The Autoimmune Epidemic: Bodies Gone Haywire in a World Out of Balance--and the Cutting-Edge Science that Promises Hope (No Series) (25 page)

Kerr hoped that once the newly developing peripheral nerves were free to move out into the limbs, they would know what to do—they might even, he hoped, regrow along the exact same channels that they do in original fetal development, allowing the repair to happen of its own accord, as if from memory. That, however, turned out to be far from the case. The axons did not grow where they needed to—instead they wandered around aimlessly. They seemed to be struggling to find out where to go, choosing one path and then another fruitlessly, only to give up and ultimately stop growing altogether. The original wiring of the nervous system in utero is staggeringly complex, and the cues that allow the nervous system to become wired are turned off completely after development. They no longer exist in the grown mammal. The question loomed: How could Kerr re-create those original cues in an adult mammal?

The developmental cues that are necessary for “wiring” the body for the first time act as signposts in the developing fetus. Placed along the nerves in the limbs of the body, they tell myelinated axons during development whether to go left or right. These signposts are basically proteins on the surface of cells, and they wave like flags in the wind during development so that when the myelinated axon gets there it’s like a signal flag telling the axon which direction to head in to connect with the right muscle and, conversely, which direction to avoid. Together, these axons pave the road with the nerves that will form the intricate highway of the nervous system.

Kerr realized he had none of these signposts in place. And so it made sense—if frustratingly so—that the axons would then meander aimlessly and never reach muscle. Which is exactly what they did.

Kerr and his colleagues realized they had to apply some bait in or near the muscle—something that they knew that motor neurons liked and that they would respond to—so that the motor neurons would grow toward that source. Step four began to become clear. Kerr applied a particular molecule that other researchers have found acts as just this sort of signpost during fetal development to the area where he wanted the newly growing axonal nerve to go. When the axonal nerve detects that particular molecule—known as GDNF—it is attracted to it and grows toward it. GDNF binds to a receptor that’s on the surface of the axon—and when it does, it turns on the neuron so that it continues growing in that direction.

Once those signposts were placed like bait in the paralyzed rat’s muscle, the axon started to get highly motivated. It began to move right toward the paralyzed muscle.

It was a goosebump-raising moment in the lab. The smart cell was working.

“I was looking right at the axonal nerves moving straight into the paralyzed muscle tissue, but still, I didn’t trust myself,” says Kerr, recalling the exact moment when he looked through his microscope and found that the stem-cell axons had actually reached the muscle tissue throughout the animal’s legs. As the newly generated axonal nerves reached the paralyzed muscle tissue, the muscle began to twitch. Kerr stared at what he was seeing under the microscope in a state of disbelief: “I thought, wow, this is amazing that we’ve gotten this far, that we’ve gotten all these steps together—but I still didn’t trust what I was seeing with my own eyes. It didn’t seem possible.”

By 2003, getting motor neurons to reanimate paralyzed muscle in mice had already consumed five years of Kerr’s life, with a staff of nearly a dozen often working largely around the clock. Kerr—who, when he needs to unwind from the constant pace of lab research, relaxes by tooling about on weather.gov and explaining the science behind worldwide weather patterns to staffers—felt it critical to confirm those five years of work by doing a massive blind study in 150 rats.

Kerr wanted to be absolutely sure that his cocktail was a success, especially before word of his work stirred the hopes of any patients. Several patients who were involved in advocacy work for transverse myelitis had been keeping abreast of his stem-cell research. One young woman in particular, Cody Unser, the daughter of ex–racecar driver Al Unser, Jr., had been deeply involved in raising funds to help find a cure for TM, and Kerr had come to know her well.

COOKING UP A CURE FOR PARALYSIS

In February of 1999, Cody Unser had been at sixth-grade basketball practice in Albuquerque, New Mexico, when she began to feel excessively tired and have trouble catching her breath. Her legs felt heavy, numb, tingly. She developed a mind-bending headache. After being evaluated at the local hospital, Cody was sent home, but the next morning she couldn’t sit up or get out of bed. She was paralyzed from the chest down. She saw half a dozen doctors who were not completely sure of her diagnosis. Eventually she was told she might have transverse myelitis.

Cody first came to Doug Kerr during his last year of residency in 1999, seeking him out because of his reputation in cutting-edge TM research. At that point, Cody says, “I had visited so many doctors who treated me like just another number, one more faceless patient with TM who they couldn’t help. But Doug was so compassionate. He reassured us that he was going to do everything he could to try to find a cure.” On one of their visits, Cody says, “he took my mom and me into his lab and showed us his stem-cell research. I felt I was in the hands of a miracle worker.”

Despite being paralyzed and in a wheelchair, by eighth grade Cody had created the Cody Unser First Step Foundation to help establish a TM research consortium spearheaded by Johns Hopkins Hospital. “My experiences taught me that there were many doctors out there who didn’t know all they should about TM and that there were researchers in the TM field who weren’t sharing information. There had to be more awareness and collaboration. We wanted to get doctors talking about TM.” Today, Cody Unser, now twenty-one years old, has spent the last eight years of her life in a wheelchair. She follows Kerr’s work closely. Her hope, she says, is “plain and simple: for paralysis to be history, for everyone to walk again.”

“Seeing Cody’s strength and courage has been a driving force for me from the day I first met her,” says Kerr. “I feel that she and I are a team determined to help her walk again. And we are both sure that we’ll succeed.”

In 2003, with some trepidation coupled with inspiration from patients like Cody, Kerr, working on his standard five hours of sleep a night, set to work to prove his theory right. His team treated 15 of the 150 paralyzed rats with the entire recipe for axonal nerve growth, including all the necessary growth factors and signposts that had proven effective in the lab. In order to test the cocktail’s effectiveness, the remaining 135 rats were split into groups and each treated with only a partial cocktail. For instance, one group of rats was treated with the transplanted motor neuron cells with all the growth factors, but they were not given the signposts that told the motor neurons where to go. Other groups lacked a different single, essential ingredient from the recipe as well.

In order to ensure accurate findings, Kerr had each paralyzed rat coded with a different number so that even he would not know which rats had been treated with which protocols. Then the key to that code—which rat had been given which treatment and, moreover, which rat had been given the full treatment—was set aside where no one could access it. Kerr was blind as to which of the identical rats had been given the entire nerve-regenerating cocktail. The researchers carefully followed and evaluated the rats for the next six months. After three months, they began to see signs that some animals were recovering. They didn’t know which group was showing signs of greater mobility, but a few animals were starting to move limbs that had been completely paralyzed before.

“Of course we were hoping that these rats were in the group in which we’d replicated our findings,” Kerr says. “My worst fear was that it would turn out to be one or two rats in each of our partially treated groups that were getting better—and we’d never know why.”

After a total of six months, the almost unimaginable happened: 13 of the 150 rats were now scurrying around like healthy rodents. It was an astonishing sight. In February 2005 the entire group of researchers gathered in Kerr’s lab to break the code. They started reading off each rat’s code and looking to the original cipher to see which rats had been treated with which protocol. If all thirteen of the now healthy rats belonged to the group of fifteen that had been treated with Kerr’s complete nerve-regeneration cocktail, it would mean that he had developed a revolutionary approach to make motor neurons reach out their “wires” from the spinal cord and move into paralyzed muscle, retracing complex pathways of nerve development that had been long shut off—recreating in an adult mammal the neural development that originally takes place in the womb.

When it became clear, only a few minutes into the process, that five of the recovered rats all belonged to the group that had been treated with Kerr’s entire cocktail for curing paralysis, the excitement in the lab became palpable. As they continued to read off the codes, each additional recovered rat also turned out to belong to the same fully treated group. When they read the code on the thirteenth and last cured rat and found that it, too, belonged in the group that had been fully treated with Kerr’s cocktail, people began to shout and jump up and down, hugging and clutching one another. A staffer grabbed a bottle of champagne that had been left in a lab fridge after a recent staff celebration. Kerr called his wife to tell her over the din that his dream had come true. Adult paralyzed rats—treated in a large-scale, fully controlled, blind study—were running around their cages again as if they had never been paralyzed at all.

“That’s your eureka moment,” says Kerr. “It’s an amazing moment when you say to yourself, ‘We did it in the most rigorous way possible, we blinded ourselves, and we found that we had it right.’”

Next, Kerr and his team will use the same basic framework to attempt to cure fifty pigs, looking to show safety and efficacy. Within five years he hopes to move on to human trials. One thing he will be looking to answer in his pig study is the question of distance: it’s one thing to grow new axons the short fourteen centimeters it takes to travel from a rat’s spine to his feet. But what about the greater length nerves must run from a pig’s spine to its toes? And what about the distance motor neurons have to travel in, say, a six-foot-tall man, whose longest nerve spans a full three feet?

Kerr is hoping to start clinical trials in paralyzed adults within five years—before 2012—if all goes well in his study on pigs. Still, there are formidable hurdles given that embryonic stem cells remain a political no-no in today’s federal funding arena. Although researchers have tried to use already-differentiated stem cells—taken from umbilical-cord blood, thus negating the need to use controversial embryonic stem cells—experiments striving to use this line of stem cells to regrow nerves have failed. Efforts are in the works to use stem cells from amniotic fluid, but many researchers say they would be seriously surprised if amniotic stem cells have all the capability of an undifferentiated embryonic stem cell, which has unlimited potential.

Some states, like California, have passed their own propositions to circumvent the federal ban on stem-cell research. And in Maryland, in 2007, legislators allotted $15 million for stem-cell research—including embryonic stem cells. About fifty Hopkins researchers, including Kerr’s group, have entered grant proposals hoping for some of the $100,000 to $500,000 grants being offered. But to get from where Kerr is now in his research to clinical trials “will take millions of dollars,” says Kerr. “With the current political climate, it’s not clear where that money will come from. We know that the federal government will not help. Drug companies are reluctant to step in because of patent issues—and because each of these diseases, taken individually, does not afflict a large enough number of patients. We go month to month hoping that something will happen with funding that will allow us to keep going.”

Although the idea of using embryonic stem cells for research is one that each scientist, politician, and voter must wrestle with for him-or herself, when the question arises among the four hundred sufferers of multiple sclerosis at the annual MS meeting where Kerr recently detailed his work on stem cells, their position is unanimous: embryonic stem cells hold the potential promise for them to live normal lives as mothers and fathers. Certainly embryonic stem cells are most promising when growing as an embryo inside a woman’s body, but once embryonic stem cells that are by-products of in vitro lab fertilization are discarded, they no longer hold any glimmer of promise at all.

Beyond the hurdle of embryonic stem-cell funding, even if researchers succeed in regrowing axons in paralyzed humans with multiple sclerosis, or in those with Guillain-Barré who have not had good recoveries, or in patients with chronic inflammatory demyelinating polyneuropathy, a cousin to Guillain-Barré in which demyelination persists, they still face the issue of how to keep the hyperactive immune system that is the hallmark of these autoimmune diseases in check and prevent it from going after and damaging the myelin and axonal nerves time and again—after an initial stem-cell treatment. One might have one’s nerves restored only to lose those connections each time the original neurological autoimmune disease flares.

It may be that stem-cell therapy will emerge as a kind of co-cure, along with therapies and lifestyle changes that help to keep the immune system from malfunctioning in the first place. Little by little, preventive therapies are being developed. “In five or ten years we’re going to have good ways to tamp down the immune system and keep severe paralysis from happening—ways that do not carry the severe side effects of many of the drugs in use today,” Kerr says. But, he ponders, “What about those people who are already in a wheelchair? Or who are struck suddenly and without warning by autoimmune disease and end up paralyzed before treatment to stop severe damage can even begin? We need to be able to give these mothers and husbands and children and grandparents back the lives they deserve to have. Then we can use newly developed immune-system therapies to help keep the immune system from attacking their nervous system again.”