can spark inflammation, damage organs, and contribute to long-term disease. Yet the fine-grained details of what actually happens at the molecular level often remain invisible.

One overlooked piece of this puzzle is what happens when red blood cells rupture – a process that can occur during infections, exposure to toxic metals, or conditions like sickle cell anaemia. When these cells burst, they release a flood of proteins into the bloodstream.

One of the most important of these proteins is an enzyme called carbonic anhydrase I that helps carry carbon dioxide out of our tissues so we can breathe it out. Despite its abundance, scientists have not actually known what happens to carbonic anhydrase I once it escapes into the bloodstream.

In 2024, researchers Maryam Doroudian and Jürgen Gailer decided to answer this surprisingly overlooked question. Their study, published in Metallomics, uses a specialised analytical approach called metallomics to track what happens to carbonic anhydrase I after red blood cells rupture. Their findings reveal that it behaves in an unexpected way and may play a bigger role in health and disease than previously imagined.

To understand their work, it helps to picture human blood plasma not as a simple liquid, but as a dense molecular soup containing more than 5,000 different proteins. Many of these proteins carry essential metals like copper, iron, and zinc to organs. Because carbonic anhydrase I is a zinc-containing enzyme released in large amounts when red blood cells burst, it could easily bind to other proteins floating in plasma. This is what one would expect given that the iron-containing protein hemoglobin, which gives red blood cells their colour and which is also released when these cells burst, effectively binds to a protein in plasma. Yet no one had ever measured carbonic anhydrase I directly in human plasma under physiological conditions.

Doroudian and Gailer approached this puzzle using a clever tool: a combination of size-exclusion chromatography coupled to a detector that can observe zinc and other metals. The chromatography step sorts plasma components by size as they move through a column. Then, instead of looking for the protein itself, the team tracks the metal signals – specifically zinc, copper, and iron – coming out the other end. This ‘metal-focused’ view cuts through the overwhelming complexity of plasma and lets the researchers watch metalloproteins in action without taking them out of their natural environment.

When the team added pure carbonic anhydrase I to human plasma and watched what it did over two hours, a clear pattern emerged. Carbonic anhydrase I did not latch onto any other plasma proteins. It remained free, intact, and was observed separate from all the other zinc-binding proteins. In other words, despite the crowded environment of plasma, carbonic anhydrase I avoids binding partners and travels alone.

This matters because free proteins can behave very differently from proteins locked in complexes. The authors suggest that free carbonic anhydrase I might directly interact with the cells that line our blood vessels, which are sensitive to chemical insults. When this zinc metalloprotein is released in large quantities during infections, toxic metal exposures, or blood disorders such as sickle cell anaemia, it might contribute to harmful processes like inflammation, damage to vessel walls, atherosclerosis, or even vision loss. Doroudian and Gailer emphasise that more research is needed, but their findings highlight how much we still don’t understand about the chain reaction that is triggered by the rupture of red blood cells.

This 2024 study is a strong example of how metallomics techniques let researchers observe tiny but crucial events in real biological fluids. It also illustrates the broader approach of Gailer and Doroudian, which blends chemistry and biology to investigate how toxic metals that are present in food behave once they invade the bloodstream and how that behaviour may influence health.

In their most recent work, the researchers show how liquid chromatography is becoming an essential tool for studying the bioinorganic chemistry of toxic metals such as cadmium and mercury. These toxic metals are far from rare. Cadmium and mercury contaminate soils, water, and food chains worldwide, exposing millions of people to levels that may slowly harm organs over years or decades.

Scientists can measure how much of these metals end up in someone’s blood, but that number alone does not reveal how dangerous the exposure is. What matters more is the specific form – or species – of the metal that enters the bloodstream, because different forms behave in dramatically different ways. Some may remain in the plasma, some may enter cells, and some may cross protective barriers, such as the blood–brain barrier.

This is where liquid chromatography methods shine. Mathew Sara and Gailer describe an approach that involves the direct analysis of real biological fluids – such as blood plasma – to which a toxic metal has been added on a chromatography column. The addition of different biomolecules to the liquid that flows through the separation column can be used to observe processes between the toxic metal that is bound to proteins and the biomolecule of interest at conditions that mimic what is going on under physiological conditions. Tiny shifts in retention time of the metal can reveal the formation or breakdown of metal complexes. By linking chromatography to metal-specific detectors, the researchers can observe how these toxic metals interact with natural molecules that are present in all human cells, such as cysteine or glutathione.

For example, liquid chromatography experiments have helped to show how methylmercury can form a complex with the small molecule homo-cysteine in plasma. This matters because such a complex may be able to cross the blood–brain barrier using the same transport systems that carry amino acids into the brain. This provides a chemically grounded explanation for why methylmercury is such a potent neurotoxin. Similarly, liquid chromatography experiments helped identify the cadmium–cysteine complexes that may be preferentially taken up by the kidneys, shedding light on cadmium-induced kidney damage.

Further experiments revealed how N-acetyl-l-cysteine can attach to methylmercury at conditions resembling cells and help to remove it from tissues. This observation may explain why N-acetyl-l-cysteine has shown promise in speeding mercury excretion from animals.

Together, the team’s two studies show how much can be learned when researchers combine careful analytical chemistry with real-world biological conditions. Doroudian and Gailer’s work on carbonic anhydrase I gives us a new way to think about what happens when red blood cells rupture – a process influenced by ageing, infection, disease, and exposure to toxic metals. Meanwhile, their liquid chromatography approach demonstrates how chromatographic tools can uncover the molecular identity of toxic metal species as they move from blood to organs. These insights deepen our understanding of the mechanisms of bioinorganic chemistry that underlie metal toxicity in organs.

Importantly, this work remains firmly rooted in the natural sciences. Rather than designing drugs or exploring medicinal pathways, the researchers focus on the natural interactions between metals, proteins, and small molecules inside the body. Their tools reveal how metals behave, transform, bind, and travel – processes that are essential for predicting health risks and protecting vulnerable populations.