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The Surgeon Scientist

UCLA Medicine Fall 2009-Dr. Linda LiauWHETHER IN THE OPERATING ROOM OR HER LABORATORY, DR. LINDA LIAUWORKS ON THE CUTTING-EDGE OF SCIENCE TO EXTEND THE LIVES OF PATIENTSWITH BRAIN CANCER.

LINDA LIAU,M.D., PH.D., stands outside the neurosurgical operating room on an August morning, amiably talking with her husband about who is going to pick up the kids after school. Her spouse, Marvin Bergsneider, M.D., is also a UCLA neurosurgeon, and he mentions that he has a meeting to attend, to which Dr. Liau, jabbing with her thumb over her shoulder toward the OR, responds, “Yes, but I have a brain surgery to do.” Brain surgery trumps meeting, and 15minutes later, Dr. Liau, having resolved the minutia of everyday family life, is scrubbed and standing over a patient’s open skull preparing to save his life.

ON AVERAGE, Dr. Liau operates about four times a week – two-a-day on Mondays and Thursdays. One day a week, she is in clinic. For one week out of every six, she is on 24-hour call for emergencies, and she is the editor-in-chief of a prestigious academic publication, the Journal of Neuro-Oncology, which she works on at home, between the hours of 9 p.m. and 2 a.m., when her children, Bianca, 8, and Brendon, 11, are in bed.

And the rest of the time? Between meetings, rounds, responding to e-mails and collaborating with other physicians and postdoctoral fellows on various projects, Dr. Liau has made her mark as a pioneering scientist, working in her laboratory to refine a promising new vaccine that is custom-tailored to each patient to thwart the recurrence of brain cancer once it has been surgically removed. The vaccine is compounded from the patient’s own tumor and immune cells and is now undergoing its third clinical trial and showing remarkable promise. For some of the patients in Dr. Liau’s studies, it has probably added months, even years, of life following a disease that is frequently, and often quickly, fatal. To manage all this work and her family, Dr. Liau averages about four hours of sleep a night, “which for me is plenty,” she says, although she does admit to being a little grumpy when she first wakes up in the morning.

IN A FIELD DOMINATED BY MEN, Dr. Liau’s reputation as a surgeon and scientist is international. Other top-ranked medical centers have tried to woo her, offering her chair positions in their neurosurgery departments. She is, say professional colleagues, among an elite handful of neurosurgeons who are leading the way in translational research to find solutions to a terrible disease. And in addition to being a gifted surgeon and innovative researcher, “Dr. Liau is an inspirational educator and mentor for the next generation of clinician-scholars,” says Joseph Piepmeier, M.D., vice chair of neurosurgery at Yale University School of Medicine and Dr. Liau’s predecessor as editor of Neuro- Oncology.

Although there have been many offers, she has elected to stay at UCLA, where she received her neurosurgical training and earned a Ph.D. in molecular neuroscience, and her patients are grateful. Many have come to Los Angeles from other parts of the country after learning about her from their own independent research.

That is how Dominic Bakewell, the patient on the table inside the UCLA hospital operating suite that August morning, found Dr. Liau. A singer-songwriter who played guitar for a time with the New Wave band Berlin in the 1980s, Bakewell was at home in 2006 with his 2-year-old son, Julian, when he had a seizure that left him unconscious. When Bakewell woke up, he was lying in his bed, and there was blood on his pillow. To this day, he has no memory of how he got there.

“I blacked out and must have hit my head, but somehow I made it to my bed. When I woke up and saw the blood, I couldn’t make sense of it,” Bakewell says. “What just happened?”

His wife, Sarah, met him at a nearby ER, where an MRI failed to reveal a problem. It was not until he had a second seizure a month later, and a second brain scan, that his diagnosis was made. The MRI showed that a tumor had formed on the left frontal side of his brain. Bakewell had a glioma – a tumor that forms from glial cells that normally provide support and nutrition to the brain’s neurons. Patients with a grade-1 glioma, the slowest growing, can live for years. A grade-4 glioma, called a glioblastoma, is the fastest growing and most lethal.

When Bakewell and his wife started looking for the best surgeon they could find, they were quickly attracted to Dr. Liau. She was young, she was cutting-edge and she was a researcher as well as a surgeon. She was not just excising tumors; she was looking for ways to stop them in their tracks.

But when Bakewell and Dr. Liau met, the news was not good. There was the problem of the tumor’s location. Before meeting Dr. Liau, neuropsychologists at UCLA’s Brain Mapping Center had scanned Bakewell’s head to identify the critical regions in his brain that control speech and motor movement. “Imaging gives us what amounts to a GPS system for the brain,” says Dr. Liau, “which gives us more confidence during the surgery about where we are in the brain and what can be safely cut.”

It was found that Bakewell’s tumor was pressing against the motor and speech areas of his brain. It was devastating enough to be diagnosed with a brain tumor, but for a guitar-playing singer and songwriter, the news of its location made things much worse.

And as detailed as the brain map is, there is no clear demarcation in the brain that says speech is here and motor ability is there. Every human brain varies slightly from every other human brain. Mere centimeters could be critical. Cut a little too much this way or that way, and Bakewell could lose his ability to speak.

And then there’s the standard litany of potential complications that are always a possibility with any surgical assault to the brain – bleeding, allergic reaction to medications, infections, seizure, stroke, paralysis, loss of sensation – the list goes on. Bakewell’s surgery was risky business.

IT WAS HER mother’s death from a brain tumor that inspired Dr. Liau to pursue her current course. Her mom had long been Dr. Liau’s chief cheerleader, encouraging her over and over that she could do whatever she wanted to do in life. Dr. Liau was in the third year of her residency at UCLA when her mother was diagnosed with cancer that had started in her breast and then progressed to her brain. Two weeks before Dr. Liau’s sister was to be married, their mother entered the hospital at UCLA. “My sister changed her wedding plans and was married in the hospital by my mother’s bedside,” Dr. Liau recalls. “The UCLA chaplain did the ceremony, and the nurses were the bridesmaids.” It was a nice moment, and a memorable one, but it was bittersweet – her mother died shortly after. She was only 51.

“After her death, I was angry as well as heartbroken,” Dr. Liau says. “I remember thinking, ‘Why hasn’t there been more progress with this disease?’”

It was the motivation for her to begin a dual-career path as a surgeon and a researcher, and it had a positive side effect. “Doing lab work helped me deal with the emotional aspects with regard to my patients. It makes me feel better, because I feel that I am contributing to knowledge about this disease,” she says.

Her dedication in both the OR and the lab has made Dr. Liau, in the words of one admiring colleague, “the classic triple-threat.” “She is an innovative and caring physician; a superb teacher, mentor and example; and an investigator of international renown,” says Webster K. Cavenee, Ph.D., director of the Ludwig Institute for Cancer Research at the University of California, San Diego.

UCLA Medicine Fall 2009-Dominc Bakewell
Singer-songwriter Dominic Bakewell underwent an awake craniotomy to remove a glioma. Today, he is back to enjoying being a husband to Sarah and father to Julian.
AS DOMINIC BAKEWELL is wheeled into the OR, following an emotional, tear-filled parting from Sarah, Dr. Liau and her colleagues are preparing to perform a procedure that only a handful of medical centers in the United States offer: an awake craniotomy. To the uninitiated, the procedure sounds ghastly, like something from a lowbudget horror movie – the patient, a section of his skull sawed open and his brain exposed, is brought out from under anesthesia and awakened. It is possible to do this because the brain has no pain receptors. And it is a key surgical strategy when a tumor like Bakewell’s is pressed tight against the brain’s speech and motor centers.

Once the chunk of Bakewell’s skull is taken out and a palm-sized area of brain revealed, it is time for Dr. Liau to go to work. Over the course of several hours, she resects, or cuts out, as much of the tumor as she safely can, based on what the multiple brain images show her. Finally, though, she is as close as she can get to the borderless margin where tumor and healthy brain matter intersect. It is time to wake Bakewell.

Neuroanesthesiologist Barbara Van De Wiele, M.D., carefully lightens Bakewell’s sedation, allowing him to awaken from his sleep. “Sarah!” The first thing a foggy Bakewell does is cry out for his wife. The second thing he does is try to sit up.

But Bakewell has nowhere to go. His head is held tightly in a metal clamp; his body is strapped to the table; and nurses and doctors surround him, firmly holding him in place.

“Dominic, it’s Susan. Can you hear me? You are in the operating room. You are waking up.”

The voice is that of Susan Bookheimer, Ph.D., a professor of psychiatry and member of the Brain Mapping Center. Dr. Bookheimer led the team that plotted Bakewell’s brain to identify the location of the critical areas.

Dr. Bookheimer leans closer to Bakewell. “Dominic, I need you to open your eyes and be very still.” Bakewell responds, groggily asking for water.

Using a grid developed from the brain map as her guide, Dr. Liau begins to probe Bakewell’s brain, trying to define the border between the tumor and the cells that control Bakewell’s ability to speak. With a nod to Dr. Bookheimer, Dr. Liau uses an electrified wand to touch the surface of the brain to temporarily short-circuit the ability of Bakewell’s neurons to communicate. At the same time, Dr. Bookheimer holds up a flashcard inches from Bakewell’s eyes. On it is a picture of a cat. As long as Dr. Liau stimulates those verbal cells to block their neural activity, Bakewell is unable to remember the word for cat. He knows what it is; he just cannot think of the right word.

When Dr. Liau lifts the wand, stopping the current, Bakewell responds. “Cat,” he whispers.

“Good,” replies Dr. Bookheimer.

Dr. Liau uses the wand to touch a different area of his brain. Dr. Bookheimer holds up another card, a house. Bakewell can’t think of the word until Dr. Liau lifts the wand. “House,” he says.

And so it goes. Stimulate. Picture. Answer. When Dr. Liau stimulates a part of the brain and Bakewell can still respond, she knows she can safely slice away at the tumor without doing damage. At some point in the process, Dr. Bookheimer has Bakewell hum – they are searching for the exact location of his musical ability – and then has him wiggle his fingers to mimic the playing of a guitar. Finally, at the end of a tiring six-hour surgery, Bakewell is put back under anesthesia, and his skull and scalp are replaced.

It has been three years since Bakewell’s surgery, and he is doing well. There was a scare in the months afterward; swelling in his brain prevented him from speaking yet, oddly, not from singing. But after therapy and hard work, he is singing and playing guitar again, and enjoying life as a husband and father. Last year, he released an album of children’s songs.

He has resumed driving, although he remains on anti-seizure medication. Every three months, Bakewell undergoes a nerve-wracking MRI to check for any new tumor growth; so far, his brain is clear, but it is always a “pins-and-needles” moment, says his wife. She notices her husband’s conversational skills are not as sharp as they once were, and he is a little quicker with his temper. Bakewell says he has not discerned either one. Asked if he has anything else to say about his experience, he pauses, and then says simply, “I’d like to thank Dr. Liau for saving my life.”

DR. LIAU WAS A YOUNG whippersnapper when she started working on a brain cancer vaccine in 1998. At the time, she was a 31-year-old assistant professor, working with Michael Roth, M.D., a professor of medicine in the Division of Pulmonary and Critical Care Medicine, and James Economou, M.D., Ph.D., a professor of surgical oncology and molecular and medical pharmacology. Both were working on vaccines – Dr. Roth on cellular vaccines for lung cancer, Dr. Economou on immunotherapy for melanoma.

“It was certainly not a eureka! moment,” says Dr. Liau. “It was more just a question that came to me. If it could possibly work for lung cancer and melanoma, why not brain cancer?”

While Dr. Liau has refined her brain cancer vaccine over the years, the process by which it is made has remained basically the same, with each vaccine custom made for each eligible patient. (In her current clinical trial, only patients diagnosed with grade-4 glioblastomas are eligible.) Dr. Liau’s lab first extracts proteins from the patient’s tumor, then extracts the patients’ own dendritic cells from their blood. These dendritic cells are a special type of cell, says Dr. Liau, that are absolutely essential for the start of any immune-system response, be it to a bacterial infection, a virus or a tumor.

The dendritic cells are then loaded with extracts of the tumor cells and injected back into the skin of the patient, where they behave as if they just encountered an infection: They travel to the lymph nodes to “tell” the immune system about the tumor cells. The ensuing activation of the immune system results in the generation of killer T-cells that travel through the body. When these cells encounter a tumor cell, they kill it.

The ultimate goal, says Dr. Liau, is to make a clean sweep of whatever cancer cells are left behind after surgery. What makes glioblastoma so lethal is the speed at which it grows and sends microscopic shoots into different areas of the brain. Even the most talented neurosurgeon cannot excise a complete tumor cell by cell by cell.

“So we are hopeful that cancer vaccines have the potential to do more than kill what’s left of an existing tumor,” says Dr. Liau. “Once we are able to prolong life through molecular targeted cocktails of treatment, I think the next step is to cure the disease by giving a vaccine that can get rid of the microscopic cancer cells and hopefully prevent the cancer from coming back.”

Is the vaccine working? Dr. Liau has patients who have lived four and five years beyond the expected life span for glioblastoma. One has survived nine years.

SCOTT BURK is among those survivors. His doctors in Cincinnati offered him “no hope,” says his wife, Andrea, giving him at most two years to live when he was diagnosed in 1999 with an oligodendroglioma. He has survived three brain surgeries, all by Dr. Liau, in 2000, 2004 and 2008. He has been on the vaccine since 2004, when his tumor advanced to a malignant glioma, making him eligible for her trials under the protocols of Dr. Liau’s National Institutes of Health grant. Now Burk and his wife fly to L.A. every three months for him to receive a booster shot.

Burk was diagnosed at the age of 33, when he had a seizure after jumping into a swimming pool and passed out. “If Andrea hadn’t been there to pull me out of the water, I would have drowned,” he says.

His diagnosis embittered him for a time. Like Dr. Liau, Burk is an M.D./Ph.D., a Harvard-trained ophthalmologist and a molecular biologist. He was at the top of his game, performing some 10 cataract surgeries a week when the tumor struck. “It was about as not fair as it could be,” he says. They grieved and they cried, says Andrea, and then they got on with it. The consummate researcher, Burk found Dr. Liau.

At first, the tumor colored everything in their lives. They waffled back and forth about whether to have kids (they did). They consulted a lawyer to get Burk’s affairs in order. Andrea, an ophthalmologist trained in her native Brazil and now a full-time mom, still thinks about returning to medicine.

But the days now are no longer so dark. They meet each hurdle as it comes. In 2004, when the seizures came back and Burk needed another surgery, he lost the fine motor skills in his right hand. He had to give up surgery but still sees patients in his practice. In 2008, he had his third surgery, which has affected his left leg, throwing off his gait.

Burk and his wife refuse to give in to pessimism. “We try not to suffer in advance of things,” says Burk, now 43. “And we don’t argue anymore,” says Andrea. “About anything. Nothing is worth arguing about. We are simply grateful for every day.”

UCLA Medicine Fall 2009-Vaccine
To create the brain cancer vaccine, proteins are extracted from the patient’s tumor and then loaded into dendritic cells taken from the patient’s blood. Once injected back into the patient, the modified dendritic cells behave as if they’ve encountered an infection and direct the lymph nodes to tell the immune system to launch an assault to kill the cancerous cells.
THESE ARE THE LIVES that fuel Dr. Liau’s efforts with the vaccine. But developing a vaccine is an excruciatingly slow process. The main reason? Money. With just 20,000 or so new patients diagnosed with primary brain cancer each year, there is not a big profit to be made in developing a vaccine for this disease. “Most companies want to find the next blockbuster drug,” Dr. Liau says. And since each personalized vaccine must be developed for each individual, creating the vaccine is expensive as well.

But Dr. Liau soldiers on. She is careful to tell each of her patients the “what-ifs.” The tumor may always come back, “maybe next week, maybe in five years.” Still, she is cheered by the number of patients whose lives she has extended. “It does make me feel good. I do tend to get involved in the lives of my patients. They are, as a group, nice people leading interesting lives – musicians, fi remen, doctors. But I really hope we can fi nd a cure.”

Yet, always hovering over everything is the sobering realization that the cancer still wins. Last August 29, Dr. Liau lost one that really hurt. Kevin Carlberg was a father and husband, a musician like Bakewell, and a Dr. Liau cheerleader. He raised money for her research, he spoke to media, he wore a “Don’t worry, be happy” T-shirt to every medical appointment. He never gave in. He was a four-year survivor, and in that time he married, had a child, ran a marathon and cut a CD of his music.

It was Dr. Liau, surgeon and scientist, who gave him those precious, extra years.

Mark Wheeler is a senior media relations officer for UCLA Health Sciences covering neuroscience, and a former writer and editor for Discover magazine.

 





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