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an online version of the magazine Winter 2007
The Free Radical Dilemma Blind person with cane
  Peter Campochiaro is determined to halt the blindness that strikes everyone with retinitis pigmentosa. To get there, he’s relying on one of the hottest areas of research

By Greg Mone

Peter Campochiaro speeds out of his eighth-floor laboratory at the Wilmer Eye Institute, hustles down a flight of stairs into his office and pulls on a white coat hanging on the back of the door. Immediately, the mustachioed researcher is transformed into a physician. It’s a standard makeover for him. Several times each day, this 54-year-old Eccles Professor of Ophthalmology and Neuroscience goes from being a scientist who deciphers blinding diseases of the retina to a doctor who takes care of patients with those same diseases.

Campochiaro’s laboratory work has actually led to some remarkable treatments for retinal conditions. A decade ago, for instance, his research group helped determine that the damaging blood-vessel growth in the retina that causes the age-related eye disease macular degeneration is promoted by a certain protein. Until then, there had been little help for the creeping loss of vision that afflicts millions of older people. They would simply notice a loss of sight at the very center of their visual field. Then, over time, the blind spot would move outwards, until a massive darkness would cover all but the extreme periphery of their visual field. The most familiar faces would become hazes; activities like reading or watching movies would become impossible. Now, a clinical trial has demonstrated that blocking the culprit protein with an antibody fragment called lucentis stops the abnormal blood-vessel growth. For the first time, ophthalmologists have a way to slow macular degeneration. 

These days, though, Campochiaro’s chief nemesis is another affliction—retinitis pigmentosa or RP—a genetic blinding condition that affects 100,000 people in the United States and which no drug or surgery can halt. “Having no remedy for a disease is awfully frustrating,” Campochiaro says, “when you’re in the business of trying to make patients better.” And so, finding a treatment for RP has become his current quest.

But RP is no simple disease. In fact, it’s considered a family of diseases. Not only does its cause vary from patient to patient, different genes incite its effects in different people. In all, scientists have identified over 100 genes involved with RP’s progress. So, although targeting the genetic roots of RP would probably halt blindness in certain forms of the disease, it wouldn’t be a cure-all. But Campochiaro isn’t trying to attack RP’s genesis. He’s chosen instead to close in on a particular downstream effect of this disease—oxidative stress—a perfectly natural process run amok.




Oxidative stress is an unfortunate byproduct of an utterly basic phenomenon. As our cells use oxygen to produce the molecule that gives us energy—adenosine triphosphate or ATP, the very molecule we require for breathing—they also give out extra baggage called reactive oxygen species, or free radicals. But free radicals can be dangerous because they cart around an unpaired electron that makes them highly reactive, driving each to find another molecule to bond with. The trouble begins when free radicals choose the wrong partner: molecules like protein, lipids and DNA that can alter their structure in critical ways, disrupting their function. The result is oxidative stress, a condition, it turns out, that can wreak untold havoc on the human body. 

Every one of us, of course, encounters oxidative stress in the course of our lives, and usually it doesn’t cause problems. The cell’s self-defense and self-destruct mechanisms simply work together like sponges to soak up the free radicals before they attack critical molecules that can’t be spared. So proficient, in fact, is our natural defense system that even when free radicals do manage to slip through—latching onto proteins, lipids or even going after DNA—the cell intuits that something fishy is going on: Enough free radicals have clung to enough proteins, its instincts tell it, and it activates its self-destruct mechanism.

Human bodies, though, don’t always work perfectly. Scientists now know that many disease processes actually begin when free radicals swamp cells’ self-defense mechanisms, causing a self-destruct response so sweeping that massive cell death occurs. This phenomenon is particularly menacing when it occurs in the nervous system, where dead cells can’t be replaced. Several neurodegenerative diseases, in fact, stem directly from this malfunction.

And just like Campochiaro, brain science researchers—intrigued by the idea that they might arrest diseases like Parkinson’s and Alzheimer’s by learning to understand oxidative stress—have been flocking to this line of study. They’re hoping to stave off these neurlogical afflictions by identifying the source of free radicals and then coming up with a way to either reduce their production or bolster the cells’ self-defense mechanisms to handle the increased load. Two years ago, in fact, a Hopkins team demonstrated that reducing oxidative stress can slow the accumulation of amyloid plaques—the very protein deposits believed to be a major contributor to Alzheimer’s disease.

Another neuroscientist here, pathologist Lee Martin, is trying to figure out if oxidative stress relates to the death of neurons in ALS—Lou Gehrig’s disease. Do rampant free radicals in the highly vulnerable motor neurons in the spinal cord actually kick-start the pathogenesis of ALS? Or is oxidative stress merely a consequence in these cells? In other words, are we just looking at signs of sick neurons or are we looking at the causes of the disease?”


- click to enlarge diagram and view associated captions

image showing positive results of eyes treated withantioxidants


All the noise in this field, Martin says, is happening because new technology has made it so much easier to explore questions that have been around for a long time. “It allows us to analyze just how oxidative stress works.” It was “fluorescent markers,” for instance, that enabled his team to tally the number of free radicals in motor neurons. Now, Martin’s used those markers to identify a free-radical population boom in mice predisposed to ALS. Oxidative stress, his lab team has discovered, kicked in before any effects of  the disease even took hold. “It puts it more in the timeline of an antecedent than an effect,” he says.

Neurologist Ted Dawson has found that in some Parkinson’s patients, nitric oxide, a common free radical, attacks and destroys the function of the gene parkin. And since this gene normally acts as a kind of guardian for neurons, Parkinson’s disease can bombard those neurons when the gene is shut down. “If you could lower oxidative stress,” Dawson postulates, “some of these genes might function better. The neurons might survive longer.”




Meanwhile, Campochiaro keeps plugging way on deciphering the role of oxidative stress in retinitis pigmentosa. Tiny figurines and mementos decorate the shelves and cabinets in the laboratory where he toils. Most are gifts from lab colleagues. Adjacent to his desk, there’s a kind of Wall of Fame filled with framed photographs of former fellows. These flow over to surround a large poster, a gift from his wife titled “Peter’s Laws: The Creed of the Sociopathic Obsessive Compulsive.”

It’s a surprising label for a shy, mild-mannered guy like Campochiaro, but the poster’s points, he admits, are a lot more than jokes. “There’s a bit of truth in my life to each of those laws,” he says. His workday, for instance, is pure number 3—“Multiple projects lead to multiple successes.” On an average day, he runs from monitoring clinical trials for several potential new drugs for retinal conditions, to juggling ongoing basic science studies, to intense sessions with patients with serious visual problems.

But law number 13—“No simply means begin at one level higher”—Campochiaro says, pretty much sums up his entire approach to doing science. That whole method for thinking through a research project was hammered into him by the respected neuroscientist Joseph Coyle, whose picture also graces his Wall of Fame. Coyle, who left Hopkins for Harvard in 1991, ran the lab that Campochiaro worked in as a medical student here.

“A lot of times, the results wouldn’t be what I expected,” Campochiaro recalls, “and I’d be upset. “Dr. Coyle would tell me, ‘Oh, that doesn’t matter. What counts is what it is. Now we have to explain it.’” Hypotheses are just tools, Campochiaro learned, and “being wrong isn’t any big deal.” Often you learn more by being wrong.

Still, in the case of retinitis pigmentosa, it turned out to be an unexpected result that led him to oxidative stress. Several years ago, Campochiaro had begun to suspect that one of the conditions of the disease, a thinning out of blood vessels in the retina, stemmed from an overabundance of oxygen. To test this idea, he placed mice in an incubator, flooded it with excess oxygen, then studied tissue samples of their retinas under a microscope.

. . .
“There’s an observation that starts you down a particular path,” Campochiaro says, “and one step just leads to another.”  
> “There’s an observation that starts you down a particular path,” Campochiaro says, “and one step just leads to another.”

These tissue samples showed Campochiaro that his theory had been correct that oxygen was dampening the behavior of a protein responsible for blood vessel growth. But the experiment had a more surprising effect. Campochiaro discovered that the high levels of oxygen were also killing off the photoreceptors in the retina, meaning that they must be highly susceptible to oxidative damage.

Right away, Campochiaro started thinking about the sequence of events that cause RP: First, genetic mistakes (mutations) lead to the death of the rods, the nerve cells that are responsible for vision in low-light conditions and consume the most oxygen. Then, in a clearly scripted march toward death, the cones—the cells that process color, work in bright light and are responsible for our reading vision—begin to die. But why those cones die when they aren’t directly altered by the mutation that affected the rods has been one of the central mysteries surrounding RP. Scientists have proposed several theories through the years, most involving some sort of toxic reaction triggered by the death of the rods. But Campochiaro realized something else might be going on, as he stared at those tissue samples.

The retina’s light-sensitive photoreceptors, the ophthalmologist knew, were especially sensitive to oxidative damage. In normal, healthy eyes, the rod cells consume huge amounts of oxygen, but as the rods died off, it stood to reason that oxygen consumption would go down, ending in an oxygen surplus. This over-supply would then result in generation of excess reactive oxygen species. Might not it be these free radicals, Campochiaro asked himself, that were attacking the cones and causing them to press their self-destruct buttons? This malfunctioning system, he conjectured, could then be triggering cell death in the vital cones that allow sight to take place. “I thought, wow, here’s a situation in which oxidative damage may be leading to the death of cones.”

If his theory were right, it would at last offer one unifying principle within this complex group of diseases called retinitis pigmentosa.  Campochiaro hadn’t just found a tidy hypothesis explaining the death of the cone cells. This idea reached far beyond simple scientific satisfaction. He now saw the chance for a treatment for RP where none had existed before. 




Peter Campochiaro is not one for sudden flashes of inspiration—eureka moments. Rather, his mind, thoughtfully and methodically, almost never drifts from his work. (One of Campochiaro’s research fellows, Katsutoshi Yokoi, mentions that insightful e-mails from the ophthalmologist pop into his inbox anywhere from 7 o’clock in the morning to 10 at night.) What does keep Campochiaro going is the scientific method. He gets really excited when he talks about it. His trust in the timeworn approach is so firm, in fact, that he succeeds in making his own work sound almost pedestrian—as though anyone following the same trail of biological breadcrumbs would have arrived at the same results. “There’s an observation that starts you down a particular path,” he says modestly, “and one step just leads to another.” 

In truth, the succession of papers that make up Campochiaro’s work on retinitis pigmentosa might serve as a textbook case for how the scientific method is supposed to proceed. His studies move forward with a steady, deliberate progression, with each new set of findings flowing logically from the last.

Ideally, this pathway will lead to the development of a treatment. And that’s what he is concentrating on now. After proving that free radicals were indeed chewing up the cone cells—or, more precisely, destroying protein function and tricking those cells into killing themselves—Campochiaro started looking for a way to neutralize them. One obvious option was to use antioxidants, molecules that bind to the free radicals, rendering them powerless before they can do any damage. 

But this isn’t as simple as feeding laboratory rats a few extra blueberries (the supermarket antioxidant of choice, these days). Those free radicals act quickly, latching on to other molecules almost instantly. And it’s not entirely clear where in the cell they’re doing most of their damage. It could be in the cytoplasm. Or it may be that they’re affecting mitochondria, the engine of cells.

“If most of the damage is occurring in mitochondria or just outside, it doesn’t do much good for an antioxidant to be off in a different part of the cell,” Campochiaro says. “So in order for antioxidants to be helpful, they have to be targeted at the right place, at the right time, in the right concentration. It’s a tall order.”

ALS researchers, he mentions, are facing the same dilemma, and it’s proven to be especially tricky. Back in 1993, neuroscientists demonstrated a link between a genetic mutation and antioxidative damage.  The implication seemed fairly clear: If ALS stemmed from a mutant protein that was causing oxidative damage, then antioxidants should help. Subsequent trials, however, with numerous antioxidant-based treatments have proved inconclusive in fighting the disease. 

Campochiaro is further along the path in searching for a treatment for RP. Recently, one of his outstanding postdoctoral fellows, Keiichi Komeima, tested an antioxidant cocktail in mice and found that it did reduce cone-cell death and preserve retinal function. In this methodical way, before moving forward to testing the approach on RP patients, Campochiaro is analyzing the results of a variety of antioxidants given alone and in combination, to see which ones are most effective.

“We’d like to try to maximize the regimen,” he says, “so we can discover the greatest effect we can achieve in the animal models. If it’s sufficient, there would be reason enough to test that regimen in clinical trials on humans.”

There’s another possibility, too. The body has built-in defense mechanisms against free radicals, and it may be that finding a way to piggyback on this system, or to strengthen it in some way, could prove even more effective. “What we plan to do,” Campochiaro says, “is to characterize the antioxidant defense system in rods and cones, figure out which are the most important components and then determine if we can overexpress them or increase their levels to see if we can decrease cone cell death.”

Still, despite the steady progress of his research so far and his well-developed plans for future studies, Campochiaro acknowledges that finding a treatment won’t be quick. What keeps him focused is his dual role of clinician and scientist.

“When you’re working in a lab,” he says, “you always have the sense that you’re doing something worthwhile, but you sometimes lose the forest for the trees.” To remind himself of why he keeps staring at those slides in his lab, why he works such long hours, puzzling over the complex interactions of cellular molecules, all he has to do is walk down one flight of stairs.*

 The Alfredo Story
 A Minor Balancing Act
 The Free-Radical Dilemma
 Circling the Dome
 Medical Rounds
 Annals of Hopkins
Class Notes
 The Brain Voyager
 Learning Curve
Johns Hopkins Medicine

© The Johns Hopkins University 2007