Paul Ehrlich had just injected aniline dye--used to color blue jeans--into a rat's bloodstream. For years the immunologist had been working on ways to stain cells so they would be more visible under a microscope, and aniline looked promising. Soon all the animal's muscles, blood vessels and organs were deep indigo. But for some confounding reason the central nervous system--the brain and spinal cord--remained untouched.

Ehrlich's experiment, done at Berlin's Charit hospital in 1885, provided early evidence for the blood-brain barrier--a vital wall that controls which molecules in the bloodstream can enter the brain or nerve pathways. Oxygen, sugars and amino acids are allowed in; most compounds are kept out. As a result, the brain can do its job inside a secure perimeter not available to any other organ. Which is handy, because substances in air, water and food--as well as toxins and even the body's own hormones--can severely impair the brain's functioning. Easy access would quickly lead to mental chaos.

This brilliant defense can be a cursed impediment to curing brain diseases, however. Almost no therapeutic drugs can penetrate the blockade. William Pardridge, professor of medicine at the University of California, Los Angeles, says 98 percent of drugs that have some effect on the central nervous system cannot cross into the brain. Pharmaceuticals cannot battle meningitis, rabies, tumors, Alzheimer's or multiple sclerosis, because they cannot reach the sites where the diseases are wreaking havoc. Nevertheless, scientists have greatly improved their understanding of the sophisticated mechanisms the blood-brain barrier uses to grant or deny admission, and they are devising ways to exploit those mechanisms to sneak therapeutic drugs through.

No Trespassing
It can be hard to visualize the blood-brain barrier. It is not a filter at the base of the head or an envelope surrounding the brain and spinal cord. It is a layer of special, tightly knit cells--a carpet--that lines the inner walls of all the small blood vessels that reach into the brain and spinal cord. Like soldiers standing shoulder to shoulder, these endothelial cells allow only certain molecules to pass from the blood on one side of them into the region of nerve cells on the other.

Thomas Reese and Morris Karnovsky, faculty members at Harvard Medical School, first made the blood-brain barrier visible in 1967, using an electron microscope. They discovered endothelial cells tightly packed along the blood vessel walls. Tough proteins tie each endothelial cell to its neighbors, filling the space between them so nothing can squeeze through. (In blood vessels serving other organs, the endothelial cells are loosely connected, so substances can readily slide between them.) The only way that a molecule in the bloodstream can reach the nerve tissue is to pass right through the endothelial cell bodies themselves.

Of course, the brain cannot be completely shut out. Its cells need nutrients to survive and function correctly. Because of their tiny size, molecules such as oxygen can diffuse right through the guard cell bodies. But so can alcohol, nicotine, heroin and the party drug ecstasy [see box on preceding two pages]. Larger molecules such as glucose are funneled in through selective gates, and others such as iron are cloaked inside special transporters that ooze through the cells.

A few substances, especially ecstasy, actually damage the barrier as they cross it. Bryan Yamamoto, a pharmacology professor at Boston University, gave the party drug to rats, then injected them with a dye that is normally too large to cross the blood-brain barrier. The dye easily reached the brain. The rats received no more ecstasy, yet even 10 weeks later newly injected dye still was able to enter the brain. The ecstasy had made the blood-brain barrier far more permeable for an extended time--exposing the brain to pathogens. Yamamoto cannot say how long the drug's effect lasts in humans, but 10 weeks in a rat's life corresponds to five to seven human years.

Certain viruses and bacteria, such as those causing rabies, meningitis and cholera, trick the blood-brain barrier by attacking proteins on the endothelial cells, forcing open the gates. Brain tissue may then become dangerously inflamed, but there is at least one positive consequence: the swelling weakens the barrier, making it a bit easier for immune system cells to push through and fight the infection.

In the case of multiple sclerosis, the same mechanism goes out of control. Hordes of immune cells shove their way into the brain, exacerbating the inflammation reaction. Multiple sclerosis is indeed a disease of the blood-brain barrier; only after immune cells are suddenly able to flood across the border do they attack the myelin sheaths around nerves. These sheaths insulate the nerves, enabling them to conduct signals quickly and cleanly; as myelin is destroyed, nerve impulses become erratic and destructive.

Trojan Horses
Many therapeutic drugs that might fight brain diseases are simply too large to diffuse through unnoticed, the way ecstasy and heroin do. Ironically, another defense mechanism thwarts the transport of even small medications past the barrier. So-called export pumps snare "foreign" molecules as they begin to cross the endothelial cells and expel the invaders back into the bloodstream. Scientists are therefore devising tricks to sneak drugs around the export pumps or temporarily disable them.

Researchers at the University of Veterinary Medicine in Hannover, Germany, have constructed a blocking molecule that binds to a protein that operates the pumps, preventing the protein from initiating the pumping action. In rats the inhibitors make the barrier more permeable. Initial tests on epilepsy patients have reduced the number of seizures related to overactivity of the pumps.

A basic problem exists with this general approach, however. Disabling the export pumps in the brain also disables the pumps in linings that protect other organs throughout the body, exposing them to influxes of harmful substances that are normally rejected. Therefore, Gert Fricker, a biochemist at the Institute for Pharmacy and Molecular Biotechnology at the University of Heidelberg in Germany, is trying a different scheme: devising disguises for drugs.

Fricker and his team are crafting tiny, hollow spheres called liposomes that will sneak drugs through the wall like Trojan horses. The spheres are made of lipids--fatty complexes--and slide through the lipid-embracing epithelial cells while holding drug molecules inside their hollow cores. He is also tacking natural antibodies onto the outsides of liposomes that can latch onto receptors in the wall that will, in turn, pull the liposome through [see box on pages 36 and 37]. At U.C.L.A., Pardridge has had similar successes. Victor Shashoua, formerly a biomedical researcher at Harvard Medical School, has used a fatty acid to sneak in dopamine, a neurotransmitter that is lacking in several brain illnesses, such as Parkinson's disease.

Doctors already use such Trojan horses--sometimes called drug taxis--to deliver medication to other organs, for example, to fight stomach cancer. For brains, researchers have used this method only on lab animals thus far; clinical human studies are still in the planning stage.

Fricker's team is also working on alkylglycerols with the National Institute of Environmental Health Sciences in Research Triangle Park, N.C. These molecules are soluble in both lipids and water and in limited tests have succeeded in opening the barrier to chemotherapeutic compounds. For reasons that are not fully understood, the alkylglycerols open the vital barrier for just a few minutes so the therapeutic agents can cross. Then the wall seems to close naturally again. The short span of permeability would make it less likely that dangerous molecules could also reach the brain, the way ecstasy is allowed in. Experimenters at U.C.L.A. and at Ohio State University have introduced anticancer compounds into a rat's bloodstream that open up only the part of the barrier that is close to a brain tumor.

These advances and others are giving scientists hope that one day doctors will have a full bag of tricks they can use to exploit the blood-brain barrier. In these cases, the brain won't mind being fooled.