Inside our body, a continuous exchange of signals takes place that we barely notice. This inconspicuous dialogue between the organs and the nervous system happens every second — some signals report inflammation, others report damage or tissue repair.
Organs do not exist in isolation. The intestines, heart, pancreas, skin, and immune tissues are constantly "talking" with the nervous system, exchanging information about what is happening inside. But for a long time, scientists saw only part of this conversation.
They could study the organ itself or an entire nerve ganglion. But it was difficult to determine precisely which neurons are connected to a specific tissue and what is happening inside those cells at a given moment. It is like a huge hall full of people, but it is unknown who exactly is talking to the organ we are interested in.
Now a method has emerged that makes it possible to trace this connection almost from the organ down to an individual neuron, breaking down the wall of silence between them.
In September 2026, researchers from Heidelberg published in the journal Nature Protocols a detailed protocol for the technology Trace-n-Seq — a method that combines anatomical tracing of neural connections with analysis of gene activity in individual cells. This is the work of Vera Thiel's group, which first developed this approach while studying neurons associated with pancreatic cancer.
Why these neurons were so hard to see
Let us imagine a nerve fiber that ends in the pancreas. Its ending is located inside the organ, but the body of the neuron itself may be situated far away — in a peripheral nerve ganglion, sometimes several centimeters from the organ.
And here a classic methodological trap arose that puzzled researchers for years.
When scientists took a sample of the organ and performed modern single-cell RNA sequencing, they could see all the types of cells that make up the tissue: immune cells, vascular cells, fibroblasts. But the cell bodies of the neurons that control this organ were simply absent from the sample — after all, they are located in a completely different place, in a distant ganglion.
If, however, one studies an entire nerve ganglion, the opposite problem arises: it contains thousands of neurons connected to completely different parts of the body and organs. One can obtain a rich molecular portrait, but understanding which neurons belong to the organ we are interested in is almost impossible.
Trace-n-Seq makes it possible to find the right interlocutors.
How Trace-n-Seq works
The name combines two key principles: to trace the path of a neuron and then to read its molecular profile.
First, a special fluorescent tracer, Fast Blue, is injected into the tissue under study. This substance is taken up by nerve endings and begins a journey in the reverse direction — up the axon, toward the cell body of the neuron, in a process called retrograde axonal transport. In this way, the neurons that are truly connected to the tissue under study begin to glow blue.
The researchers then extract the corresponding nerve ganglia and, using a special cell-sorting technique (FACS), isolate precisely the labeled neurons, filtering out the thousands of other neurons in the same ganglion that are not connected to the given organ.
After that, single-cell RNA sequencing is applied, revealing the genetic portrait of each selected neuron.
And here scientists obtain no longer merely a beautiful anatomical map of connections. They can see which genes are active in each individual neuron, which molecules it produces, which receptors it has on its surface. The method merges two questions into one:
"Where does this nerve go?" and "What is happening inside the cell that goes there?"
It is precisely the combination of these two levels — the anatomical and the molecular — that makes the technology especially powerful.
The nervous system turns out to be far more plastic than it seemed
Trace-n-Seq makes it possible to compare neurons connected to healthy tissue with neurons innervating inflamed or diseased tissue. One can see whether gene expression changes, whether new functional states appear, and which types of neurons respond especially strongly to disease.
The method is capable of detecting even comparatively rare groups of cells that are easily lost when an entire nerve ganglion is analyzed. This is critically important, because a nerve connected to an organ is not necessarily an unchanging "cable."
Its cells can adapt, changing their molecular signature in response to what is happening in the tissue. Disease can change the nervous system — and the nervous system, in turn, can change the course of the disease. This mutual influence remained hidden for years, invisible precisely because we could not look inside an individual neuron connected to a diseased organ.
Pancreatic cancer showed how important this dialogue is
In fact, Trace-n-Seq did not emerge yesterday. Vera Thiel's research group first applied the approach in detail while studying pancreatic cancer. In a paper published in the journal Nature in April 2025, the scientists used this technology to analyze more than five thousand neurons, about four thousand of which were connected to the healthy pancreas and to tumor tissue.
The results were stunning: the tumor is capable of reprogramming the neurons connected to it, radically altering their molecular state. That is, the nervous system does not merely pass alongside the tumor. It becomes part of the complex microenvironment of the disease, an active participant in the development of cancer, rather than a passive observer.
It was precisely this work that became the key foundation for the new detailed Trace-n-Seq protocol, now published in Nature Protocols, making the method accessible to the broad scientific community.
Now the method can be applied much more widely
What is especially interesting is that the technology is not tied only to cancer. The authors point out that it can be used to study neural regulation in inflammation, autoimmune diseases, fibrosis, tissue regeneration, and other pathological conditions. This opens up a very broad field for research.
One can study, for example, how neurons connected to the intestines change during chronic inflammation — whether they develop entirely new functions or, conversely, lose their capacity for adaptation. How the nervous system interacts with immune cells and whether it is capable in some way of controlling their behavior. How damaged tissue informs the nervous system of its state. And how the neurons themselves participate in recovery or, conversely, in sustaining the disease.
From a map of organs — to a map of conversations
For a long time, biology operated with a convenient division. Here is the nervous system. Here is the immune system. Here is an organ. Here is a tumor. But new technologies increasingly show that the boundaries between them are far more conditional than they seemed, and that the body works as a single network, not as a collection of separate parts.
Trace-n-Seq is interesting precisely for this. It makes it possible to study the body not as a set of separate components, but as a network of constantly interacting cells, each of which responds to the signals of others and influences them in turn.
At the same time, it is important not to ascribe to the technology more than it shows. Trace-n-Seq does not read thoughts, does not measure consciousness, and by itself does not yet cure anything. It is a research tool, like a microscope or a calculator.
But such tools sometimes change science more profoundly than a single loud discovery, because they make it possible to ask questions that previously could not even be correctly formulated. They fill in the blank spots that once looked like insurmountable barriers.
We can already compile atlases of the cells of the human body, and we understand the spatial organization of tissues. The next step may prove even more interesting: to understand not only who is where, but also who is talking to whom — and how that conversation changes during illness, recovery, and life.
And perhaps it is precisely on such maps that a far more holistic picture of the connection between brain and body will one day emerge — the connection that long seemed mystical and insoluble, and now is beginning to open up under the beam of a new light.
