A new study in which an Israeli scientist also participates may optimize the introduction of drugs into the brain
The German doctor Paul Ehrlich was one of the pioneers of medical science in the 19th century. His many studies dealt with, among other things, microbiology, hematology, drug development and the study of the immune system - a field for which he received the Nobel Prize for Medicine in 1908. As part of some of the experiments, he studied how different substances spread in the body, and injected dye into experimental animals. Ehrlich noticed that in most animals almost all internal organs are colored, except for the brain. Ehrlich's student, Edwin Goldman, noticed in follow-up experiments the opposite phenomenon. A dye injected into the fluid surrounding the brain did not spread from there to any other organ. The conclusion reached about 100 years ago was clear: there is some sort of barrier between the blood and the brain. It took decades more before the scientists were able to prove that such a barrier actually existed physically and its identity.
A dangerous defender
Like every organ in our body, the brain needs a constant blood supply, through which it receives the oxygen and other substances it needs. The carotid arteries divide at the head into thinner and thinner blood vessels, up to really thin capillaries. The cells that make up the wall of these capillaries are the ones that transfer the materials to the cells adjacent to them. However, in the brain - unlike other tissues - the transfer is done in a very selective manner: almost only small, fat-soluble molecules manage to pass into the brain. The blood-brain barrier (Blood-Brain Barrier, or BBB for short) has an essential role: it prevents chemical changes in the very sensitive environment in which the nerve cells operate (any such change may damage the electrical conduction), prevents infections, and protects the brain from the entry of substances that may damage its function. By the way, one of the molecules that does manage to penetrate through the barrier, and even easily, is ethanol - the alcohol we drink - and it is known to have a great effect on the brain. Despite the great importance of the blood-brain barrier, it can also create problems. For example - the BBB prevents the passage of most drugs to the brain, and greatly limits our ability to treat infections and other problems. It also does not provide easy access to the immune system and does not allow, for example, the passage of antibodies into the brain. On the other hand, deficiencies in the functioning of the barrier may cause certain diseases, such as multiple sclerosis and Alzheimer's, or at least greatly increase the risk of such diseases. The barrier is two-way, and not only prevents the entry of unwanted substances into the brain, but also ensures that the waste materials of the nervous system are cleared from it as required.
Start small
Controlling the blood-brain barrier can have a great medical benefit - both in its controlled opening, and in its repair when it is not functioning properly. However, until now not only have the scientists not been able to approach such a control ability, even the understanding of the mechanism of action of the barrier and the proteins involved in it has been quite limited. A team of researchers from Harvard University approached the problem from a different angle: embryonic development. An embryo begins to develop from another cell (fertilized egg), which divides repeatedly. Gradually the cells differentiate into different types, forming the organs and tissues. The researchers worked with a method that is not very different from the one used by Ehrlich about 100 years ago, although with much more advanced means. They examined the spread of a drop of dye inside a mouse embryo. In the very young embryo, the dye also spread to the brain cells, but once the barrier was created, the spread stopped. This allowed them to identify the precise time window in development when the blood-brain barrier was formed. At the same time, the researchers examined which genes are active in the same time window, and identified a certain gene, Mfsd2a, which is essential for the formation of the barrier. In fact, the researchers identified several possible genes that may be related to the process, but Mfsd2a caught their attention because it is active in other tissues where there are selective barriers to the passage of substances, such as the placenta and testicles. The bet on this gene paid off: when the researchers neutralized it, transgenic mice were obtained without a blood-brain barrier: it was not formed and, of course, did not function during their entire life. The identification of the gene also led the researchers to identify the protein that is responsible for its creation.
Surprising findings
What separates our body cells from their environment is a thin membrane made up of fatty acids. The unique structure of the membrane allows the cells to transfer substances between them in an interesting method. The material to be transferred adheres to the membrane on the inside of the cell, so that a kind of vesicle or fatty bubble is formed around it. This bubble eventually detaches from the cell, and when it reaches the adjacent cell, it fuses with its membrane and releases its contents inside it. This is not the only method of moving substances between cells, but it is quite common. The researchers from Harvard discovered that the protein created from the Mfsd2a gene, neutralizes the ability of the cells in the wall of the capillaries in the brain to transfer substances from cell to cell using this method. This finding is surprising, because until now the studies on the BBB have focused on a different method of moving substances between the cells, and believed that it is the key to understanding the mechanism.
The research was led by Dr. Eil Ben Tzvi, a postdoctoral student in the laboratory of Prof. Chenghua Gu (Gu), who is said to soon join the faculty of the School of Medicine at the Hebrew University. The research findings are published in the journal Nature, along with another study that deals with the same protein from a different angle. A team of researchers from Singapore, found completely by chance that the protein Mfsd2a is also responsible for the penetration of omega-3 cells, fatty acids of great nutritional importance, and apparently also of medical importance. According to Ben Zvi, one of the challenges now is to understand the connection between the activity discovered in his research and the activity related to omega-3. The researchers also note that the Mfsd2a gene has been largely conserved during evolution. That is - the gene and the protein in mice are almost completely identical to their counterparts in us, humans.
Not just in the brain
The findings of Ben Zvi and his colleagues provide for the first time an opportunity for controlled control of the blood-brain barrier. Now that the researchers know about at least one active protein in the system, and even understand its mechanism of action, it is possible to start planning a substance that will neutralize it, and allow the barrier to be opened. Such a treatment could complement, for example, the administration of drugs needed by the brain, and ensure that they reach their destination, and on the other hand, it is possible to ensure that it will only work for a short time, and will not permanently disrupt the activity of the barrier. At the same time, the findings can improve the understanding of the relationship between the activity of the barrier and its disruptions to a long list of neurological diseases, and perhaps even help in the development of methods of treatment or prevention. Along with the search for such breakthroughs, the researchers at Harvard and Jerusalem will continue to try to better understand the other components of the mechanism, which apparently involve more proteins, and possibly other types of cells. A better understanding of this mechanism may have a great impact not only on brain research, but also on other systems in the body that deal with the filtering and absorption of substances, for example the digestive system, liver, kidneys and embryonic development.
