A Delivery Straight to the Brain

Diseases of the brain, whether congenital or degenerative, which cause the gradual death of brain cells over the years, are a major focus for many in the fields of medicine and research, who strive to cure them or at least find solutions to improve patients' well-being. However, they face a key challenge: treating the brain with medication is difficult. The main difficulty arises from the blood-brain barrier, a characteristic of the blood vessels around the brain. This barrier, based on unique molecular mechanisms like tightly packed cells, makes it hard for substances to exit the blood vessels and reach brain cells. As a result, it blocks the entry of foreign substances, such as large proteins and most bacteria, into the sensitive brain. While these features of the brain's blood vessels protect against harmful invaders, they also make it difficult to deliver medications to the brain through the bloodstream and treat brain diseases.

Over the years, various strategies have been employed to try and temporarily bypass the blood-brain barrier, with varying degrees of success. However, the search for a method that allows us to deliver drugs to the brain is still ongoing. A new study conducted in Israel presents a surprising approach to this problem: using an existing parasite capable of penetrating the brain, genetically engineered to deliver specific proteins. This method could potentially revolutionize the treatment of brain diseases in the future.

Makes it difficult for substances to exit the blood vessels and reach brain cells. The blood-brain barrier | Gunilla Elam / Science Photo Library

Be brave, mouse!

The study utilized a single-celled parasite called Toxoplasma gondii. This parasite is very small—only slightly larger than a bacterium—and tends to infect many mammals, though it only undergoes sexual reproduction in the bodies of felines. It is particularly well-known for its unique effect on mice: according to past studies, the parasite alters their behavior, making them less likely to flee from cats. This allows the parasite to easily reach the cats and continue reproducing.

Toxoplasma gondii is also common in humans, more so than one might expect. About one in three people carries the parasite in their brain cells. The parasite is usually dormant, and most carriers are unaware of its presence. However, when the immune system is weakened, as in the case of HIV/AIDS patients, it can become active and pose a serious health risk. Fetuses are also at risk, as their immune systems are still underdeveloped, and the risk increases if the mother becomes infected early in pregnancy. Newborns infected in the womb may suffer from severe congenital disease, which is why, for example, women in Israel undergo tests for the parasite before and during pregnancy.

One in three people carries it in their brain cells. Toxoplasma gondii | Kateryna Kon, Shutterstock

The Parasite in the Room

The Toxoplasma gondii parasite has coexisted with mammals for millions of years, developing complex mechanisms that allow it to efficiently infect their cells. That’s why, in the lab of Oded Rechavi at Tel Aviv University's Faculty of Life Sciences, where the study was conducted, researchers sought to use the parasite instead of eliminating it. "We like the idea of solving problems using developments that already exist in nature," said Shahar Bracha, the study's lead researcher, in an interview with the Davidson Institute website. "In many fields, like medicine and research, we can find suitable situations in nature where relevant mechanisms evolved, and draw inspiration from them rather than engineering a new solution entirely from scratch."

In an interview with Haaretz, Rechavi described the parasite's mechanism: "It knows how to hitch a ride on the immune system and reach the brain through it. Once in the brain, it penetrates neurons and can stay there for life. It builds itself a kind of protective bubble, then sits in this bubble and secretes proteins." Given these traits, the researchers planned to harness the parasite's ability to reach brain cells and secrete proteins. Normally, these proteins help the parasite take over the cell, but using molecular tools that allow genetic editing in various organisms, it can be made to secrete other proteins—such as those with medical benefits.

A Ride to the Brain

As a first step, the researchers chose to focus on Rett syndrome, a severe and rare disorder that primarily affects girls, leading to a decline in their motor functions and mental abilities. Rett syndrome is caused by a defect in a protein called MeCP2, which is essential for brain cells. Therefore, treating it systemically might be simpler than diseases involving multiple proteins. If doctors in the future could add the healthy protein to the brains of girls with Rett syndrome, their condition might improve.

When it infects brain cells, Toxoplasma gondii secretes the proteins it produces into them. The researchers used genetic engineering to attach the MeCP2 protein to these secreted proteins, allowing the parasite to release it into brain cells alongside the other proteins it produces and secretes. The method proved highly effective, and in an experiment on human cells, the genetically engineered parasites successfully introduced large amounts of MeCP2 into the cells, reaching the cell nucleus where it needs to function.

Next, the researchers wanted to verify that MeCP2 was functioning in the cells it had been secreted into. They used organoids—three-dimensional structures of cells that mimic an organ, in this case, the brain. The infected organoids efficiently received the protein and also produced additional proteins typical of normal MeCP2 presence. Finally, the researchers wanted to test the effectiveness of the protein delivery in a living organism. They infected mice with the parasite and monitored its spread in their bodies. They found that the genetically engineered parasite was as effective as regular parasites, primarily infecting the mouse's brain cells. The successful secretion of the desired protein into the mouse’s brain demonstrates the method's effectiveness in crossing the blood-brain barrier in a living organism, not just in cell culture. In the brains of the mice, the parasite functioned as expected and efficiently secreted MeCP2.

Rett syndrome is caused by a defect in the MeCP2 protein, which is essential for brain cells. MeCP2 protein complex with DNA | Source: Ramon Andrade 3dciencia / Science Photo Library

Just the Beginning

Although the research demonstrates the feasibility of this new method, there is still a long way to go before parasites can be used for routine medical treatment, and this is not planned for the near future. While Toxoplasma gondii does not pose a threat to most people who carry it, further research is needed to prove that it can be harnessed for medical purposes without causing harm. In the future, it may even be possible to genetically engineer it to reduce any associated risks.

Moreover, significant development and improvement are required to use this new method effectively. The study did not attempt to control the location of the protein release or the exact amount of protein the parasite secretes into brain cells. In the future, it may be possible to engineer parasites that target only specific areas of the brain and control the timing and levels of protein secretion. In the meantime, we can hope that this research will inspire future treatments for diseases currently considered incurable, illustrating humanity’s ability to leverage existing natural mechanisms for medical benefit.