The brain is surrounded by a protective barrier designed to keep infections out. But it can also block out medicines intended to treat brain diseases. Now, scientists have developed a way of sneaking helpful proteins across the barrier by giving them fake molecular ID.
Using genetic engineering, a group of scientists have developed a way of sneaking a virus past the brain’s defences. Don’t panic – this isn’t some nightmare scenario. It could be the first step to curing a huge number of brain diseases.
The brain seems incredibly well protected amid its shell of bone and cushioning fluid. But even the strongest of forts needs supply lines, and brain is no exception.
A dense network of blood vessels carries vital oxygen to its cells. These vessels are a potential vulnerable spot, providing access for bacteria and other disease-causing organisms to migrate in from other body parts.
But even these weak spots are heavily guarded. The blood vessels in the brain are lined with a tightly packed layer of cells that restrict the flow of molecules from blood to brain. These cells form a protective shield called the blood-brain barrier, or BBB.
It is a superb defence but it can do its job too well. Not only does it block out dangerous microbes, but it can also exclude large proteins and drugs designed to treat brain diseases. Usually, these large molecules need to be distributed throughout the entire brain to be effective. With the BBB in the way, they don’t stand a chance.
Now, Brian Spencer and Inder Verma from the Salk Institute of Biological Studies have come up with a way to disguise helpful molecules to sneak them past the brain’s defences.
Their method exploits special gates in the barrier that control the import of essential nutrients and molecules like cholesterol into the brain. These molecules are escorted by a large protein called apoliprotein B (apoB), and are presented to sentinel proteins that guard the gates.
One of these guardians, called LDLR, is designed to recognise a specific segment of apoB. Once it has confirmed the visitor’s identity, it escorts apoB and the molecules it accompanies through the barrier. The whole system works with the tight control of a maximum security prison.
Spencer and Verma managed to fool the system. They took the part of apoB that is recognised by LDLR and stuck it to various proteins, giving them the molecular equivalent of a fake pass.
First, they tested their method in mice. They injected the animals with a harmless virus designed to travel to its liver and spleen. There, the virus sets about building the disguised protein, which is secreted en masse into the bloodstream.
The beauty of this method is that it works after a single injection that transforms the liver and spleen into factories for the protein of choice.
Their first candidate was GFP, a jellyfish protein that glows in the dark with a greenish hue, allowing it to be easily tracked. Sure enough, the injected mice soon gave off a greenish glow from their brains and the rest of their central nervous systems.
Better still, their method showed real practical potential by sneaking an enzyme called glucocerebrosidase (right) into the brain. Glucocerebrosidase is vital for the storage of fats. People who lack it suffer form a condition called Gaucher’s disease, where fatty desposits collect on various organs and cause brain damage, among other symptoms.
The disease is relatively easy to fix using regular injections, but the resulting brain damage is not for the injected enzyme is usually repelled by the blood-brain barrier. But Spencer and Verma’s method may change all that.
The duo fully admit that their work is merely a first step, but it is an important one nonetheless. The technique must first be refined and tested in people before it can be widely used. Developing drugs and proteins for treating brain disorders is pointless if those new medicines just congregate uselessly outside the blood-brain barrier. Spencer and Verma may have given them a way in.
Reference: Spencer & Verma. 2007. Targeted delivery of proteins across the blood-brain barrier. PNAS 104: 7594-7599.