The blood-brain barrier (BBB) is a layer of specialized endothelial cells around the brain that protects it—letting in only what is needed and keeping out what could be harmful. It crucially maintains the right ionic balance within the brain and blocks substances that would disrupt essential neural functions. In many ways, it’s a barrier between life and death.
What happens, however, when there’s a cancer or a neurodegenerative disease like Alzheimer’s within the brain? The BBB is so good at its job that it prevents most therapeutic drugs from entering, too. This has fatal consequences. Beyond surgery, there are essentially no viable treatments for glioblastomas, for instance, the kind of brain tumor Senator John McCain has.
Margaret S. Bynoe, Microbiology and Immunology, studies the BBB, its structure and composition, and how to modulate it in order to safely deliver drugs to the brain. In 2011, she and her team discovered that an FDA-approved drug, currently used for cardiac imaging, can open the BBB—a literal, scientific breakthrough. “We can use this not just for the purposes of tumors,” Bynoe says. “Think of Alzheimer’s, Parkinson’s, even depression. Being able to get drugs into the brain, to treat a tumor or shift that chemical balance in mood disorders, can make a huge difference in a person’s life.”
The Drug Lexiscan, a Bouncer for Brain Disease Therapeutics
The FDA-approved drug Bynoe uses is called Lexiscan, and it works by binding to certain receptors, A2A adenosine receptors, on the luminal or outer surface of the BBB. This alters the tight junctions between the epithelial cells that seal the barrier.
Lexiscan also works by down-regulating a key protein that the BBB uses to guard against invasion, P-glycoprotein (P-gp). P-gp is a bouncer for the cells, kicking out unwanted substances, including many drugs. Lexiscan lowers the expression of P-gp, making it easier for drugs to cross the BBB.
“There are these two mechanisms for opening the blood-brain barrier, and Lexiscan targets both pathways for entry,” Bynoe says. “It’s a double-positive.”
If chemotherapy or other drugs are administered with Lexiscan, they can enter the brain during a short window, which Bynoe’s group has established. “It allows both small and large molecules to enter, but the half-life of Lexiscan is short,” Bynoe says. “You get maximal increase in 30 minutes and right at 30 minutes, it starts to close.”
In mouse models, Bynoe’s group has seen no adverse effects of permeating the barrier for this amount of time. They’ve also tested the use of Lexiscan on an engineered model that mimics the human BBB, with human primary endothelial cells, and found similar results as in their mouse models. They are now assessing the effectiveness of chemotherapy drugs on glioblastomas in mouse models; preliminary results are encouraging. Bynoe is also collaborating with a team of scientists at Johns Hopkins Kimmel Cancer Center, spear-headed by oncologist Stuart Grossman, who are using Lexiscan to treat glioblastomas in human patients.
Lexiscan, Effective for Difficult Cancers?
There’s even more good news about Lexiscan, because the A2A adenosine receptors it binds to are not only found on the BBB but also in places prone to cancer and on chemo-resistant tumors. Triple-negative breast cancer (TNBC), the most difficult form to treat, is one example. “The reason these cancers are triple negative is that they’re negative for the receptors you can use to treat the patient,” Bynoe says. “But we found this A2A adenosine receptor highly expressed on TNBCs, so there is hope that Lexiscan can act on them.”
Adenosine receptors are also found on colon tumors, other kinds of breast cancers, lung cancers, and more. Lexiscan could be used to target these tumors and to permeate them, providing an opening to directly administer chemotherapy or other therapeutics.
“The downside of that is if you administer Lexiscan along with a drug for, say, colon cancer, the drug is also going to get into other parts of the body where those receptors are expressed,” Bynoe says. “One of the things we’re working on is to see if we can get targeted permeability. That’s going to take a longer time, but it’s the eventual goal.”
“Now that we know what Lexiscan can do, we may also try to design our own drug that could open the blood-brain barrier for a longer duration, maybe two hours, for larger size compounds.”
For now, Bynoe is working with the Cornell Center for Technology Licensing to commercialize the use of Lexiscan or other compounds that activate A2A adenosine receptors. “Now that we know what Lexiscan can do, we may also try to design our own drug that could open the blood-brain barrier for a longer duration, maybe two hours, for larger size compounds, because the bigger the molecules, the longer it takes to cross the barrier,” Bynoe says.
Bynoe’s lab is broadly interested in neuroinflammation—what causes it and how it relates to disease. The lab recently showed, for instance, that Toxoplasma gondii, a parasite found all over the world, infecting up to half of the population, contributes to brain inflammation and the buildup of Alzheimer’s plaques in the brain.
Studying inflammation in the brain has also led Bynoe along the gut-brain axis, the increasingly established link between the gut and the brain. With Rodrigo Bicalho, Population Medicine and Diagnostic Sciences, she is studying how diet and the gut microbiome affects neuroinflammation. “What we have found is that if we put mice on a high-fat diet, they develop a very potent inflammation,” Bynoe says. “And we get this shift called dysbiosis in the gut microbiome, where the population of pro-inflammatory microbes predominate, shifting it to a more pathogenic, inflammatory microbiome.”
When Bynoe and her team took the inflammatory microbiome out of the high-fat mouse model and put it into mice whose microbiome had been cleared out, the brains of the new mouse models immediately became inflamed. “They developed rampant brain inflammation in one week,” Bynoe says. “That really confirmed for me this definite link between gut and brain. We also found that the type of cytokines produced are the ones linked to Alzheimer’s and dementia.”
Recently, Bynoe’s group has realized that neuroinflammation alters the BBB as well. “The blood-brain barrier is there to protect the environment of the brain, so imagine it’s gradually being broken down,” Bynoe says. “This would allow changes in the environment of the brain by allowing salts, sugars, water, and anything else to get in, and that could have very detrimental consequences to the patient.” Bynoe is pursuing funding to further study this connection between the microbiome and the BBB.
Research That Pursues Real Human Problems and Its Challenges
The thing Bynoe loves most about scientific research is the challenge. “The thinking part of it, the problem solving,” she says, “it’s constant problem solving. It challenges your intellect, and I think it’s what drives us. Even if something fails, it becomes an even bigger question, and drives you crazier. I like that a lot.”
The motivation also comes from pursuing real human problems, Bynoe continues. “It’s not so abstract,” she says. “When I think about fundamental research, I also think about how the fundamental questions can benefit disease or health. It’s a challenge, but I do both.”
Challenge, and rising to it, has defined much of Bynoe’s career inside the lab and out. She came to the United States in her early twenties from Saint Vincent, a small island in the Caribbean. She navigated a new culture and even raised a daughter while in graduate school. Along the way, as a woman and a minority, she has faced discrimination both in academia and in industry. “There is a lot of negative connotation that has been placed on us and our lives for generations, and it’s really hard to shake off those biases,” she says. “But by no means does it make me want to quit or even slow down.”
Quite the contrary. “Look out,” Bynoe says. “They’re going to hear me coming. And I have not even gotten started. I have not even scratched the surface.”