Better Brain Surgery

Neurosurgeon Keith Black is determined to enter the brain in a friendly way.

By Le Anne Schreiber|Wednesday, April 21, 2004
RELATED TAGS: MENTAL HEALTH

If neurosurgery were Mount Kilimanjaro, with a broad base rising volcanically toward a single snowcapped peak, Keith Black would stand poised, virtually alone, at its summit. Of the 4,500 or so practicing neurosurgeons in the United States, only about 100 work routinely within the brain; the other 4,400 stay within the relatively safer, lower base camps of the neck and spine. Of those who venture into the skull, about half restrict themselves to repairing blood-vessel damage on the brain’s surface. That leaves about 50 who delve deeper into the brain’s recesses. Each performs an average of 100 surgeries a year. A handful, including Black, perform closer to 250 operations a year. Alone among that handful, Black won international acclaim for his research as a neuroscientist by the age of 39. A man who thrives on challenge, Black once climbed the actual Kilimanjaro, but the struggle that consumes him is his daily search for a cure for the deadliest form of brain cancer.

As he sits across the conference table in his corner office at Cedars-Sinai Medical Center in Los Angeles, it is clear that such descriptions make him nervous. Like most men who scale high mountains, he has had close calls with hubris. He knows the double edge of outsize ambition—its power both to set one’s course and to undo it. In fact, he remembers the precise day on which his course was set—and the day, several years later, when it was undone, then reset.

“I was 19,” Black says, in a soft-spoken voice that bears traces of his Alabama boyhood, “in my first year at the University of Michigan, when I opened up my first neuroanatomy textbook, and knew what I wanted to do.” Until then, he had devoted himself precociously to the heart, publishing his first scientific paper, on damage to red blood cells from open-heart surgery, at age 17. “But it took just one look into that neuroanatomy book,” Black says, “and I sort of forgot about the heart. If you look at the anatomy, the structure, the function, there’s nothing in the universe that’s more beautiful, that’s more complex, than the human brain.”

What compelled his interest was the mystery of consciousness. “I wanted to understand how sensory information enters the brain and gives rise to thought,” he says.

And so, Black says, “I studied everything I could get my hands on about neuroanatomy, neurochemistry, neurophysiology, but at some point I realized I was just learning more and more about less and less. I wasn’t getting any closer to explaining consciousness.” In medical school, he expanded his studies to include philosophy but hit dead ends like the classic paradox, How can a brain ever understand itself if an organism has to be more complex than the organism it is trying to comprehend? The next avenue for Black was “studying different religions, looking for common truths.”

“I became very spiritual,” he says. He began meditating, hoping to stumble upon a secret route to understanding consciousness. “One day, when I was about 24, I was meditating, and I had this out-of-body experience. I felt myself sort of rising up to the ceiling, looking down on myself, and I heard this voice saying, ‘If you want to understand consciousness, go through the ceiling.’ And I remember being very afraid.

“Then the voice said, ‘But if you go through the ceiling, there’s no need to come back,’ as if the message was: If you actually understood consciousness, you would also understand there was no reason to be here on Earth anymore.

“I said, ‘I think I want to stay here.’ ”

That day Black decided to leave the mystery of consciousness alone for a while and to apply himself instead to doing some earthly good for the human brain.

If he couldn’t master what he calls the sacred brain, he could at least serve it. And with that attitude, he embarked on a neurosurgical residency at the University of Michigan in 1982. He focused almost immediately on the challenge of defending the brain against its deadliest enemy—glioblastoma multiforme, the most common and rapacious form of primary brain cancer. Mean survival time without surgery is five months, and if a tumor is located near parts of the brain that control essential functions, like speech, perception, or motor activity, most surgeons consider it inoperable.

Black’s goal was to develop the skills to operate on the inoperable, and the awe with which he regards the brain helped him develop those skills. During his residency, he saw the damage done to the brain by the instruments of surgery. His approach: “I never touch the brain.” His goal is to touch only the tumor.

“The whole concept,” he says, “is to slip in and out like a thief in the night, stealing the tumor without ever waking the sleeping brain.” Advances in imaging technology over the past two decades have greatly enhanced the precision of neurosurgery, but as Black says, “you still have to integrate that technology in a way that allows you to decide what the safest corridor is into the brain, and you still have to remove the tumor.”

If you want to get an approximate feel for the delicacy required, try removing a peach pit from a bowl of jelly without making it jiggle. What it takes, Black says, is “partly a matter of eye-hand coordination, dexterity, focus, knowledge of neuroanatomy, the ability to visualize eloquent areas and abnormalities in a 3-D configuration. But it also becomes a matter of judgment, and then, in some way, it also becomes a spiritual sense. Sometimes you just get a sense of how you should do it.

“It’s a very delicate balance,” he adds, “staying just at the edge of the envelope, getting out all the tumor, and only the tumor, leaving the patient with absolutely no loss of function.”

That ability to stay just at the edge of the envelope is what has made Black one of the world’s most sought-after neurosurgeons, first at UCLA, where at 36 he became the youngest-ever full professor of neurosurgery, and now at Cedars-Sinai, where at 46 he has already performed more than 4,000 brain surgeries, the medical equivalent of closing in on baseball’s all-time career hits record.

Yet, as a surgeon, Black is not a success in the terms that matter most to him. “I don’t want to see any more of my patients die,” he says. “Next month I will have patients diagnosed with glioblastoma, and I know that even with the best surgery, I can only double their survival time, say, from 6 to 12 months, or one year to two.”

Glioblastoma is a disease so resistant to conventional treatment that the grim statistics—5 percent survival two years after diagnosis—have not budged in 40 years. “After surgery, you always have microscopic cells that spread,” he says, “and they hide throughout the brain, beyond the areas we can visualize by any kind of imaging technology. Radiation has a narrow window before you start killing normal brain. And chemotherapy is not very effective because most chemotherapeutic agents don’t pass out of the bloodstream into the brain.”

The obstacle to chemotherapy is the blood-brain barrier, the tight mesh of small capillaries within the brain, protecting it from many toxins in the bloodstream but also preventing chemotherapy from entering. So both at Michigan and at UCLA, Black’s long days of surgical training and practice were followed by long nights in the laboratory, looking for a stealth agent that could open the blood-brain barrier. In 1993 he found it—bradykinin, a peptide that occurs naturally in the body and could temporarily open only the portion of the blood-brain barrier supplying blood to a feeding tumor. Then he turned his attention to a synthetic analogue of bradykinin, called RMP-7, that allowed 10 times more chemotherapy to be delivered to the tumor during the 20-minute window that the blood-brain barrier was open.

In 1996, when RMP-7 was first used on brain cancer patients in a Phase 1 clinical trial at UCLA, it was found to be safe, with virtually no side effects. Black became a medical superstar at age 39, profiled in an hour-long documentary on PBS called Outsmarting the Brain and elaborately honored with awards by his peers. In October 1997 he was featured on the cover of Time as a “Hero of Medicine.”

Black wasted no time luxuriating in success. He knew that outwitting the brain is not the same as outwitting brain cancer. He might have discovered a safe way of delivering anticancer agents to the brain, but unless he—or someone—discovered what should be delivered, lives would not be saved.

During the years he worked on blood-brain barrier research, a parallel growth of medical knowledge had occurred in genetics, immunology, and molecular biology. Black grew frustrated that so little of that knowledge had been translated into effective new treatments for patients. The problem, as he saw it, was that the explosion of scientific knowledge had coincided with the implosion of academic medicine under the ecocomic pressures of a costly health-care system. The gap between clinical practice and laboratory science had become a chasm.

“When I entered medicine,” Black says, “academic surgeons were provided protected research time, a salary, office space, lab space, and support personnel. But that paradigm is gone. A surgeon who wants to do research is expected to fund it through his own patient fees and get his own grants. Young physicians think: I might as well be in private practice.” The result is a two-track system in which medical research is conducted by Ph.D.’s, and medical practice is conducted by physicians with little access to what is discovered by the academics.

Concluding that universities were not the answer, Black used his newly minted hero status to talk a private medical center into taking up the challenge. In 1997 he moved across town, from UCLA to Cedars-Sinai Medical Center, where he founded the Maxine Dunitz Neurosurgical Institute. “What we said,” says Black, who is so conscious of his team that he uses we even when I is clearly called for, “is we’re going to break down those walls, put the Ph.D.’s and physicians together, so we can begin to work on the same problems.” At the institute, in addition to serving as Cedars-Sinai’s chief of neurosurgery, he presides over a team of 46 physicians and researchers whom he personally recruited for what he calls a Manhattan Project directed at brain cancer.

Soon after he founded the institute, Black had reason to be grateful that he could draw on its funding and support. His work on RMP-7 came to naught in 1998: “We demonstrated in the Phase 1 and 2 trials that when RMP-7 was delivered directly into the carotid artery that fed the tumor, we could open the blood-brain barrier and get clinical responses to the chemo. But when it came time for Phase 3 trials, the pharmaceutical company we had licensed RMP-7 to decided to deliver it intravenously rather than arterially, because that wouldn’t require hospitalizing a patient and so there would be a much bigger market.” Despite Black’s efforts to convince the company “as forcefully as I could” that RMP-7 would not be effective if delivered intravenously, the company proceeded against his advice. When they didn’t get significant results, that failure was effectively the end of RMP-7 as a treatment for brain cancer.

Black’s description of the brick wall into which more than a decade of his research crashed is delivered in calm, measured tones, without the slightest tinge of righteous indignation or even regret. He calls it a learning experience. With the resources of the institute to draw on, he says, “we went back to the laboratory and came up with a better pathway to open the blood-brain barrier.” He gestures toward a broad expanse of office wall, decorated with framed covers of medical journals that have given top billing to results published by the institute’s research teams. He points to the June 2002 issue of The Journal of Pharmacology, the cover of which sports an elaborate diagram of his “better pathway.”

“We’ve discovered that calcium-dependent potassium channels are the gateways to brain tumor capillaries and to the tumor itself, and we’ve found agents that will keep those channels open much longer than RMP-7,” Black says. And, he adds, the agents can be delivered intravenously.

This time, however, Black is not licensing his method to a pharmaceutical company. “We’re forming our own company,” he says, “and we’re going to do it right this time, with a study that is designed appropriately.” Phase 1 trials should begin within a year if all goes as expected.

So, on top of performing 250 surgeries a year, directing the work of five research teams, administering the institute and fund-raising for it, on top of a demanding speaking schedule and active service on many medical boards, on top of preserving Sundays as family days often spent sailing with his wife, Carol, a urologist at UCLA, their son, Keith Quinten, 13, and daughter, Teal, 16, Black has become a biotech entrepreneur.

“It’s all necessary,” he says. “You can have a great laboratory discovery, but if it just sits on the lab shelf, you haven’t completed the process.”

Black’s equanimity in the face of obstacles seems a direct inheritance from his father, whom Black describes as “the ultimate educator.”

“I taught my sons what my father taught me,” says Robert Black, for whom the paradigmatic obstacle was racism. “Don’t create a problem out of a solution. When there’s a barrier to overcome, don’t agitate it, solve it.” As principal of a segregated elementary school in Auburn, Alabama, during George Wallace’s racially heated reign as governor, Robert Black could not integrate the student body legally, so he integrated the faculty instead. When his son’s educational needs outstripped the school’s capacity, he provided the resources at home. When he saw 9-year-old Keith cadging chicken hearts from the kitchen sink to practice dissection, he got his son progressively larger hearts so the boy could get a bigger picture, first from turkeys and finally from cows, acquired at the local slaughterhouse.

When the family moved to Cleveland, Ohio, and couldn’t afford to buy a home in suburban Shaker Heights, which boasted one of the country’s best school systems, Robert Black decided it would be better to rent than to own until his younger son graduated from high school. At Shaker Heights High School the young Black won the Westinghouse Science Award.

Asked whether he is the model for his son’s deft, sidestepping approach to problem solving, the father laughs and sidesteps the question: “No, Keith learned that from paramecium. When a paramecium bumps into something, it just slides off in a different direction.” Of his father, to whom he still turns for advice, Black says, “He made us feel there was nothing we couldn’t do.”

Does that include finding a solution for brain cancer at Manhattan Project speed? “Absolutely,” says Black. “We’re not a Pfizer. I don’t have an army of 15,000 researchers all working on a problem, but I think we’re poised to make very significant progress in brain cancer treatment with our small band here, probably more than has been done in the last 30 or 40 years. And it may not be one approach but four or five approaches.” One index of his small band’s productivity is their publication of more than 120 articles in peer-reviewed journals in the six years since the institute was founded.

What most encourages Black, in addition to the new breakthrough in blood-brain barrier research, are the results of a Phase 1 clinical trial of an anticancer vaccine that began at the institute in 1998. To make the vaccine, cancer cells are harvested from a tumor after surgery and stripped of their proteins; then those proteins are cultured with dendritic cells, a subclass of white blood cells, drawn from the patient’s blood. The specialized immune-system function of dendritic cells is to sample proteins and serve as a sort of security guard, sorting out alien proteins from the home team. When they find an intruder, the dendritic cells brandish a sample (think of a most-wanted poster) and rush to the lymphatic system, where they present it to T cells, whose role is to form a posse and fan out through the body to hunt down and kill any proteins that look like the poster.

Dendritic cells are too large to pass through the blood-brain barrier, which is one reason they have to be cultured with brain tumor cells outside the body, then injected back into the patient’s skin as a vaccine. “Naive” T cells (those still waiting for an assignment) are also too large, but activated T cells condense themselves to a size that is capable of crossing the barrier. Subsequent surgery on vaccinated patients has shown that the T cells are finding and killing tumor cells in the brain, but not enough of them.

“The first results looked good,” says Chris Wheeler, a research immunologist recruited by Black from Stanford to work on the vaccine, “but then it didn’t hold up.” Fifty brain cancer patients received the vaccine between 1998 and 2001, and the first patient to receive the vaccine, Lindsay Glassford, now 32, says, “There were no side effects at all. I really feel the way I did five years ago, before all this happened.” But Lindsay had a grade III anaplastic astrocytoma, one step below glioblastoma multiforme, the most aggressive form of brain cancer. For patients with glioblastoma multiforme, the vaccine did not seem to prevent the recurrence of cancer, so those patients were offered follow-up chemotherapy. What happened surprised everyone, including Black and Wheeler. Although the vaccine alone did not increase two-year survival rates beyond 8 percent, and chemotherapy alone had never increased survival beyond 8 percent either, when chemo was given to previously vaccinated patients, the survival curve began to go up.

“Among the subgroup of vaccinated patients who chose to have chemo later, we are seeing 40 percent survival at two years and 20 percent survival at three years,” says Black. “This is unheard of among glioblastoma multiforme patients.” Wheeler, who is trying to identify the mechanism responsible for the results, believes that combining the vaccine and chemotherapy is not simply “additive” but “synergistic.” He is investigating the possibility that the vaccine induces chromosomal change within those tumor cells that manage to escape the immune attack, and that the change makes remaining tumor cells more vulnerable to chemotherapy.

Papers detailing these results, the first research ever to look at the synergy of immunotherapy with conventional chemotherapy, have been submitted to peer-reviewed journals, and Black thinks publication will generate considerable excitement among cancer researchers, who have until now seen mostly disappointing results from vaccine therapies against other cancers. “They will be intrigued,” Black says, “but they will want to see the results repeated in a larger, randomized clinical trial.” That trial is exactly what Black plans as soon as he gets necessary approvals, probably within a year.

Meanwhile, his research teams are moving several other novel therapies toward clinical trials, each of which has potential for use in the synergistic model of cancer treatment that Black believes will offer the best hope for his patients. A team headed by neurosurgeon John Yu has discovered that neural stem cells have the ability to track metastasized brain cancer cells as they migrate from the tumor. Furthermore, they have found that neural stems cells can be culled from the patient’s bone marrow, thus circumventing ethical and political obstacles to neural stem cell therapy as well as problems with immune rejection that sometimes arise when researchers must employ embryonic stem cell lines. Their in vivo studies in mice have shown that neural stem cells can be genetically modified in the lab to secrete anticancer agents, like interleukin-12, so that they will track down and kill cancer cells in both the tumor and its satellites without harming normal brain tissue.

At the institute, gene discovery is the province of Julia Ljubimova, a molecular biologist who has isolated laminum-8, a gene she believes is responsible for the rapid growth of new blood vessels in the most invasive cancers. Using a technology called antisense, she has been able to switch off laminum-8, and its synthesis of protein, in mice. “We saw the formation of new blood vessels in tumors reduced by 70 percent,” she says. She expects she will find laminum-8 uniquely overexpressed in other invasive cancers, like lung and colon cancer, but to date she has tested for it in only human brain and metastatic breast cancer.

Like many of the researchers at the institute, Ljubimova is ebullient about her research. “This is,” she says, “the most important work I have done in 15 years of cancer research. And I am very proud of it. This is the advantage of working with Keith Black. Not many clinicians have the ability and will to support science so fully and to immediately see the potential for treatment.”

Yu describes the institute as a “mom-and-pop shop” that will revolutionize the way neurosurgery is practiced around the world. “Most neurosurgeons, when they see a brain tumor, don’t do anything different now from what they would have done 50 years ago. They just take the tumor out and pass the patient on to an oncologist, schedule a follow-up in a year, and see if the patient comes back alive. It’s very nihilistic. Here, surgeons and researchers feed off one another’s experience, so if we come up with something promising in the lab, we can have a clinical protocol for patients within six months.”

Yu, one of only a handful of surgeons in the country who keeps up with Black’s pace of roughly 250 surgeries a year, says, “I think about the research ideas we’re working on every waking moment. I operate and think about it. I golf and think about it.” And, he adds, “It’s hard to do research these days. You have to have a committed institution that sees a long-term vision and not just the monthly accounts receivable, as well as a visionary director.”

Black, as befits the visionary label, has an extraordinary gaze. He holds body and face still, as if conserving energy for the turning of mental wheels, and from that stillness emerges a steady stare, supercharged with intelligence, that is simultaneously wide-eyed and intensely focused—as if his lens were permanently set on both panorama and close-up. That’s the way his mind appears to work. He sees the big picture and the detail—or to use a metaphor often applied to cancer, the battle and the war.

“Our concept,” he says, “is a multipronged attack because we know the tumor is going to fight back. But you can imagine taking stem cells, modifying them with an immune-stimulating protein like interleukin-12, putting the stem cells in the brain, where they seek out tumors like a heat-seeking missile. Then the stem cells release the interleukin, which is like a beacon to tell the immune system to come in and attack, right here. That’s the Special Ops. Then you activate the killer T cells with the dendritic-cell vaccine, so now you’ve got all your smart bombs and your cruise missiles coming in from outside. Then you open the potassium channels, and let the chemo, the conventional troops, come in. . . .”

Would all this carefully targeted weaponry that destroys cancer cells without inflicting collateral damage on normal tissue work on cancers outside the brain? “Yes,” Black says, “because if you can do it in the brain, you can do it anywhere.”

If the war is won, what then? “Once we’ve solved the problem of brain tumors,” he says, eyes widening to full panorama, “I want to return to the study of consciousness. That’s what I’ve always wanted to do. My whole plan was to work on some real research and then come back to consciousness. I hope that one of my more important contributions might ultimately come in that area.”

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