Illustration by JVG for Fortune
By Erika Fry
June 28, 2016

For years the darndest thing kept happening to drugs in clinical trials to treat brain disorders: They never made it to the brain. For pharmaceutical companies this problem was as costly—developing treatments for the central nervous system takes an average of 15 years and $1.5 billion—as it was, in hindsight, kind of obvious. The drugs were impeded in part by the blood-brain barrier, or BBB, a formidable physiological feature whose properties were discovered in the 1880s.

Composed of blood vessels connected by “tight junctions” and studded with receptor proteins, the BBB is more a gateway than an impenetrable wall. It lets in materials the brain needs (sugars and amino acids), while pumping out or deflecting the many it does not. Alcohol, nicotine, and some small-molecule drugs can get in, but substances that do not pass include chemotherapy agents, “biologics,” and other pharmaceutical breakthroughs. “Unfortunately the blood-brain barrier has effectively excluded the brain from the entire biotech revolution,” says James Callaway, CEO of ArmaGen, a California biotech.

Increasingly research suggests that the BBB becomes leaky as we age—a weakening linked to neurodegeneration. People who suffer traumatic brain injury have a disrupted BBB, as do those with multiple sclerosis. And patients with Alzheimer’s appear to have a leakier BBB than most, though whether it’s a cause or a consequence of the disease is a matter of debate.

This porousness is one reason drugmakers have thought their meds might make it into the brains of such patients. But the race is on to find more certain strategies that could unlock treatments for diseases like Alzheimer’s and brain cancer. Biotechs like Biogen (biib) and Genentech (genentech) have dozens of researchers working on the issue, while Janssen, Johnson & Johnson’s pharmaceutical arm, has sought partnerships (including with ArmaGen) to bolster in-house efforts. All are trying to hitch molecules to receptors on the BBB for delivery into the brain. (Key to some of these efforts: shark and llama antibodies.)

Impel NeuroPharma is trying to circumvent the BBB altogether, developing a device to spray a drug into the brain via the nose’s passageways. Others are experimenting with lasers, nanoparticles, ultrasound, microbubbles, and the FDA-approved drug Lexiscan to either cross the barrier or briefly pry it open. While frequently disrupting the BBB may pose safety risks, the strategy is considered promising for attacking tumors.

It’s likely to be a couple of years before a biologic engineered to breach the wall is approved. For now the most proven way to get drugs safely and effectively into the brain involves a method pioneered in 1979 by Ed Neuwelt, a neuro-oncologist at Oregon Health & Science University. He injects patients with a solution that temporarily shrinks the cells in the BBB, creating space for drugs to slip by. Patients endure 12 three-day hospitalizations in a year—but it works. (His 450 brain cancer patients include some who are healthy more than 25 years after treatment.) Neuwelt, too, hopes for less invasive methods of bypassing the BBB. “I need to be put out of business,” he says.

A version of this article appears in the July 1, 2016 issue of Fortune with the headline “The Riddle of the Wall in the Brain.”

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