True Grit

With thousands of asbestos workers demanding compensation for lung disease, a radiology researcher here finds that most cases lack merit.

Sometime in the mid-’90s, Joe Gitlin decided enough was enough. For some 25 years, the radiology researcher had watched uneasily as attorneys for asbestos workers sought compensation for what they said was the occupational lung disease, asbestosis. By then, the cases—the longest-running mass tort litigation in the United States—had cost some $70 billion. Gitlin, who’s spent much of his professional life trying to bring consistency to the reading of images used to identify pneumoconioses—the class of lung diseases caused by inhaling asbestos dust or coal—suspected that many of these people didn’t actually have asbestosis.

What stirred Gitlin was that the medical evidence was often being glossed over in the legal tangles. Even small quantities of asbestos can prompt the diaphragm or body wall to make flat, fibrous plaques. But Hopkins’ studies had shown that plaques don’t automatically signal asbestosis and merit compensation, as some lawyers and radiologists were claiming.

Around that time, Gitlin received a fateful phone call from a group of attorneys. They wanted to know if the researcher, with his reputation for measuring image-reading accuracy and straight shooting, could tell whether chest X-rays previously called positive would hold up to scientific scrutiny.

“These lawyers were fed up with the status quo,” Gitlin says. “They were genuinely interested in facts, not merely defending corporations to save money.”

Gitlin was ready to go: He would put the cases to the ultimate test—a rigorous review by reputable radiologists with nothing to gain except truth itself.

That Joe Gitlin should be involved in dust policy seems fitting. Growing up in the coal mining town of Scranton, Pa., the epidemiologist says almost every family he knew had deaths or sickness from inhaled coal dust. “In ours, it was my uncle.” After serving in World War II, Gitlin joined the U.S. Public Health Service and earned a doctorate in public health at Hopkins. “Otherwise,” he says, “I’d have been digging coal.” 

Today, Gitlin, who turned 80 this summer, has spent almost four decades refining methods for interpreting X-rays in clinical radiology. Many of those have related to chest examinations that have served as a basis for lawsuits, Since the late 1960s, federal and state governments have required companies to screen workers for chronic chest disease due to occupational exposure.

The system the government uses to identify these chest ailments was actually devised at Hopkins in the 1970s by Radiology’s first chair, Russell Morgan: Radiologists who pass a nationally recognized course in dust-reading become A readers. They then often move suspect images on to B readers, who are skilled in detecting the pneumoconioses. Gitlin and two of his Hopkins colleagues, Bob Gayler and Paul Wheeler, helped Morgan develop the system. Gayler and Wheeler maintain their qualifications as B readers.

But diagnosing asbestos-related lung ailments is no clear-cut process. To demonstrate that point, Wheeler displays the X-ray of a woman in her 80s who spent years making asbestos mattresses for ships’ boilers. Her plaque shows up as a shadow. But in her case, it is all benign.

Still, plaques do signal asbestos exposure, and for legal cases brought to Hopkins, the radiologists go way beyond government criteria in making their diagnosis. Instead of using only the required single posterior-anterior chest X-ray, they take three or four X-rays at angles and do CT scanning if they feel it’s necessary. “On routine films, ribs and soft tissues overlie the lungs, so they’re never crystal-clear,” Wheeler says. “But high-res CT cuts right through that.”

To launch the “confirmatory” study requested by the lawyers, Gitlin asked six of the country’s best radiologists to go over 90 films of claimants who had previously been diagnosed positive for asbestosis. When it appeared clear that most of these asbestos workers had been diagnosed incorrectly. Gitlin then expanded his study to 492 cases. In August 2004, in a paper published by Academic Radiology, the blue-ribbon panel reported that compared to the 96 percent of images called positive the first time, only 4.5 percent of them actually read that way.

Last year, that study helped sway a federal judge to hand down a decision against five B readers who had churned out positive X-ray findings. The Gitlin report, the judge made clear, made her more comfortable with her decision. Since then, reporters in The Wall Street Journal and The New York Times have used the report to demonstrate corruption in the asbestos awards.

Next, Gitlin would like to study several thousand X-rays in cases after awards were made—“to tell us, really, how many are ill with something else. A lot of those people are sick,” he says, “but not with asbestosis, despite what they’re told, and they need appropriate care.”

Marjorie Centofanti

Kidney Swapping to Make a Match

It’s no secret that the number of people living with renal failure far outstrips the supply of cadaver donor kidneys. Some 66,000 patients are on the transplant waiting list, and more than 5,000 of them will die this year for want of a suitable organ.

What especially bugs the Hospital’s transplantation chief, Robert Montgomery, about these figures is that in the last two decades, the number of people willing to be live donors has tripled. Yet more than a third of the time, their blood or tissue type doesn’t match the person they want to give their kidney to.

Now, after five years of working with a program he established here to deal specifically with this “mismatch” problem—the first of its kind in the nation—Montgomery is convinced he knows the best way to defang the incompatibility issue. He has thrown his weight behind a method called kidney Paired Donation that enables incompatible donor-recipient pairs to find their matches among other mismatched pairs like themselves. Of the 80 or so KPD transplants performed in the United States, since the program began, more than a third have been done here—including the world’s first triple exchange (in which three people simultaneously receive a kidney from another patient’s living donor).

With Hopkins’ concentration on the mismatch issue, it has now become the nation’s largest referral center for incompatible kidney donors and recipients. Furthermore, by analyzing their outcomes data, Montgomery and the transplant team have shown that KPD has the same survival and success rates as compatible living donor kidney transplants. The next step, Montgomery says, is creating a national program that deals with the mismatch problem.

Mary Ann Ayd

Andy Feinberg, Chief Explainer

Befuddling epigenetics has gone mainstream.

Not long ago, when Andy Feinberg would tell doctors about a revolution he saw coming in cancer treatment, he could barely get them to listen. Feinberg, a pioneer in the field of epigenetics—information inherited during cell division that doesn’t involve DNA (even though it’s associated with it)—was convinced that screening for certain epigenetic traits would make it possible to identify patients at risk for, say, colon cancer. Eventually, he suggested, drugs might be able to ward off the cancer.

These days, Feinberg, who received an M.D. and an M.P.H. from Hopkins and has been a professor here since 1994, heads a new division of the Department of Medicine devoted entirely to epigenetics. And when he gave a keynote address this year at the meeting of the American Society of Clinical Oncology, he found himself speaking to a standing-room-only ballroom and receiving a rock star’s reception.

“Oncologists were coming up to me saying, This is what we’ve been waiting for,” he recalls with amazement.  

Epigenetics, however, is no straightforward discipline. Even physicians with years of training can feel befuddled by it. Put simply, it’s the information passed on when a cell divides that isn’t written into the DNA sequence itself—what reminds a gut cell to divide into two gut cells, or a liver cell to spawn a second liver cell. Scientists now know that several factors can spur changes in this progression, and the results can be disastrous. Methylation—the addition of one carbon and three hydrogen atoms to a critical section of DNA—for instance, can silence vital genes. Modifications of proteins called histones—vital in forming the structure of chromosomes—also can close off (or open) certain genes.

“We really know a lot about DNA methylation now,” Feinberg says. “We’re starting also to learn a lot now about the histones and how they are modified and how they control gene expression. What we don’t know a lot about is how the marks are recognized and preserved when the cell divides.” 

One thing is clear: the potential impact of epigenetics reaches far beyond cancer. The field could explain the roots of ailments as disparate as bipolar disorder and Alzheimer’s and play a major role in stem cell research. For all those reasons, Hopkins Medicine is getting behind it in a big way.

This past spring, the School of Medicine created an Epigenetics Center at the Institute for Basic Biomedical Sciences (IBBS), to be headed by Feinberg and Cynthia Wolberger, a professor of biophysical chemistry and an expert in the mechanisms that underlie epigenetic change.

Slated to be housed in the Rangos Building—due for completion in 2008—the center will serve as home for scientists from all over the University as well as new recruits. Placing it with the basic sciences confirms its importance at the most fundamental areas of medicine, says molecular biologist Steve Desiderio, director of the IBBS. “A cell in the retina of the eye and a cell in the lining of the gut both have the same genomic DNA sequence, but a rod cell and a gut epithelial cell behave very differently. To understand what makes a cell a cell, what makes us, us, it’s essential to understand epigenetics.”  

Such details may now be everyday fodder for Feinberg, but he doesn’t forget his early days in the field. The director of one of the organizations funding his research, he says, even called epigenetics a dead end and threatened to pull his money. Feinberg, who kept plugging away, marvels at what’s happened since then. “Epigenetics,” he says “has become mainstream.”

Gregory Mone

Hunting and Gathering Sperm

Karen Boyle might be one of only a handful of women nationwide who specialize in sperm harvesting. But the men she treats are straightforward about what they want—help in conceiving a child. Studies show that 30 percent of the time when couples can’t conceive, the sole problem is male infertility. Boyle, a urologist who specializes in reproductive medicine, often uses surgery to get around that.

When a man doesn’t ejaculate sperm, she explains, the problem usually is either obstructive or productive. But, even total absence of sperm in the ejaculate doesn’t automatically mean that the swimmers don’t exist. And if they do, she can choose from several extraction methods.

In patients with a known obstruction, one option is micro-epididymal sperm aspiration. This open-surgical procedure requires putting the patient under general anesthesia and using the operating microscope to search for dilated portions of the epididymis—the coiled tubule that stores sperm and carries it to the vas deferens. The postoperative discomfort of this procedure is slightly greater, Boyle says, but the sperm harvest is usually better because she can see the dilated areas. The extracted sperm are then used in a planned in-vitro fertilization.

For men who prefer less-invasive surgery, Boyle can potentially offer  sperm aspiration—either percutaneous epididymal or testicular. With these approaches, she inserts a needle to retrieve the sperm, using only a local anesthetic. But since she can’t directly view the dilated areas, the sperm yield is generally smaller.

Finally, if the problem has to do with sperm production, Boyle can excise a small piece of testicle to analyze the seminiferous tubules where the sperm are produced. She’s also one of a handful of specialists trained to use a microdissection technique to locate the area of the testicle most likely to have sperm. Microdissection testicular sperm extraction, Boyle notes, has given new hope to men with the chromosomal abnormality Klinefelter’s syndrome.

Our sperm-retrieving approaches range from simple to complex, Boyle acknowledges. But they sometimes allow infertile men to conceive

Mary Ann Ayd

Big Hope for Marfan Patients

Dietz demonstrates that a common drug could prevent a lethal complication.

>"It was truly a jaw-dropping moment," Hal Dietz says.

Hal Dietz has spent his whole career figuring out Marfan syndrome. And now, at 48, it looks like the pediatric cardiologist may have come up with a way to halt the disorder’s most lethal complication—a potentially fatal rupture of the aorta. Last spring, in one of the most exciting research breakthroughs in a while, Dietz and his colleagues demonstrated in mice that a common blood pressure medicine, losartan, could prevent the deadly problem.

For the 30,000-plus Americans with the inherited disorder, the news sent out ripples of elation. Caused by a defect in the connective tissue protein fibrillin-1—which gives organs their structure and strength—Marfan wreaks havoc on the body’s blood vessels. Its victims—characterized by their unusually long legs, arms and fingers—develop dislocated lenses in their eyes, damaged lungs and—most frighteningly—an increasingly enlarging aorta. Without major surgery to replace the aorta, it often ruptures.

To test their theory that the blood pressure drug might halt this process, Dietz, a Howard Hughes investigator, and his colleagues engineered a group of mice with Marfan. When the mice were 2 months old and their aortas had already begun to change, the researchers began adding losartan to the drinking water for 15 of them. Fifteen more mice were fed placebos and a final 15 received a beta blocker currently being used by physicians to treat patients with the aortic abnormality.

When the Dietz group checked the mice after six months, they found that those in the losartan group appeared indistinguishable from the normal mice. Their aortas no longer showed any damage. Meanwhile, the aortic damage in the mice that had received placebos or beta blockers had grown worse.

“It was truly a jaw-dropping moment—beyond anything I could have anticipated or hoped,” Dietz told Science magazine. So clear-cut, in fact, were the study’s results that the National Institutes of Health—in collaboration with the Pediatric Heart Health Network— is quickly launching a clinical trial of losartan in more than 700 young Marfan patients.

“It’s a beautiful story,” Kenneth Chien, the director of Massachusetts General Hospital’s cardiovascular research center, told Science, “one of the most classic examples of translational science I’ve seen.”

ERN

Reaming and Bolting in the Spinal Cord

Standard surgery with a signature twist

“It’s an easy operation, but very dangerous,” Don Long says of the procedure that he and his fellow neurosurgeon Ira Garonzik performed last spring on Judy Christmann’s neck. “Perforate the trachea or the esophagus, and the patient could die. Nick the vocal-cord nerve, and she can’t speak. Injure the spinal cord, she dies or is paralyzed.”

Christmann arrived at Hopkins with unrelenting pain in her neck and shoulders, plus tingling and numbness in her arms. Driving and typing were becoming impossible. An MRI showed that arthritic degeneration in three of her cervical discs was causing compression of the vertebrae and pressure on the spinal cord. Worse, bone spurs were pinching the nerves that branched off the spinal cord, making the already small openings, “neural foramen,” in her vertebrae even smaller. “My family doctor said unless I had surgery, I’d ultimately be paralyzed,” Christmann recalls. “One of my co-workers steered me to Dr. Long.”

To relieve Christmann’s increasing discomfort, Long and Garonzik did an operation called a Smith-Robinson ACDF (for anterior cervical discectomy and fusion) on her. Pioneered here in the 1950s, the procedure—literally, yanking and scraping out spinal discs, reaming bigger openings in vertebrae, perfectly hammering in pegs, drilling and bolting bones—is now done worldwide, but Hopkins-trained surgeons give it a signature twist.

“Everybody else does it from the right side of the trachea and esophagus,” Long explains, “because that’s easier for a right-handed surgeon. We do it on the left side, because the vocal-cord nerve is more protected there.”

In Christmann’s case, Long performed the decompression half—removing the damaged discs. Garonzik then handled the delicate instrumentation and reconstruction—fitting pegs of cadaver bone between the vertebrae as spacers and screwing on a titanium plate to immobilize the neck while the vertebrae fuse with the cadaver bone. Hopkins’ success rate with ACDFs is the highest anywhere—the vertebrae fuse in nearly 100 percent of patients. Those results, Long says, are achieved by fitting the pegs of cadaver bone perfectly, like dowels in fine furniture.

Three months post-op, Christmann reported her neck pain had disappeared right after surgery. “The numbness is mostly gone and getting better all the time.” Her only complaint? “I’m wearing this contraption around my neck until my six-month checkup. It encourages the bones to fuse. But it makes me look like a suicide bomber.”

Jon Jefferson

Step by Step, Beating Back Paralysis

A new study demonstrates that severed nerves in a limb can be persuaded to regrow.

> Ronald Schnaar eyes a lab rat’s progress

When it comes right down to it, Ronald Schnaar notes, lifelong paralysis is the fault of stubborn nerves. And so this professor of pharmacology is on a mission of persuasion—to convince nerves they should grow.

The culprits that block nerve regrowth in our bodies, Schnaar explains, are axon regeneration inhibitors (ARIs). But scientists have learned that certain enzymes, like sialidase, are able to block the blockers. Perhaps, Schnaar conjectured, sialidase might also be able to give injured nerves just the right push to grow. Not all nerves are obstinate, he points out. Peripheral nerves—those in our fingers, for instance—can repair themselves when they’re severed and reattached.

“That’s because peripheral nerves are laid out like railroad tracks,” Schnaar explains, “whereas CNS [central nervous system] nerves in the brain and spinal cord are more like a ton of spaghetti in a trash compactor.”  The result of this confusing mess—the evolutionary price humans pay to cram more information into a smaller space—is that ARIs keep injured CNS nerves from regrowing. Their higher density and complexity also make repair much more challenging. 

To get around this problem, surgeons have tried to capitalize on the growth capabilities of peripheral nerves by grafting pieces of peripheral nerves onto damaged CNS nerve endings. But they’ve discovered that ARIs can be so adept at inhibiting nerve growth that CNS nerves can’t even make it into the graft. Now, Schnaar’s lab has found out that sialidase can thwart those ARIs and emancipate the nerves.

In a study spearheaded by University of Michigan scientist Lynda Yang, who spent last year as a visiting scientist with the Schnaar team, the researchers created a rodent model that mimics a limb-paralyzing injury in humans. They then surgically attached a peripheral nerve graft to the rat’s severed nerve ending and continuously pumped sialidase around the injury for 14 days. Finally, by slicing open the peripheral nerve graft and dipping the severed end into a tiny beaker of red dye, “we were able to trace the nerves into the graft and count them,” Schnaar says.

Remarkably, rats treated with sialidase had 2.6 times more nerve growth than the control group. The study appeared in the July 18 issue of the Proceedings of the National Academy of Sciences.  

As Schnaar recounted the details of this research, he grinned with enthusiasm beneath his moustache . “This is only a first step toward overcoming paralysis,” he says. “But so far, our results are looking very cool.”

Erika Gebel

Erika Gebel is a School of Medicine graduate student in biophysics