To assess whether a compound holds promise in treating a disease, researchers usually begin by studying its use in animals. This allows us to see if the compound has a chance of curing the disease.
However, animal models rarely reproduce all aspects of the disease. An alternative is to represent the disease in cell cultures. While at first glance, Petri dishes look very different to a person with a disease, the reality can be very different when you look at them closely.
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Alzheimer’s disease has been treated more than 400 times in laboratories. How then can we still consider Alzheimer’s disease incurable? The reason is that it was only treated in animals.
A mouse does not naturally develop Alzheimer’s disease, it must be induced. To do this, scientists use our limited knowledge of what triggers Alzheimer’s disease and reproduce it in mice. In short, these mice do not have Alzheimer’s disease: they have our misconception about Alzheimer’s disease.
As a doctoral student in psychology, I completed a research internship at the University of Montreal Health Center (CHUM) in Professor Nicole Leclerc’s lab, with the goal of developing new models for the study of Alzheimer’s disease while discarding our limited theories about the disease.
In modern science, a new, untested compound cannot be used to treat a human disease because it poses an unacceptable risk. Therefore, the disease model, which replicates our observations of disease in humans, is used to test whether the new compound shows promise. Disease models, which often include animals, allow researchers to develop treatments and diagnostic tools. It also gives us the opportunity to better understand the processes behind the disease under study. Models are an essential tool in the biomedical sciences.
future disease models
Studying disease would be easier if we could observe and act directly on which cells stop working properly. In the case of Alzheimer’s disease, it is impossible to take a slice of the brain from a living person to sample the neurons inside.
However, I’m developing a technology that comes very close to replicating this process. By taking a small piece of a patient’s skin, I can grow the cells in a petri dish and turn them into neurons in about a month.
While at first glance a petri dish looks very different from someone with an illness, the reality may be very different when you look at it closely. (stock struggle)
The method takes advantage of the fact that all cells in a person’s body have the same genetic code. What distinguishes a skin cell from a neuron is simply the genes that the cell expresses. This means that I can force a skin cell to express typical neuronal genes so that it gradually turns into a neuron.
These neurons retain the hallmarks of aging, which are essential for the study of age-related diseases. The advantages are clear: one can produce a colony of human neurons from a person with Alzheimer’s disease. Neurons from Alzheimer’s patients will then develop characteristics of Alzheimer’s disease, making it easier to study the disease.
However, a neuron does not operate in a vacuum. Other cell types interact with it. To improve neural culture, researchers can push the concept even further by producing organoids. These are cell cultures consisting of several types of cells. Brain organoids can more accurately recreate brain function, and be a better model for diseases of the nervous system.
Diverse disease models
If a cell functions abnormally in a person with a particular disease, we will try to understand its behavior. By observing a model of the disease, we can see if this abnormal function is similar to that observed in the brains of actual patients. If so, we can try to modify the cell function in our model to see if there is a beneficial effect.
The primary function of models is to facilitate the study of disease. A good model should represent the disease as reliably as possible. When the form is considered sufficiently representative of the disease, it can be used in preclinical studies to verify whether the compound has the potential to treat it without being harmful.
When the model replicates well for the disease, researchers can hypothesize that the treatment it’s working on is more likely to work in people with the disease. For this reason, cell cultures and organelles from patients are particularly promising. Even if we do not know all the features of the disease, there is a possibility that these also recur in the models.
Since these models come from real patients, they could be used for a unique third purpose in the future: personalized medicine. Patients with the same disease are heterogeneous and may not respond in the same way to treatment. When there are several types of treatments, we rely on trial and error to determine what’s best for each patient.
In 2021, Kimberly K. Leslie’s team at the University of Iowa showed that organelles might tackle this problem. They used endometrial and ovarian cancer tissues from patients to create the organoids, demonstrating their ability to evaluate different treatments. That same year, a team from Singapore and Hong Kong showed that organelles could be used to predict the response of oropharyngeal tumors to radiotherapy and to adjust their dose.
This method may make it possible to select the most promising treatment for the individual in a much shorter time. But it has only been tested in animal models and cell extracts, and its usefulness in humans has not yet been proven.
Promising, but imperfect models
A treatment that works in a disease model will not necessarily work in humans. This is exactly why Alzheimer’s disease is “cured”, or at least reconstructed in a laboratory animal model, more than 400 times but not in humans.
Likewise, it is possible that compounds that slow the progression of Alzheimer’s disease may have failed to treat these animals, and they were euthanized. For neurodegenerative diseases such as Alzheimer’s disease, establishing a representative model is particularly complex because the disease does not have a single cause. We know hundreds of processes that Alzheimer’s is believed to have downregulated, which include the nervous, cardiovascular, and immune systems.
It is not yet possible to reproduce these reactions in cell cultures. Even if future models allow researchers to better represent the disease, and possibly discover treatments, they will always be imperfect. So, finding a cure in a model is never the same as determining a cure for a disease.
This article was originally published in French
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