With a world-first procedure pioneered at Sunnybrook, the blood-brain barrier is no longer an impassable fortress, and cures for the deadliest diseases of our time could be at hand.
The time had come. Fifteen years of research, down to this moment. Dr. Todd Mainprize, the Sunnybrook neurosurgeon leading the charge, watched intently from the control booth of the magnetic resonance imaging (MRI) suite, where the experiment was unfolding. His patient, Bonny Hall, lay alone in an MRI machine, a head frame equipped with electrodes hugging her shaved head.
As an ultrasound beam shot through the electrodes and into Bonny’s brain, the network of capillaries known as the blood-brain barrier began to vibrate, loosen and break open. The drugs coursing through her bloodstream could now cross the barrier and reach their intended target: the malignant tumour in her brain. The video monitor facing Dr. Mainprize confirmed it: the barrier had been broken.
The blood-brain barrier coats the brain’s blood vessels like plastic wrap, preventing harmful substances from passing into the brain. As it turns out, the structure’s greatest asset – the tight seal around the blood vessels – can pose a serious obstacle to the delivery of drugs into the brain, especially the large molecules typically used in chemotherapy. It’s a challenge that has frustrated brain cancer scientists and oncologists for decades.
“In theory, our knowledge of what causes brain cancer has exploded,” says Dr. Mainprize. “Every day, we’re learning more about which biochemical pathways go awry.” Unfortunately, treatment outcomes have not kept pace with these advances. “A lot of the drugs developed to treat brain cancer do just fine in a Petri dish, but the blood-brain barrier limits their effectiveness in actual patients” – patients like Bonny, who had been living with a brain tumour for the past eight of her 57 years.
At first Bonny’s tumour grew slowly, causing almost imperceptible seizures that medication kept in check. And then, as if controlled by an invisible switch, the tumour turned aggressive. “I knew something was up, because the seizures I was starting to have were different,” recalls the Tiny, Ont., resident.
The changes in Bonny’s tumour coincided with the launch of the first human trial of a new ultrasound procedure, led by Dr. Mainprize. He asked Bonny if she would consider being the trial’s first subject – and the first person in the world to undergo the procedure. Though she knew this was science, not treatment, and would not change her prognosis, she didn’t hesitate. “Someone has to go first,” she said. From Dr. Mainprize’s perspective, Bonny’s selfless act was significant. “Medical research would never advance to treatment without people like Bonny to take that first step,” he says.
For Bonny, the day began with an injection of a chemotherapy drug, along with a contrast dye that would show up on an MRI scan. Next, she was fitted with the head frame and gas microbubbles were injected into her bloodstream. With a diameter of just three to five micrometres – smaller than red blood cells – the bubbles percolated through her blood vessels, some of them reaching the blood-brain barrier. For the next two hours, Bonny lay still in the MRI machine while ultrasound waves caused the bubbles to vibrate and pry open the junctions holding the barrier together, making it possible for the chemotherapy molecules to reach her brain. “We knew the procedure had worked because we could see the dye, which normally doesn’t get into the brain, in various locations in Bonny’s brain tissue,” says Dr. Mainprize.
– Dr. Todd Mainprize
What distinguishes the Sunnybrook technique from earlier efforts is that “we can aim the beam at specific points in the brain,” says Dr. Mainprize. “That’s why we call it focused ultrasound.” What’s more, the technique weakens the barrier only temporarily: within 12 hours, the tight junctions seal up again. A further bonus: “Without the vibration of the bubbles to pry open the barrier, we would need a much stronger power of ultrasound, which could cause tissue damage. The bubbles make the process much safer and more efficient.”
Bonny’s landmark procedure generated a flurry of media attention throughout the world. A barrier had been broken, both literally and figuratively, and the technique offered an array of therapeutic possibilities. For Dr. Mainprize, the attention has proven to be a mixed blessing. “Media reports feed off each other, and the next thing you know, I’m reading an article stating that I’ve cured brain cancer.”
Over the past few months, he has responded to more than 2,000 e-mails from people asking for help for themselves or for their loved ones – a testament to his commitment to patients. While gratified that the world has been watching and confident the new technique will find its way into brain cancer treatment, he hesitates to predict when that day might come. “Bonny’s procedure was part of a phase 1 study, which looks at safety and proof of concept,” he says. “We’ll be repeating the procedure in other patients, and if we can confirm that it’s safe, we’ll start designing studies that use the technique as part of treatment. We’re talking years.”
Dr. Kullervo Hynynen, director of physical sciences at Sunnybrook Research Institute, led the development of the technology required for the technique in collaboration with industry partner Insightec. He’s accustomed to waiting years, if not decades, before seeing his ideas bear fruit. Indeed, he and his team started their first experiments with microbubble- assisted ultrasound 15 years ago and have been refining the technology ever since, varying the amplitude, frequency and pulse length of the ultrasound waves to tweak results.
By the time Bonny stepped up to the plate, the researchers had every reason to believe the procedure would work – and be safe. Indeed, “Bonny appears to have tolerated it without any problem,” says Dr. Mainprize. The following day, she had surgery to remove her tumour and is now convalescing at home. Over the next few months, she will likely get radiation and more chemotherapy. For the time being, she is enjoying spending quality time with her family – which is as much as she’s ever wanted from life. “I just want to be normal,” she says. “A normal mom, grandma, wife. That’s all I really want to be.”
As for Dr. Hynynen, he has no plans to rest on his laurels. “We’re looking at ways to make the procedure easier to use and applicable to different diseases,” he says. These efforts involve a lot of physics experiments, such as “using more complex ultrasound wave forms to target tissues more uniformly.”
Does the long, slow arc of medical discovery ever discourage him? “Not really,” he says. “It’s a challenge to work with such long timelines, but as a scientist I’m used to it.” It’s not just the science that drives him, though. “We’re offering hope to many patients,” he says. “It’s very exciting.” Bonny puts it another way: “Cancer is becoming a word like the cold or a flu,” she says. “I’d like it to stop.”
If all goes as planned, the technique will not only become part of brain cancer treatment, but also extend its reach to myriad other diseases. Focused ultrasound to the brain is currently being studied as treatment for essential tremor disorders, and Dr. Mainprize envisions the technique playing a role in conditions as disparate as epilepsy, stroke, Alzheimer’s disease, and depression. “The great majority of molecules that could be used for brain treatment can’t get through the blood-brain barrier,” he says. This means the new technique “could help with just about all neurological disorders that are treatable with drugs.”
Why do we have a blood-brain barrier in the first place?
If we didn’t, every blip in the molecular composition of the bloodstream – say, a neurotransmitter released in response to stress or a hormonal spike after exercise – would percolate to the fluid bathing the brain, leading to uncontrolled brain activity. The blood-brain barrier acts like a traffic cop, steadying brain function by controlling what enters and leaves the brain. The barrier also prevents toxic substances from reaching the brain.
The discovery of the blood-brain barrier dates back to the late 19th century, when scientists discovered that certain dyes injected into the bloodstream stained all organs except brain tissue. When injected directly into the brain fluid, however, these same dyes stained neurons – but not other tissues. It took another 70 years and the invention of the electron microscope before researchers were able to identify the blood-brain barrier as a vast network of tiny cells called microcapillaries.
The capillaries that feed organs such as the liver or kidney have fenestrations, or openings, that allow drugs to pass into those organs. In the brain, however, multiprotein complexes called “tight junctions” bind the microcapillary cells together, limiting the diffusion of molecules from the blood to the brain. Glucose, the brain’s fuel, gets in without a problem. Brain receptors can also pull in small molecules such as amino acids, and fat-soluble compounds have an easier passage, as well. As a general rule, the larger the molecule, the less easily it can slip past the barrier.
A historic day unfolds
All photography by Doug Nicholson
How the blood-brain barrier was breached
Sunnybrook researchers have found a way to use ultrasound waves to get medication through the previously-impenetrable barrier that separates the blood stream from the brain.
Here’s how they did it.
1 – Preparation: Chemotherapy drugs, dye and gas micro-bubbles are injected into the patient’s blood stream
Microbubbles: gas-filled protein shells that are smaller than red blood cells
2 – Targeting: Patient wears a head frame fitted with electrodes. Ultrasound waves are fired at the precise area of the brain that requires treatment.
Blood-brain barrier: A tight seal which coats the brain’s blood vessels like plastic wrap, preventing harmful substances from passing from the bloodstream.
3- The Beam: The focused ultrasound waves cause the bubbles to vibrate at the same frequency as the ultrasound beam, exerting mechanical forces on the capillaries and the blood-brain barrier
4 – Access: The vibrations open spaces between the cells of the barrier. The medication and the dye (which allows the process to be monitored) enter the brain through the tiny gaps, which will close within 12 hours.
Illustration by Tonia Cowan