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Breakthrough Medicine

Fighting cancer. Curing tremors. Developing drugs. Stemming addictions. Transplanting hands. Treating aneurysms. It’s all in a day’s work for these pioneering Minnesota doctors and researchers.

Breakthrough Medicine

Aviva Abosch

University of Minnesota
Department of Neurosurgery

Dressed in blue scrubs, a surgical mask, and two pairs of rubber gloves, Dr. Aviva Abosch stands with hunched shoulders over the patient on the table in front of her, preparing to slice into his skull and peer deep into his brain.

She jokes about needing a latté and a lunch break. Then, with six nurses and technicians bustling around her, the 48-year-old neurosurgeon makes an incision into the shaved surface of her patient’s head and pulls back the pink skin like a banana peel, revealing a nickel-sized hole that had already been drilled into the skull during a previous surgery. With steady hands under two massive surgical lights, Abosch pulls out a dysfunctional, one-millimeter-wide wire. Guided by a large metal head frame, which Abosch spent an hour setting up with precision before the surgery, a new wire fitted with four electrodes begins its slow and steady path into the man’s gray brain tissue.

Nearly two hours into the procedure, known as deep-brain stimulation, Abosch moves to a computer monitor and dims the lights in the green-tiled room. With her right hand on the mouse, she watches a skinny red line squiggle up and down on the screen, and she listens to wavering static that resembles someone trying to find a station on an AM radio dial. In fact, the noise is the sound of brain cells firing as the wire moves past them. The pattern of the cellular firing gives the surgeon a clue as to what brain structure the wire is passing through on the way to its target: an almond-sized structure called the subthalamic nucleus.

Abosch suspects excessive firing of nerves in the subthalamic nucleus has been causing a form of involuntary shaking, known as essential tremor—a source of frustration for the patient, a man in his 60s who works as the head painter on a nearby college campus. Once activated, the implanted device will send a series of ongoing electrical impulses to this region of the brain, with the goal of reducing the tremor.

“You awake, Gene? You hear all that noise? That’s your brain working,” Abosch says from her seat by the man’s feet. Suddenly, the speakers squawk loudly as if air is slowly draining from a balloon. “That’s an injured cell, Gene. You’ve got bajillions of those. Don’t cry over the loss of that one cell.”

Abosch’s operating manner is remarkably relaxed, considering she is probing the brain of a conscious patient. But for her, the procedures of deep-brain stimulation (DBS) are routine. She has done more than 250 DBS surgeries for patients with Parkinson’s disease, essential tremor, and related movement disorders since she arrived at the University of Minnesota in 2005.

In addition to the electrodes that are placed directly into the brain, DBS involves a pacemaker-like battery that goes inside the chest and a wire that snakes its way beneath the skin along the neck and behind the ear from battery to electrodes. Doctors program the device to deliver just the right amount of stimulation. Patients remain awake during implantation so that surgeons can make sure they’ve struck the right location. It may sound agonizing, but brain cells have no pain receptors, which means the patient doesn’t feel the wire going in.

As easy as she makes it look, probing the depths of the human brain isn’t necessarily what Abosch thought she would end up doing, even after she left her childhood home in suburban Buffalo for Bryn Mawr College in Pennsylvania and became interested in cognition. As an undergraduate in the early 1980s, she was fascinated by the question of what makes people different from other animals, which drove her to take a psychology course. But the class lacked any mention of how one’s sense of self worked on a fundamental level, and Abosch found the course to be unsatisfying. Instead, she turned to neuroscience, earning both an MD and a PhD at the University of Pittsburgh, where she figured she’d follow in the footsteps of her advisers and study brain development in children.

It was during a two-week rotation in neurosurgery that she had her first medical revelation—and a glimpse into her unexpected future. “It was wild,” she says. “You’re actually standing there in the operating room, you see the brain, and you see what makes us different [from animals]. I didn’t get any closer to understanding it, but it was an epiphany.”

Aviva Abosch
PHOTO BY DAVID J. TURNER (10)

Abosch’s first exposure to deep-brain stimulation came during her residency at the University of San Francisco, where in the late-90s, she worked under a surgeon who was using what was then a new, cutting-edge approach to treating movement disorders. DBS was developed in Europe in 1987. But it wasn’t until 1997—a few years after Abosch arrived in San Francisco—that DBS was approved in the United States for treating essential tremor. Approval for Parkinson’s and dystonia followed in 2002 and 2003. Since then, results have been so spectacular for muting these diseases that Abosch and colleagues are now moving into ambitious new applications. She recently treated two patients with obsessive-compulsive disorder—with hopeful, if preliminary, results.

Now, she is starting work on a clinical trial for patients with depression who haven’t responded to any other treatments, including antidepressants or electroshock therapy. Eventually, as part of the double-blinded, controlled trial, Abosch’s team will treat 15 patients with recalcitrant depression, though neither she nor the patients (nor participants undergoing the same procedure at other institutions) will be told if their implants have been activated, thus removing concerns about placebo effects or biased interpretations of results. If the technique proves effective—and there is reason to believe that it will, based on imaging studies that show hyperactivity in a part of the brain called the subgenual cingulate white matter in some people with major depression—the sky may be the limit. Researchers are discussing the possibility of using DBS to treat just about any disease that has roots in the brain, including Tourette’s syndrome, morbid obesity, eating disorders, Alzheimer’s disease, memory loss, paralysis, and more.

For a procedure with such dramatic successes and so many hopes riding on it, though, we still know surprisingly little about how DBS actually works in the brain, says neurosurgeon Kendall Lee, director of the Neural Engineering Laboratory at the Mayo Clinic in Rochester. The foundations for the treatment were actually discovered by accident about 60 years ago, during an operation on a man with Parkinson’s disease. Previously, surgeons had treated Parkinson’s patients by cutting out entire sections of the brain. The method stopped tremors, but it also prevented other kinds of movements, often leaving parts of the body permanently paralyzed, among other side effects.

In 1951, a Mayo surgeon named Irving Cooper tore an artery at the beginning of a surgery on patient with Parkinson’s. After stemming the bleeding, repairing the damage, and aborting surgery, Cooper was surprised to find that his patient awoke not only mobile, but also free of tremors. It was a lightbulb-sparking event that gave surgeons a much more detailed picture of where in the brain certain problems originate, Lee says. Since then, doctors have zeroed in on more specific areas in the thalamus, sub-thalamus, and other regions near the center of the brain that are linked to various neurological disorders. And they have discovered that electrical stimulation can work like brain lesions, altering activity in localized regions—if carefully placed, for the better.

In one of the latest steps toward understanding the details of how DBS actually works, Lee’s group and others have found that electrical stimulation leads to a release of neurotransmitters, the messenger molecules that allow individual nerve cells to communicate with each other inside the brain. The Mayo team has also designed a device that can wirelessly monitor neurotransmitter levels during DBS. With advances like these, the hope is to create “smarter” DBS devices that could alter levels of stimulation as needed. Even if the device could just recognize when a patient is asleep, it would be a major step forward, Abosch says. That way, doctors wouly only have to replace batteries every nine years instead of every three. “Right now, we’re doing electroshock therapy for a lot of psychiatric diseases,” Lee says. “But rather than shocking the whole brain, with DBS we can do more focal treatments. Electroshock therapy is like a shotgun approach where you shoot everything. DBS is more like a rifle.”

After more than four hours in the operating room without a break, Abosch and her team are ready to test the electrodes they’ve placed in the patient’s brain. Earlier that morning, before the new device was in place, his left arm swung wildly when nurses challenged him to draw a spiral on a piece of paper and then write his name. The spiral looked more like a squiggle. The letters looked like they came from the hand of a three-year old. After activation, however, Gene draws concentric circles, drinks steadily from a cup, and keeps his left hand still while holding some papers.

Watching patients witness their own swift and drastic improvement remains an emotional experience, even after several hundred surgeries, Abosch says. “When you have a patient who has dealt with a tremor for 30 years of his or her life and you stop the tremor suddenly and they get all choked up or burst into tears, it’s moving,” she says. “You’ll see patients during the procedure suddenly reach up and look at their hand. And it becomes apparent to you watching the patient that they suddenly realize something is profoundly better. That is a touching moment.”
 

 

Matthew Mescher

Immunologist // University of Minnesota

Matthew Mescher didn’t set out to find a cure for cancer. He was simply interested in T cells, a type of white blood cell whose job is to recognize and attack viruses and other invaders. It turns out that T cells also recognize proteins made by cancer cells. In recent years, Mescher has isolated those protein molecules, attached them to cell-sized beads, and injected the beads into cancerous mice—Matthew Meschersuccessfully inspiring the rodents’ T cells to kill their tumors. The vaccine-like therapy has shown promise in people, too. In one recent trial, Mescher and colleagues injected 30 stage-IV melanoma patients with beads that were coated with proteins from their own tumors. Four years later, half of the patients were still alive, compared to the two or three that would’ve been expected to survive without treatment. Hoping to reduce the expense and effort of treating each cancer patient with custom-made beads, he is now looking to see if lab-grown cell lines will work just as well. “I think this will become a significant weapon in the battle against cancer,” Mescher says. “It has been a good example of how things that start out as very basic research can get to the clinic.”


 

Heidi Nelson

Bacteria researcher // Mayo Clinic

Heidi NelsonThere are 10 times more bacteria living in and on us than there are cells in the human body, and scientists are beginning to understand that all those bugs have massive effects on our health—both good and bad. They help us digest food and make vitamins. But, according to study after study, out-of-whack bacterial communities can lead to any number of health problems, from Crohn’s disease to psoriasis. Heidi Nelson’s team recently found that the “microbiome” of bacteria in the gut can interact with a person’s genetics to cause rheumatoid arthritis, even though the joints lie far away from the intestines. As the national-level Human Microbiome Project continues to give researchers a more detailed understanding of how bacterial residents influence our lives, Nelson anticipates that antibiotic drugs will one day be replaced by targeted therapies directed at specific genes within the bacteria unique to each of us. “I think we will completely redefine what it means to be an infectious disease,” she says. “Everything is on the table for re-discussion.”
 

John Wagner

Children’s Cancer Researcher // University of Minnesota

John WagnerIt was 1990, and the fate of a four-year-old boy lay in John Wagner’s hands. The patient had been fighting aggressive leukemia without success. So Wagner opted to try a procedure never attempted for this disease: an umbilical-cord-blood transplant.

The cord blood would come from the placenta of the boy’s newborn sister. Such blood is rich in stem cells, which are capable of turning into more specialized cells. Wagner believed they might help repair the boy’s ailing bone marrow.

It was a risky procedure. If I make a mistake, this child could die, Wagner thought to himself before beginning the IV infusion. Hours later, Wagner faced more than 50 reporters at a press conference, answering questions about what turned out to be a successful and paradigm-changing event.

Since then, Wagner has pushed stem-cell transplantation to heights no one thought possible. By 2000, he was transferring cord blood to patients from completely unrelated donors, and soon thereafter, he was mixing cord blood from separate donors. These days, Wagner is focused on expanding stem-cell lines in the lab, lessening reliance on cord-blood donations. By isolating cells in cord blood—cells that allow a baby to grow without rejection by its mother’s immune system—Wagner hopes to find treatments to stop organ rejection in transplant patients.

Walking through a room full of syringes, vials, and stacked cardboard containers, Wagner explains the sense of urgency that fuels the many research paths he and his colleague are forging. “You have a new idea that could change everything,” he says. “That’s the reason you see boxes lying around. Someone comes up with something and says, ‘We have to do this—now!’”
 

Dianne Neumark-Sztainer

Nutrition researcher // University of Minnesota

Dianne Neumark-SztainerOutside of infancy, adolescence is the period when kids grow and develop most rapidly, making their nutritional needs higher than ever. And yet, teenagers are notorious for their poor eating habits—something that Dianne Neumark-Sztainer is working tenaciously to change. “Someone once said to me, ‘Isn’t that an oxymoron: adolescent nutrition?’” she says. But it doesn’t have to be. As part of the large, long-term Project EAT, Neumark-Sztainer has helped demystify the food-related problems that afflict young people, from obesity to eating disorders. After following thousands of young Twin Citians for up to 10 years, for example, she found that teen girls who diet end up gaining much more weight than their peers who don’t resort to unhealthy weight-control tactics—landing an average of two BMI points higher, enough to make a major public-health impact. “I’d really like people thinking in a more holistic way about health,” Neumark-Sztainer says. “So we’re not just talking about fighting obesity, but really integrating a whole picture of body image, self-image, eating, weight, and health status to try to help people feel better about themselves.”
 

Brad Feltis

Pediatric surgeon // Children’s Hospitals and Clinics of Minnesota

Brad FeltisWhen Brad Feltis moved to Minnesota to work at Children’s in 2005, only a handful of doctors around the country would operate on unborn fetuses and, even then, only if death before birth was certain. Now, Feltis and his team perform dozens of fetal surgeries each year, including procedures that require cutting open the mother’s belly to fix problems with the baby’s developing bladder, lungs or spinal column—even in cases that are not life-threatening. The approval of fetal surgeries for nonlethal diseases is a development that nobody would’ve predicted even three years ago, Feltis says. The job’s biggest challenge is keeping the exquisitely sensitive human uterus from going into labor while operating on a fetus that may be as young as 17 weeks old—with instruments that are smaller than toothpicks. “You try not to think about it too much. You don’t want to make yourself nervous,” he says. “We’re right at the front of this wave of fetal surgery. It’s a very exciting, rapidly changing time. It’s a brave new frontier for surgeons.”
 

 

Jon Grant

Psychiatry professor // University of Minnesota

On a wall in psychiatrist Jon Grant’s office at the University of Minnesota’s Riverside Hospital hang two framed scans of human brains. One shows a healthy brain, full of overlapping nerve cells that resemble a thick tangle of spaghetti. The other contains far fewer strands.

Standing on an oriental rug a few steps from a bookshelf lined with titles like Poker and Stop Me Because I Can’t Stop Myself, Grant explains that the image with missing strands is the brain of a shoplifting addict. “The part of the brain that should be telling other parts of the brain, ‘Stop this,’ doesn’t have enough roadways to make that communication robust,” he says. Imaging studies now show similar patterns in the brains of people with all sorts of addictions—alcohol, drugs, sex, gambling—as well as obsessive-compulsive disorders.

Jon GrantBy examining structural differences between addicted and healthy brains, Grant hopes to zero in on better treatments. In a 2006 study, for example, he and colleagues concluded that a drug called nalmefene had a positive effect in treating gambling addictions by targeting specific brain chemicals to dampen cravings. He has also found that an amino acid called n-acetyl cysteine, which is available over the counter, may aid gamblers seeking to quit. The hope is that research on gambling addiction will eventually inform treatments for other addictions.

As scientists learn more about the genetics, brain regions, and neurotransmitters involved in addiction, Grant is also determined to figure out what it is that makes the brain of one addict different from another. “We tend to treat addictions as we have for the last 30 years,” he says. “Our goal is really to come up with healthier and more effective treatments. We’re getting very important pieces of this puzzle.”


 

Judy Boughey

Breast-cancer surgeon // Mayo Clinic

Judy BougheyWhen Judy Boughey meets her patients, they already know they have breast cancer. Once at the Mayo’s Breast Clinic, Boughey brings each woman into a quiet exam room. She motions the woman and her husband or partner to take a seat on the couch, and with a kind face and a soothing British accent, she leans forward, puts her hand on the patient’s knee, looks directly into her eyes, and says something like, “You’ve been through a lot. How are you doing?” There is always a box of tissues in the room. “It’s rare that I finish a meeting and we’re not hugging,” she says.

Developing trust is essential to Boughey. Over the course of each initial consultation, she is likely to present women with some surprising new ideas about how their treatment might progress—suggesting, for example, that they undergo chemotherapy before surgery instead of afterwards, a re-ordering that has led to rapid developments in how doctors understand the disease. To some patients, she also recommends joining the clinical trial she has just launched, which aims to drastically improve outcomes by personalizing care with the help of new genetic tools.

The BEAUTY Project (officially, the Breast Cancer Genome Guided Therapy Study) aims to enroll 200 high-risk breast-cancer patients. After taking a biopsy from a patient’s tumor, the doctors will inject her cancer cells into mice “avatars,” and allow the tumors to grow in the mice. By comparing gene sequencing in the tumor with the gene sequencing in the patient’s healthy cells, Boughey and colleagues hope to pinpoint molecular pathways that will explain why some patients respond better to some treatments than others do. Those results could then lead to new types of drugs that zero in on the cause of each patient’s disease. Research on 18 women is already underway.
“Breast cancer is not all one disease, and I believe there’s no one drug that’s perfect. If there was, we probably would’ve found it by now,” Boughey says. “In the future, we’ll say: ‘Your tumor genome over-expresses this particular pathway, so this is the best way to treat you.’”
 

David TubmanDavid Tubman

Neuroradiologist // Abbott Northwestern Hospital

If your ruptured aneurysm (a ballooned blood vessel in the brain) was treated in 1990, you had a 10-percent chance of ever returning to work. Today, David Tubman says, patients go home the next day, and roughly 90 percent of those treated go back to work immediately. Rapid advances in technology explain the improvement in results, says Tubman, who has treated some 1,200 aneurysms and 300 strokes and has been doing it longer than anyone else in the Midwest. Among other cutting-edge procedures, he regularly implants platinum coils in aneurysms by pushing tiny catheters through arteries, beginning in the groin and ending in the brain. The coils fill the aneurysm and cut it off from blood flow, reducing pressure and preventing rupture. Still, it’s a tricky, risky procedure. “The devices are good, but they’re very hard to use,” he says. “You’re not just throwing them in there. A mistake is a death, or worse.”
 

Brian Carlsen

Plastic Surgeon // Mayo Clinic

Brian Carlsen clicks the “play” icon on his Mac, eager to show a video of the man he recently flew to France to meet. On screen, the 22-year-old Frenchman zips his vest. He shaves his face with a razor. Then, he butters a baguette. All mundane tasks except for one exceptional detail: the hands he uses are not the ones he was born with. A year ago, the young man received a double hand transplant at a hospital in Lyon, France, making him one of roughly 50 people around the world to experience such a miracle.

Brian CarlsenThe Mayo Clinic officially launched its own hand-transplant program nearly two years ago, geared toward people who have lost both hands, often in farming or industrial accidents. But before Mayo surgeons initiate their first surgery, they want to find a patient who is physically and psychologically primed. Conditions must be right for the best possible outcome. Sometime in the near future, Carlsen expects, he and his team will perform Minnesota’s first hand transplant. “We have several promising patients,” Carlsen says. “But it’s complicated. This has to work.”

The surgery likely will last about eight hours, as surgeons attach blood vessels, nerves, skin, and more than 20 tendons in each hand. So far, Carlsen says, 95 percent of hand transplants have stuck, and many patients have been able to return to work. New hands never quite work like the originals, but recipients often report a satisfying sense of feeling.

The biggest challenge remains convincing the body not to reject a foreign set of appendages. Patients must take immune-suppressing drugs, which come with major risks. As some researchers search for drugs that are less toxic than existing solutions, Carlsen is focused on a more sci-fi solution: tissue engineering. He describes a process where all the cells are removed from part of a donated hand, turning it into a three-dimensional matrix. Recipient-generated stem cells would then be allowed to repopulate the structure, eliminating the need for chronic drugs. “That is Space Age, right?” he says. “That is the future.”
 


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