New "molecular flashlight&quot to detect brain metastasis

A new technique, which we can colloquially describe as a “molecular flashlight,” detects brain metastases by introducing a light probe thinner than a hair into the brain. It is capable of reporting on the chemical composition of nervous tissue and allows analyzing molecular changes produced by tumors and lesions. For now, it has only been tested in mice, but it is hoped that it can be used in humans.

The technique has been developed by an international consortium that includes teams from the Higher Council for Scientific Research (CSIC) and the National Cancer Research Center (CNIO), both institutions in Spain.

One of the great challenges of biomedical research is to monitor the changes caused in the brain at a molecular scale by cancer and other neurological pathologies, and to do so in a non-invasive way. The new technique, currently in the experimental phase, achieves this using an ultra-thin probe that introduces light into the brain.

The research and development team, headed by Filippo Pisano, from the Center for Biomolecular Nanotechnologies, attached to the Italian Institute of Technology, refers to the new technique with the term “molecular flashlight” because it reports the chemical composition of the nervous tissue by illuminating it. It thus allows us to analyze molecular changes produced by tumors, whether primary or metastatic, and also by injuries such as head trauma.

The molecular flashlight is a probe less than 1 millimeter thick, with a tip just one thousandth of a millimeter, a micron, invisible to the naked eye. It is possible to insert it until reaching deep areas of the brain without causing damage (to give you an idea, a human hair measures between 30 and 50 microns in diameter).

This flashlight is not ready to be used on patients; For now, it is above all a promising research tool with animal models that allows monitoring molecular alterations caused by traumatic brain injury, as well as detecting diagnostic markers of brain metastasis with great precision, according to its creators.

The work has been carried out by the European NanoBright consortium, in which two Spanish groups participate, the one led by the Neuronal Circuits Laboratory of the Cajal Institute of the CSIC, directed by Liset Menéndez de la Prida, and the Brain Metastasis Group of the CNIO , directed by Manuel Valiente. Both have been involved in biomedical research at NanoBright, while groups from Italian and French institutions have developed the instrumentation.

Neurons (red) and astrocytes (white) activated in the cerebral cortex near traumatic brain injury. (Image: Elena Cid / Instituto Cajal CSIC)

Explore the brain with light without previously altering it

Activating or recording brain function using light is not new. For example, so-called optogenetic techniques allow the activity of individual neurons to be controlled with light. However, to do this it is necessary to introduce a gene into the neurons that makes them sensitive to light. With the new technology that NanoBright now presents, the brain can be studied without previously altering it, which represents a paradigm shift in biomedical research.

The technical name for the new molecular flashlight is vibrational spectroscopy. Its operation is based on a characteristic of light, the Raman effect: “when light hits molecules, it bounces differently depending on their composition and chemical structure, which makes it possible to detect a different signal or spectrum in each case. The spectrum thus becomes a molecular signature that informs the composition of the illuminated tissue,” explains Liset M. de la Prida, from the CSIC.

In this way, any molecular change produced in the brain by a pathology or injury can be detected.

“This technology -explains Manuel Valiente- allows us to study the brain in its natural state, it is not necessary to alter it previously. But it also makes it possible to analyze any type of brain structure, not just those that you have genetically marked or altered, as was the case with the technologies used until now. “With vibrational spectroscopy we can see any molecular changes in the brain when there is a pathology.”

Raman spectroscopy is already used in neurosurgery, although in an invasive and less precise way: “Studies have been carried out on its use when operating on brain tumors in patients,” says Valiente. In the operating room, once the bulk of the tumor has been removed with surgery, it is possible to introduce a Raman spectroscopy probe to evaluate if there are any cancer cells left in the area. That is, it is only used when the brain is already open and the hole is large enough. But these relatively large molecular flashlights are incompatible with minimally invasive use for live animal models.”

For the CNIO group, an objective now is to know if the information provided by the probe allows “differentiating various oncological entities, for example, the types of metastases according to their mutational profiles, by their primary origin or from different types of brain tumors.” ”.

For its part, the Cajal Institute group has used the technique to investigate the epileptogenic zones surrounding a traumatic brain injury. “We have been able to identify different vibrational profiles in the same brain regions susceptible to generating epileptic seizures, depending on their association with a tumor or trauma. This suggests that the molecular shadows of these areas are affected differently, and can be used to separate different pathological entities through automatic classification algorithms including artificial intelligence,” explains Liset Menéndez de la Prida.

“The integration of vibrational spectroscopy with other modalities for recording brain activity and advanced computational analysis with artificial intelligence will allow us to identify new high-precision diagnostic markers, which will facilitate the development of advanced neurotechnologies for new biomedical applications,” he summarizes. the CSIC researcher.

The team presents the technical details of the new system in the academic journal Nature Methods, under the title “Vibrational fiber photometry: label-free and reporter-free minimally invasive Raman spectroscopy deep in the mouse brain.” (Source: CNIO / CSIC)