Breaking down the barrier

Almost six million people in the U.S. have Alzheimer’s disease. About 500,000 have Parkinson’s. About 16,000 per year will die from brain cancer. We have drugs to treat these diseases, but we can’t get them into the brain—they can’t cross a wall known as the blood-brain barrier.

The blood-brain barrier is a living shield that protects the delicate matter of the brain. It provides protection to the millions of neurons firing inside the skull from harmful concentrations of hormones and proteins that circulate the bloodstream of the body. Doctors want to disrupt the evolutionary safeguard of the blood-brain barrier, but opening it up to the body’s bloodstream could potentially do more harm than good.

“Almost nothing penetrates into the brain,” says Dr. Anna Herland, a researcher at the Wyss Institute of Harvard Medical School in Boston. “Which is a big problem because we cannot target certain diseases like Alzheimer’s with small molecules—no one has found a route.

The blood-brain barrier isn’t like a swim cap that encapsulates the brain inside the skull—it’s the lining of the blood vessels inside the brain. Each neuron gets its own tiny blood vessel, or capillary, which feeds it nutrients, like glucose, that it needs to power your brain. Where the neuron meets the bloodstream stands the blood-brain barrier. The cells that line these capillaries are called endothelial cells and they are connected by tight junctions—thin seams between the cells that only allow small, fat soluble molecules into the brain.

The endothelial cell membranes that make up the blood-brain barrier also house transporters that shuttle specific molecules across it. Glucose, for example, can cross with the help of its own transporter. This means that only molecules that are small in size and fat soluble, or have their own transporters can cross the barrier naturally; the drugs that treat Alzheimer’s, Parkinson’s or brain cancer don’t fit the criteria for easy passage.

The blood-brain barrier’s stringent security helps control the delicate balance of nutrients and chemicals the human brain needs to function. Although the rest of the body’s blood vessels allow for a free exchange of molecules, the blood-brain barrier restricts the flow of potentially harmful molecules. The brain needs hormones, proteins and nutrients to function, but an imbalance of one of these results in a diseased state. Too little glucose and the brain can’t power itself. A lack of the neurotransmitter serotonin leads to depression. An excess of it results in serotonin syndrome, a potentially deadly illness with symptoms like rapid heart rate and seizures. And even more disruption of the blood-brain barrier can be caused by diseases like multiple sclerosis.

 

Paul Ehrlich, a German physician, discovered the blood-brain barrier in 1880. He injected dye into the bloodstream of mice and noticed that it stained the kidney, liver and heart—but not the brain. Then, in 1913, one of his students, Edwin Goldmann, injected the same dye into the brain of the mice. The dye did not escape into the other organs; it only tinted the brain blue. These experiments showed a barrier between the brain and the body. It wasn’t until 1969 and the invention of the electron microscope that scientists visualized the blood-brain barrier and its tight junctions lining the brain’s blood vessels.

Pharmaceutical companies and doctors want to develop a safe way around the barrier to use the drugs that already exist instead of developing new ones that would cost millions of dollars to develop. Alzheimer’s disease is currently a fatal condition, but has a promising treatments in development. One of these treatments uses antibodies to target the buildup of one of the proteins during the disease—beta amyloid. But antibodies can’t cross the blood-brain barrier effectively. Over the past 20 years there have been over 120 failed clinical trials for Alzheimer’s drugs and now that we have a promising treatment to work with, companies and doctors don’t want to backtrack because of the hurdle they face—the barrier. “The problem is if you inject an antibody in the bloodstream, less than 0.1 percent goes into the brain because the barrier is just too tight,” says Herland.

Herland helped engineer the first blood-brain barrier on a chip. This chip is the size of a Band-aid and can mimic the human blood-brain barrier in ways that lab animals like mice never can. The researchers can use the chip to study the barrier in a way they never could inside a human brain. They can test a drug in development to see if it will cross the barrier the way the researchers predict it will, or if it would fail—without using human subjects—which would be cheaper and faster.

It takes about two weeks to make this almost-real blood-brain barrier on a chip. Herland and her team use the blood-brain barrier chips to study known transport mechanisms within the blood-brain barrier. She first joined the project a couple of years ago when she wanted to not only study how Alzheimer’s affects the brain, but to take it a step further to work on a treatment. Herland’s research could help find ways to deliver these already developed drugs more effectively. But in the meantime, doctors want to help patients sooner and get these drugs into the brain more effectively—the way they want to do this is by opening up the tight junctions between the cells that make up the barrier to allow larger molecules to pass through.

Edward Neuwelt, a neurosurgeon based at the Portland Oregon Health and Science University (OHSU), pioneered a procedure to deliver chemotherapy to the brain by opening up the tight junctions of the blood-brain barrier to treat difficult brain tumors. He inserts a catheter (a narrow tube) into an artery in the patient’s leg, a common entry-point for these types of surgeries, and pushes it up through to the neck at the base of the brain. Then, a concentrated sugar solution called mannitol is injected into the catheter which causes the endothelial cells of the blood vessels within the brain to shrink—opening up the tight junctions, and allowing chemotherapy drugs to glide in.

This procedure solved a problem that many oncologists face when treating brain cancer—chemotherapy drugs do not cross the blood-brain barrier well, and some can’t at all because of their size. When the drugs are small enough to pass through the barrier, the amount that gets through is not enough to be effective to treat brain tumors. Neuwelt’s method delivers these large molecule drugs directly to the cancerous brain, is safe and effective, but also time consuming. The patient must return to the hospital every four weeks for a year to receive this blood-brain barrier disruption and chemotherapy treatment.

Neuwelt’s blood-brain barrier disruption treatment is seen as safe even by skeptics like Dr. William Banks, who doesn’t think we should be trying to open this floodgate. “[Neuwelt] has selectively figured out a way to disrupt particularly the brain-tumor-barrier and get drugs in,” says Banks. “He does it very very cautiously and he has spectacular success.” Banks is a professor and doctor of geriatric medicine at the University of Washington whose major research focus is how the brain and body communicate with one another through the blood-brain barrier. Banks studies how leptin and other feeding hormones cross the barrier, which helps give insight to obesity and body weight control. He also studies drug delivery across the barrier, looking for a natural biological transporter to get drugs that treat Alzheimer’s disease into the brain without disrupting it.

Banks says that Neuwelt’s method is controlled. He carefully opens the barrier for only a few minutes at a time. But other methods in development leave the barrier open for days at a time. “I have no idea why people think they can disrupt the blood brain barrier and not let all the toxins pour in as well as their drug pour in,” says Banks.

Doctors at the Sunnybrook Health Sciences Centre in Toronto and Brigham and Women’s Hospital in Boston use focused ultrasound to disrupt the blood-brain barrier. The focused ultrasound method is also a temporary opening of the barrier, but it is less controlled, more expensive and a trickier procedure than Neuwelt’s method. But it isn’t invasive the way Neuwelt’s method is; there is no surgery. Some also believe that the way the mannitol method can lead to widespread disruption of the barrier and that the focused ultrasound method is more controlled. The focused ultrasound procedure requires the patient be in an MRI machine as the doctors use low frequency ultrasound waves to vibrate small microbubbles which push the tight juncitons within barrier open. The junctions then allow the bubbles full of chemotherapy drugs inside the cancer-ridden brain. The microbubbles are smaller than red blood cells and can be injected into the patient’s bloodstream.

In November, 2015, Dr. Todd Mainprize and his team at Sunnybrook Health Sciences Institute in Toronto were the first team to successfully perform this focused ultrasound procedure on a human patient, one of ten test subjects who were already scheduled to have their brain tumors excised in surgery before agreeing to be in the trial. It was the first time the blood-brain barrier was non-invasively opened in humans. Mainprize stressed that this is a phase 1 safety and concept study to just show that they can deliver these drugs through the barrier. The findings from the study have not yet been published.  

“Focused ultrasound is very focal and its okay for Parkinson’s Disease,” says Neuwelt. “A malignant brain tumor is a whole brain disease, what you see on the scan is just the tip of the iceberg, so to use [focused ultrasound] for this is probably not reasonable.”

The potential problem is that the focused ultrasound procedure lets the barrier stay open for at least 12 hours, usually 24, and depending on any modifications, it could stay open for up to three days. This means that there is no regulation between the bloodstream of the body and the brain during that time. Banks is skeptical, he says that disturbing the barrier enough to disrupt it could trigger an immune response from the endothelial cells that make up the blood-brain barrier. They will release chemicals to fight off the disruption which could cause brain toxicity. “Ultrasound disruption of the blood-brain barrier is probably not a good idea. I’m skeptical to it helping patients,” says Banks. Mainprize’s success in November was so publicized because it was the first successful non-invasive disruption of the blood-brain barrier in a human. But before this procedure is performed regularly in humans, it needs to be standardized—doctors must agree on a common practice for the safety of the patients—and this takes time.

Nathan McDannold, Research Director of the Therapeutic Ultrasound Lab and Focused Ultrasound Surgery at Brigham and Women’s Hospital, leads a team that is working on the same procedure Mainprize and his colleagues are using. A recent paper from McDannold showed the safety of repeatedly opening the blood-brain barrier to deliver the chemotherapy microbubbles in rats. The ultimate goal is to be the first to develop the safest and most effective practice of focused ultrasound in humans.

Dr. Ben Bleier, an ear, nose and throat specialist at Massachusetts Eye and Ear Infirmary and Harvard Medical School, is formulating a more radical approach—instead of trying to temporarily disrupt the barrier, he is formulating an approach to solving the drug delivery problem by creating a permanent “screen-door” in the outer lining of the brain. This outer lining is like a swim cap that surrounds the brain. This screen door he creates is about 1,000 times more permeable than the original lining and bypasses the blood-brain barrier altogether. Bleier and his collaborators at Boston University’s (BU) School of Engineering recently published three papers outlining a novel surgery performed in mice to replace a portion of the barrier with live nasal lining. “That is the way that we create a permanent permeable membrane in the blood-brain barrier,” says Bleier. “When I say blood-brain barrier in this case, I mean the barrier within the lining of the brain.”

Bleier and a postdoc at BU, Richie Kohman, invented a novel surgery to create a hole within the brain’s lining and then patch the hole with live nasal lining tissue. They tested the new procedure in mice, and found it allowed entry of an effective Parkinson’s drug into the brain that alleviated Parkinsonian symptoms.

He is confident that the procedure can be translated to humans because the surgery is already being done in humans—just without the drug delivery portion. Bleier lets me observe him performing the beginning of a similar surgery. He performed a septoplasty on a patient who had trouble breathing because his sinus pathways entangled in on themselves. The beginning of this surgery is just like the procedure he does on patients with tumors that sit just inside the brain from the nose, or ones that invade both areas.

He does it through the nose—he uses a video camera on a tube to find his way around the nasal cavity, cutting and scraping. To patch the tiny incision in the brain lining, he uses live nasal tissue that he harvests during the first part of the procedure. Bleier shows it to me—the lining is slimy and a pinkish red and looks fairly thick on screen, but I know it’s just a couple centimeters wide. This is what he’d use to replace the lining of the brain. “The nasal lining is not just a passive barrier, the nasal lining is actually a very dynamic organ—it has an entire immune system within it,” Bleier explains. He says this is why using a live nasal lining has “revolutionized the ability to do these types of surgeries.” The next step for Bleier is to successfully perform the surgery in conjunction with the drug delivery on rats, sheep and then humans.

Our brains house 86 billion neurons and control every function in our body—powerful machines that have been finely tuned after millions of years of evolution. To cure the incurable, the barrier into the brain is being disrupted, bypassed and viewed as the next obstacle to conquer. Numerous challenges likely lie ahead, but new knowledge of blood-brain barrier function could lead to safe treatments for the fatal diseases rattling around in our brains, just out of reach.