Generales

By Ronal Castañeda Tabares

John O'Keefe's discovery of cerebral GPS in the 1970s, which is the region of the brain where Alzheimer's disease begins, is entering a new phase. The Nobel laureate and colleagues from Colombia and the United Kingdom will try to detect early signs of the disease, and if successful, they may be able to develop biomarkers for preventive treatments. 

John O'Keefe, FRS FMedSci (born November 18, 1939) is an American-British neuroscientist, psychologist, and professor at the Sainsbury Wellcome Centre. Photo: Alejandra Uribe Fernández.

Just after visiting several families on August 29th in a village near the town of Angostura, located 3 hours from the city of Medellín, Nobel laureate John O'Keefe could not hide his face of satisfaction. The British-American neuroscientist, who gained international recognition for discovering the "internal GPS", referring to the part of the brain that allows humans to orient themselves in space, was thrilled to learn about patient experiences that may hold the key to advancing his research into new areas, such as understanding why individuals with Alzheimer's disease are unable to recognize their environment and, consequently, leading to an earlier detection of the disease, even before symptoms manifest.

"We feel very fortunate to come here to see and understand how those who have this disease live and survive," said the Nobel laureate minutes after hearing the stories in the home of the Agudelo Villegas family, located in the Canoas village, where a rare "Paisa mutation" has affected multiple members.

 “It is well known that the Agudelo Villegas family has Alzheimer's. It is present in siblings, cousins, and uncles. They begin to forget and then repeat things, eventually becoming depressed and prone to crying," was the observation made by one of the Agudelo Villegas brothers to the 11 scientists from the United Kingdom, the United States, Cuba, and Colombia, led by Francisco Lopera, director of the Universidad de Antioquia's Neurosciences Group (GNA), and John O'Keefe.

O'Keefe spent over an hour listening to the family's stories. Dr. Lopera and his team have been studying and following this family for more than 30 years, and in addition to their kinship, they share a mutated gene that causes an early form of Alzheimer's disease known by GNA scientists as "Paisa mutation" Alzheimer's disease.  

A key alliance 

O'Keefe's team specializes in animal models for experimentation and the pathology of Tau (a family of neuronal proteins), a defining feature of Alzheimer's disease. He also discovered the GNA to be the missing piece to bring their basic science research closer to population-level. "Experts in both the biological and molecular aspects of the disease as well as the mechanisms it conceals, the London group lacks access to a population such as that found in Antioquia, which is unique due to the presence of a causal gene that almost certainly triggers the disease's symptoms to manifest early in life," commented researcher Juan Pablo Sánchez.  

Eyes on Colombia 

One of the people who served as a bridge between the Nobel laureate and Dr. Lopera was Juan Pablo Sánchez. "The scientists in the United Kingdom found out that we had common interests. I was the person to help them approach Dr. Lopera's group, whom they already knew," said the researcher Sánchez, who was doing his doctoral thesis in epidemiology a year and a half ago based on the development of a test in a video game to analyze patients' spatial cognition. 

Dr. Lopera had met the Nobel Prize winner during the pandemic in an online affair in which both participated. Since then, relations and the possibility of scientific collaboration have only grown stronger.

"We're looking for what is going wrong biologically, affecting the brain's ability to remember a path and move around a place," said John O'Keefe. 

John O'Keefe became interested in the GNA's work, and in August, after several meetings and planning, they announced an alliance centered on the research project. "Early diagnosis of Alzheimer's disease in the preclinical phase: cross-species multidisciplinary studies to understand the relationship between entorhinal-hippocampal dysfunction and spatial behavior," in which 180 people from Colombia and 150 from the United Kingdom will be studied, and laboratory tests with mice will also be carried out, which together show a new scenario in his life as a scientist. 

"I've spent my entire career as a researcher trying to understand how the brain works, but now we have a clear idea of the benefits that knowing more about the brain would bring to the people of Colombia and the world," Professor O'Keefe told the newspaper, Alma Mater.  

The relevance of their studies

According to Dr. Lopera, the GNA group was fortunate to cross paths with O'Keefe because the "internal GPS" is the area of the brain where Alzheimer's disease is thought to begin and alter first.

Scientists John O'Keefe and Francisco Lopera, on a field trip in Angostura. Photo: Marisol Londoño.

The finding of this area in the hippocampus served as the basis for subsequent research on space and memory. "It was as if all of a sudden the door was opened for us to understand all the complexities of the human mind. Even now in 2023, more than 50 years after making the discovery, it is almost unique and just as relevant," explained scientist Dennis Chan, who has focused on developing next-generation methods and tools for the detection of Alzheimer's patients in preclinical stages, as well as being one of those who best knows O'Keefe's scientific career, with whom he has had contact since 1988, when the Nobel laureate was his tutor during his doctoral studies in Neurosciences. 

"Until John's work with the "internal GPS", which began in the 1970s, we didn't understand how individual brain cells and all the billions of brain cells controlled something as complicated as spatial navigation. He did experiments and discovered how the cells inside our brain work, a hopeful breakthrough for the whole field of science," said Dr. Chan, who has a background in animal and clinical biological studies, meaning he can move from basic to applied sciences. 

In fact, O'Keefe provided the tool to understand the disease process, as Professor Juan Pablo Sánchez points out: "He revealed the mechanism that underpins all the tests we are considering. He discovered that cells in the hippocampus respond differently to how we process space, an area that is functionally sensitive to Alzheimer's disease. We only realized this because of John's efforts.” 

"He somehow unlocks the black box, revealing the engine's mechanism, and we can understand what's wrong, if not find a cure. That is a significant step forward." Juan Pablo Sánchez. 

Teamwork 

This initial meeting between researchers from several countries and the families of Angostura left an aura of hope amid the turmoil, the surprise of the first meeting, and the expectations of the next one. The Nobel Prize winner seemed motivated because he would be able to advance his studies by finding clues in the families.

John O'Keefe and his team visited families of patients with a type of Alzheimer's disease studied by the Neuroscience Group of Antioquia at a farm in Angostura at the end of August. Photo: Ronal Castañeda.

This emotion was shared by all of the other researchers and families, regardless of last name. Some of the patients referred to Dr. Lopera as their "Father Marianito," alluding to the priest from Yarumal, beatified by the Catholic Church in 2000 as a beloved figure in this sub-region of northern Antioquia for his miraculous presence.  

Hope was placed, paradoxically, in science and in God at the farm where they were gathered, something O'Keefe understands and names; he calls it courage, an indispensable attitude for any investigative success: "Faith in your religion, as well as faith in science, can be extremely beneficial. Nobody expects it to be easy, but tomorrow we'll wake up and say, 'Oh, that's the killer.' It will take a lot of effort, and they will have to contribute. They are extremely brave," the scientist pointed out.