Current therapy consists of low doses of the cancer drug cyclophosphomide, first taken once a month for six months, then once every three months for two years. But only about 25 percent of patients respond to the treatment. And for some, the cure is worse than the disease. Long-term exposure to cyclophosphomide causes horrendous bone, bladder and ovarian problems and a high risk of developing cancer.
But Petri sees a ray of hope. Hopkins researchers recently produced astonishing turnarounds in severe aplastic anemia, an even more-lethal autoimmune disease. They’ve also had interesting results with lupus. The new approach uses a shorter but higher dose of cyclophosphamide. “The idea,” Petri explains, “is to blast the lupus once and wipe out the abnormal immune system, and then allow the body to relearn without further therapy.”
A couple of years ago, Petri conducted a small clinical trial using the method on lupus patients with significant organ failure who hadn’t improved with conventional therapies. Thirty percent went into long-term remission. Two and a half years after the study, there is no evidence of the disease in their bodies. About 50 percent had a partial response and continue to take lower doses of previously ineffective immune-suppressing drugs. “That’s a huge advance,” Petri says. “Even when the disease came back, it didn’t come back full force.”
In other words, says surgical oncologist Martha Zeiger, when an FNA can’t confirm whether a thyroid lesion is malignant, we have two less-than-perfect options. One is to take out half the thyroid and, if it comes back cancerous, bring the patient back for a second surgery to remove the rest of the gland. The other is to take the whole thing out, when that may not even have been necessary.
So concerned has Zeiger been about these harder-to-diagnose patients that for the past eight years she’s been in the lab searching for molecular markers that make clear if thyroid tissue is benign or malignant without the need for a surgical biopsy. Using gene expression techniques, in 1999 she found telomerase, which had been shown to be active, or “expressed,” in breast and prostate cancers, to be 93 percent accurate in picking up some, but not all, cancers in suspicious thyroid lesions.
Now she’s chosen another marker, a mutation of the BRAF gene. Hopkins otolaryngologist David Sidransky showed recently that BRAF is present in two-thirds of papillary thyroid cancers, the most common type of thyroid malignancy, which is found most often in women (Journal of the National Cancer Institute, April 16, 2003).
“From the patient’s point of view, finding the marker is a major step forward, because it allows us to avoid putting them through unnecessary surgery,” points out Zeiger. Almost 100 percent of the time, if someone has the mutation we can be certain the person has a cancer. In that case, I would take out the whole thyroid in one operation. On the other hand, if there’s no marker, it means the tumor is benign, and we avoid surgery altogether."
What’s different in cardiology since you were in training 20 years ago?
It was still about lead pipes and plumbing then. I’d listen to a patient tell me he had trouble exercising, then hear fluid in his lungs and extra heart sounds. Those are the sounds of congestive heart failure, which afflicts millions of people, but at the time we didn’t have a clue what was happening. A lot of interesting biology was beginning, how the vascular wall reacts to cholesterol, how heart failure weakens the contractions of the heart, why instabilities of rhythm arise during heart attacks. But the models that were being used were very static. Today, we’re poised for a revolution.
Is that affecting treatment yet?
In one of the first applications of fundamental biology to a treatment, we’re beginning to use coated stents. Instead of focusing on the mechanics of opening up a clogged artery and putting in a spring, we’re coating these springs with biological factors, reducing the risk of re-stenosis.
Now, go back to congestive heart failure. How would you treat that today?
We know this disease occurs when the heart doesn’t beat strongly enough. Its muscle has grown weak, perhaps from coronary artery disease or high blood pressure. We have a host of medications now that prolong life—beta blockers and ACE inhibitors. We also have amazing devices to help the problem.
The biventricular pacemaker can resynchronize a damaged heart by sending an electrical current into the chambers on both sides. Automatic internal defibrillators, like the one that Dick Cheney wears, can keep people alive. And LVADs, left ventricular assist devices, which once were just bridges to keep people alive until they could have a transplant, today are taking the place of transplants.
Tell us what’s coming next.
Gene and stem-cell therapy are what’s most exciting.
I actually believe that in two or three years, we’re going to be able to put stem cells, grown from bone marrow or even from heart tissue, back into damaged hearts to regrow myocardial tissue. I’d say the future for battling heart disease looks very bright.
A recent explosion in obesity research within Hopkins helps Brancati look at obesity from several angles. He studies the benefits of time-honored behavioral approaches to weight reduction, but he also knows that such methods lead to weight loss in about only 7 percent of people who are 40 percent overweight. He’s therefore searching for potential new drugs. And he’s investigating environmental causes, trying to determine why, for instance, Colorado produces the thinnest people and Mississippi the heaviest.
“Maybe it’s those mountains people trudge up and down,” Brancati says.
In his latest foray, he is working with basic science researchers on flow-perfusion. Fat, like normal tissue, receives oxygen and nutrients via the body’s vascular system. But too much fat can create blockages, triggering the body to push harder, and raising blood pressure in its effort to deliver high concentrations of nutrients like insulin, lipids and sugar to tissues on the periphery.
“We see all these levels go up with additional fat,” Brancati says. What’s key, though, is that “if flow turns out to be the problem, it could suggest new ways to break the connection between obesity and its complications.”
Normally, nerve growth is damped down once the brain and spinal cord are fully developed. The stalling preserves useful nerve connections and discourages undesirable ones in the central nervous system. “If we could only understand the damping process,” says Schnaar, “we could potentially reverse it in injury, freeing damaged nerves to repair themselves.”
Schnaar’s group has focused on a key player in inhibition, a molecule called myelin-associated glycoprotein (or MAG). Scientists have long known that even the smallest amount of myelin, nature’s fatty insulator for nerve cells, acts like a wet blanket for nerve repair. A few years back, they discovered that MAG linked with myelin’s surface. But how MAG does its job remained elusive. Then the Schnaar lab found that MAG, on the myelin, binds to molecules known as gangliosides, which are copious on nerve cell surfaces and are made up of both sugar and fat molecules. As MAG links to the sugar, individual gangliosides form a cluster on the nerve cell surface. “It’s a bit like flypaper,” Schnaar says. Now, he believes that clustering somehow advances the stalling process. His experiments should tell him if he’s right.
This man would have better odds. He would benefit from a method developed by Gokaslan himself for reaching these hard-to-get tumors. To call the operation complex would be an understatement. Gokaslan must cut through the back of the neck to remove the tumor-engulfed cervical bone, a technique requiring the most extraordinary finesse: One slip could injure the nerves on each side of the spine or the vertebral arteries that supply blood to the brain stem, which controls breathing and heart rate. One of the vertebral arteries also is inundated by tumor and will need to be removed. A single nick to the other artery, though, and the man will die in the operating room. “We’ll never take the part of the artery that’s within the tumor itself unless we’re 100 percent certain the other vertebral artery is fine,” Gokaslan explains.
Finally, to remove the part of the tumor in front of the spine, Gokaslan must actually split the patient’s jaw and tongue. Removing this much cervical bone leaves the patient’s head destabilized, literally flopping to the side, but that too is correctable. Gokaslan now anchors a cylindrical steel cage to the remaining bone above and below the gap. Then, he fills the cage with a cadaveric bone matrix to help fuse the new cervical spine.
The most satisfying aspect of the new surgery, Gokaslan says, is that patients with spinal tumors that used to be inaccessible have gained a second chance.”They may have difficulty with swallowing and tongue function for awhile,” he says, “but that usually recovers over time and they actually end up having a good quality of life.”
This was no simple leg ache. A sonogram at a nearby hospital showed Leiby had developed a post-surgical blood clot in a vein, a deep venous thrombosis (DVT) that extended from her mid-calf to her navel. Patients with DVT can lose full use of their leg. The blockage also can break up and send a fragment of tissue up the vein straight into the heart or lungs.
Doctors quickly began stomach injections of blood thinners on Leiby and bed rest, the only treatment available for DVT, they said. But after three days in intensive care, “my pain was 10 times worse,” she says. “I couldn’t stop crying.” Then, a physician on call told Leiby about a little-known technique that could probably cure her. Called catheter-directed thrombolysis, it would send clot-busting drugs directly into the blockage. It could be performed at Hopkins by interventional radiologist Lawrence “Rusty” Hofmann. Within days, Leiby had signed on for the procedure.
During surgery, Leiby lay on her stomach while Hofmann threaded a catheter though a 2-millimeter incision into the vein in the back of her left knee. He guided the catheter into the obstructed blood vessel and injected the clot-dissolving drug tPA. To keep the pelvic vein open, he inserted a stent. Two days later, Leiby was walking and the clot was 95 percent gone. By September, she was back on the water for Cornell.
Hofmann, who’s performed the procedure often and on patients as old as 80, is mystified why most physicians haven’t heard of it. “There’s no doubt it can get rid of terrible pain and keep limbs functioning,” he says.
Yet if several tactics now moving into trials pan out, real change will come, he says. “And none too soon.” The approach Bergey is shepherding reflects recent thought that mildly zapping the central nervous system with electrical currents can be therapeutic. “Seizures are abnormal brain excitation that we’ve countered with drugs that inhibit neural activity,” he says. “But new ideas on how seizures begin and propagate are leading us to try to disrupt them with an excitatory stimulus.”
Basically, the implanted External Responsive Neurostimu-lator System, a device half the size of a Ritz cracker, delivers currents in response to seizures. A computer chip is “tuned” to detect a seizure pattern specific for each patient, sensing the earliest seconds of wayward activity. Then, the researchers anticipate, the brief, mild stimulus that’s released will disrupt or stop the seizure. The stimuli appear safe even with repeated application.
ERNS, which is both light and thin, rests in a cavity in the skull. Only the electrodes of its attached probe touch the target brain surface. Patients can’t feel the stimuli.
Earlier, work here helped verify some ideas that underlie the system. Bergey’s team, for example, showed that each patient’s pattern of seizure onset is remarkably consistent. And his team’s computer models of seizures bolstered the idea that stimulation could turn them off. Also, neurologist Ronald Lesser, has shown current can disrupt mild seizures in epilepsy patients undergoing brain-mapping.
Now Hopkins is collaborating with several other major centers in testing the first implants of the device. “Our hopes for the studies are high,” Bergey says. With ERNS, we’re looking at responsive stimulation directed at each seizure.
Literally “on genes,” epigenetics refers to changes in gene functioning that don’t arise from alterations in the DNA sequence itself. More than 20 years ago, as the first postdoc working with renowned researcher Bert Vogelstein, Feinberg pioneered cancer epigenetics when he discovered abnormal DNA in tumors. Later, he and his lab found the first evidence in humans of gene imprinting, another epigenetic phenomenon in which only one parental copy of a gene is active and the other is silent.
These events make sense with the abnormal cell growth that is the hallmark of cancer. But until recently, few people have asked whether epigenetic changes could be involved in other widespread ailments: diabetes, heart disease, psychiatric disorders. Today, says Feinberg, that line of inquiry, formerly a curiosity, has become a major focus in his lab thanks to researchers who’ve signed on with him through pure serendipity.
One such find is Hans Bjornsson, a human genetics graduate student whom Feinberg met three years ago while he was teaching a session in Victor McKusick’s famous Short Course in Medical and Experimental Mammalian Genetics, held every summer in Bar Harbor, Maine. “Hans has this idea,” says Feinberg, “that epigenetics may underlie the Barker hypothesis,” a theory based on studies by a British epidemiologist that show a correlation between low birth weight and adult-onset health problems.
Bjornsson, who hails from Iceland, further whetted Feinberg’s interest with his knowledge of his nation’s sophisticated medical system and rich lode of detailed health information on generations of Icelanders. Now, working with the Icelandic Heart Association, the two hope to mine these data for evidence that epigenetic alterations precede disease. “We know, for example, that DNA methylation changes as people age,” Feinberg says, “but we haven’t had a way to study the effects over time. Now, we’re coming up with the analytic tools.”
Another of Feinberg’s unexpected new collaborators is James Potash, a Hopkins psychiatrist who got hooked on the idea that imprinting, or its loss, could play a role in triggering the swings between mania and depression that define bipolar disorder.
“I was looking for a method to screen for imprinted genes,” says Potash, “and came across a paper by a Japanese author, so I e-mailed him to see if I could have access to his cell lines. He answered almost immediately, ‘I’m collaborating with Andy Feinberg. Why don’t you talk to him?’ That’s how I stumbled on the fact that a five-minute walk away from me was this world expert in imprinting. Hopkins is like Manhattan. Every day you can turn a corner and find 15 things you never knew existed.”
What so intrigues Potash is that epigenetic events could decode such puzzles as discordance in identical twins, why one develops schizophrenia, for example, and the other doesn’t. “In psychiatry, causes have always been this complete mystery,” he says. “Consider the episodic nature of bipolar disorder: It comes on ferociously, then goes away, leaving the person just the way they were before.”
Today, Potash spends his days tucked away in Feinberg’s lab on the 10th floor of the Ross Research Building, scrutinizing films of gene products. “One thing I found recently,” he says, “is an extension of the imprinting idea, the possibility that instead of an imprinted gene being only on or only off, there may be relative degrees of expression. And the expression ratio itself may be heritable.
“The idea of understanding the neurobiology of mental illness is relatively new,” Potash points out. “But with epigenetics, for the first time ever, we have the potential to reach the truth. It feels like an exciting moment in history."
Mary Ann Ayd
Right after coronary artery bypass surgery, more than two-thirds of patients may find themselves with problems remembering and learning. They also may be slower at tasks like writing and drawing. But, and it’s a major “but,” neuropsychologist Ola Selnes, Ph.D., along with neurology and cardiology colleagues, has discovered these changes generally last no more than three months.
“Casual reports from some patients and their families that they don’t function as well cognitively after the surgery have long raised questions,” says Selnes. “Several studies showed bypass patients actually did have cognitive decline. But none of the research had proper control groups with a similar cardiovascular staus. We wanted something definitive.”
The study compared 140 patients who underwent bypass surgery with a second group of 92 coronary artery disease patients who did not have surgery. Both groups received neuropsychological tests to measure cognitive abilities, things like attention and verbal memory, as a baseline. Then the surgical group underwent the bypass procedure. Tests were repeated three and 12 months later and compared.
“We found there is cognitive decline, but it’s transient and reversible,” says Selnes.