Peering more closely down the microscope at that slice of kidney, Pluznick saw the fluorescent glow was emanating from the macula densa, a group of cells that play a central role in this chemical back-and-forth, sampling the forming urine as it goes by and sending out alerts to adjust the blood filtration rate. “The macula densa is the only cell type in the kidney that you would think of as being a chemical sensor,” says Pluznick. “It made a hell of a lot of sense, and it made me think it was real.”
The next step was to figure out what would happen if these receptors were absent in this region of the kidney, using engineered mice that lacked one of scent receptors Pluznick identified in the kidney, called Olfr78. Tests revealed these mice had kidney problems involving their blood filtration rate and the production of renin, a hormone which stimulates the constriction of blood vessels to increase blood pressure. Both of these are controlled by the macula densa.
Pluznick now began to devote herself full-time to the puzzle. Identifying which chemical "keys" – known as ligands – were binding to the Olfr78 receptor "locks" would help her understand the bigger picture of what the receptor was responding to. In doing so, her work took her from one weird and wonderful discovery in biology to another: the microbiome.
Our bodies contain trillions of bacteria, fungi, and other microorganisms. Those in the human gut fulfil various important functions, such as breaking down certain foods into energy and useful nutrients, suppressing harmful microbes, preventing allergies and assisting the immune system in a number of other ways. The evidence that the balance of different microbes we have inside us is important to our health has been growing rapidly in recent years. People with irritable bowel syndrome, obesity, Alzheimer's disease, Parkinson's and depression have been shown to have differences in gut bacteria when compared to healthy people.
As a study published by Pluznick last March showed, Olfr78's ligands are short-chain fatty acids, molecules produced when gut bacteria digest components of plant-based foods. Other scientists have documented their roles in human health, such as stimulating immune-cell production, reducing heart-disease risk, stabilising blood glucose levels and protecting the colon lining.
Pluznick acknowledges the picture is a complex and incomplete one, further work indicates another receptor that also binds to short-chain fatty acids has a greater and opposite effect. However, she believes the work shows the scent receptors she accidentally discovered are a previously unknown means for bacteria to tell the kidney to make blood pressure changes that allow them to best carry out their health-related functions.
As Pluznick was unravelling this mystery, other researchers were investigating taste and scent receptors elsewhere in the body. Yehuda Ben-Shahar, now a professor at Washington University in St. Louis, found cells in the human airway equipped with bitter receptors. These cells are covered in microscopic hair-like protrusions called cilia which flap when dangerous chemicals are breathed in, helping to flush them out of the body. Bitter receptors in the tongue are thought to have evolved to help us identify poisons, and Ben-Shahar wondered whether those in the airway might be protecting us in a similar way.
He and his collaborators found that when receptors in these cells were exposed to certain noxious molecules, it triggered a cascade of events that culminated in the flapping of the cilia. This made Ben-Shahar think that what we know as bitter receptors might better be called danger receptors. “We call them bitter but that's only because when we taste with them that's what we get," he says. "Probably what's uniting them is things that we try not to take in."