The Autoimmune Epidemic: Bodies Gone Haywire in a World Out of Balance--and the Cutting-Edge Science that Promises Hope (No Series) (24 page)

To see how this process occurs in real time, Fairweather works in her lab with mice that have been exposed to a common virus such as coxsackievirus B3, known for short as CVB3, which can cause low-grade abdominal distress and diarrhea. When coxsackievirus B3 first enters the immune system, it enters the mast cells, where it gets broken down and chopped up. Toll-like receptors on the surface of the mast cells take a bit of that chopped-up virus and communicate the information they’ve gathered by presenting a piece of the virus to the T cells as if to say, “Hey, look, we’ve got a virus here!” The immune system must now decide whether to fight the coxsackievirus B3.

What happens next is critical. Should the mast cells signal the immune system to stay turned on just long enough to fight that virus, all is well. But should the mast cells stay turned on for too long and continue to release cytokines that further stimulate the immune system to attack the invading virus—and then seconds later send that same message alerting the immune system to respond to a chemical in a processed, food-colored cheese sandwich, and a second later do it again when it senses that the body has been exposed to flame retardants—the innate immune syst em never gets to rest from its state of high alert. The cellular interaction that puts on the brakes fails.

What ought to be putting the brakes on these cellular high jinks? At the crux of Fairweather’s research is the discovery of an entirely new gene, called
Tim-3.
The job of
Tim-3
is to tell the immune cells to stop firing off fighter cytokines.
Tim-3,
when able to do its job correctly, is the master brake in the system.

THE ALLERGY CONNECTION—AND WHY EVEN THOSE WITHOUT A GENETIC PREDISPOSTION TO AUTOIMMUNITY ARE NOW AT RISK

Ironically the
Tim-3
gene turns out to sit in a location where no scientist would ever have dreamed to look: smack on the chromosome that determines certain types of allergic reactions. Finding the
Tim-3
gene on this spot completely shocked researchers, says Fairweather. “At first they were confused; what was the
Tim-3
gene, involved in autoimmunity, doing on the allergy gene?”

As it turns out, this makes complete sense. The way in which mast cells ignite a rapid blast of cytokines that leads to autoimmune disease is very “reminiscent of the hypersensitivity of mast cells during allergic responses,” says Fairweather. When mast cells respond to allergic stimuli or infections they release cytokines and start an inflammatory response, which is the same process that initiates autoimmune disease.

As she talks about her research, Fairweather charts out these cellular interactions on the papers she’s spread before us: a rough Rube Goldberg diagram. It’s not easy to follow, and it’s incredible to consider that in the time it’s taken to read these last few paragraphs, our mast cells have made such split-second decisions about whether to launch an attack on each and every substance we’ve come into contact with thousands, if not millions, of times.

Like Fairweather’s Rube Goldberg drawing, the immune system seems booby-trapped with control mechanisms that, when breached, cause the body to go haywire. When that point is reached—because, as in the case of Fairweather’s mice, the immune cells never get the message to put on the brakes—her lab animals develop myocarditis, an autoimmune disease in which the body’s immune fighter cells attack the tissue of the heart. “It’s a matter of balance,” says Fairweather. If the body is constantly fighting new autogens, that balance goes out of whack. Mast cells begin to proliferate even more, causing more cytokines to be produced—when the exact opposite ought to be happening and the immune system ought to be damping down. All gas, no brakes.

Fairweather believes that this overwhelming response of our mast cells, and not the hygiene hypothesis, is what’s driving today’s autoimmune and allergy epidemic. Indeed, Fairweather contends, the synergistic effect of shifts in our lifestyles over the past fifty years is so profound that even people who do not possess a genetic predisposition to autoimmunity may now be at risk for developing autoimmune disease.

This is a big, big statement. The idea that so many chemicals, pesticides, heavy metals, and viruses are burdening our mast cells that we can be struck with autoimmune disease even if we do not carry any of the genes that predispose us to autoimmunity is almost revolutionary. Still, the idea is not completely unprecedented. We already know that some environmental triggers to autoimmunity are so potent that one does not need to have predisposing genes to be vulnerable to disease: recent research shows that smoking almost always doubles the odds of developing rheumatoid arthritis in women who have not inherited the well-established genes for the disease.

The standing worst-case scenario assumption has long been that 25 percent of people carry some genetic susceptibility to autoimmune disease. Even if every single one of that vulnerable group developed an autoimmune disease, we’d still be looking at a ceiling of, say, 75 million Americans developing autoimmune disease at some point in the future, around triple the current rate. Scientists have long assumed that the other 225 million Americans would remain largely invulnerable to autoimmune diseases. Given that current rates of autoimmune diseases have tripled in the last thirty to forty years and that levels of dozens of known autoimmune-stimulating chemicals and heavy metals have been rising in human breast milk, blood, and urine every few years, the idea that 75 million Americans might be suffering with lupus or multiple sclerosis or some other autoimmune disease by 2050 is not far-fetched.

If Fairweather and her colleagues’ discovery is correct—that autoimmune disease, when stimulated through the mast cell interaction, does not require any genetic predisposition to be set in motion—then the ceiling on how many people in the United States stand at risk for developing autoimmune disease is far higher than the 75 million (or 25 percent of) Americans who carry the genetic predisposition to autoimmunity. There is, in fact, no ceiling at all.

To bring this point home, Fairweather poses the scenario of a woman who does not possess any genetic autoimmune-disease predisposition who, in the afternoon, takes a walk with her two-year-old down the sidewalk of their townhouse complex, rounds a corner, and walks right into a cloud of atrazine herbicide being sprayed on the crabgrass in the community. Meanwhile, unbeknown to her, her two-year-old is coming down with a coxsackievirus she picked up at daycare, and Mom just shared the end of a Popsicle with her, so the virus is beginning to work on her mast cells as well. Mom sets out cheese nachos for lunch, served from their plastic wrapper fresh from the microwave, estrogen-disruptor laden, and some strawberries heavily sprayed with insecticides. At this point, our young mom’s mast cells are being hit nonstop, overwhelmed by the pesticides she’s taking in through her skin, the virus through her nose and mouth, the chemicals and additives through her food. A triple whammy. All these cause mast cells to stay turned on for far too long. The cytokines, running amok, begin to signal the immune system to target the body’s own tissue and organs and fire away. A similar triple whammy might occur when the immune system gets hit with a virus, a vaccine, and heavy metal exposure in one fell swoop.

For someone who does possess the genes for autoimmune disease, or who already suffers from autoimmunity, the process of cytokines running haywire might just happen all that more quickly, with each mega combo of environmental hits exacerbating his or her disease.

As we begin to understand better how different molecules and genes interact to set autoimmune disease in motion—whether it is John Harley’s discovery of the Epstein-Barr virus causing molecular mistakes that lead to lupus, or Fairweather’s mast cells being overstimulated and leading to autoimmune disease—we splice together more of the clues we need to decode the mysteries of the human immune system. However slowly, practitioners at the front lines of diagnosing these diseases are formulating clearer guidelines about what to look for in patients, and researchers are better able to develop lab tests for biomarkers that provide telltale clues as to what combination of potential triggers to autoimmune disease might already make up each patient’s barrel.

As this understanding emerges, researchers are likewise better able to test for certain biological markers in the immune system that may signal trouble long before disease strikes—as well as work toward novel interventions. Around the world, as the number of patients suffering from these diseases surges—and few efforts are made, meanwhile, to eliminate the very pollutants that trigger these diseases in the first place—scientists are starting to put their muscle into developing cures that are so outside the box they seem like something straight from a sci-fi movie.

O
n an unseasonably windy October Sunday in 2006, four hundred multiple sclerosis patients are gathered at the Maryland chapter of the Multiple Sclerosis Society’s annual conference in Towson, Maryland, to hear scientists discuss hopeful research for MS. Outside, the first fall leaves bluster past the hotel lobby windows like bright, pantomiming hands. But inside the banquet room all eyes are riveted on a short film clip playing on a screen in the front of the room. In the scene a white rat, paralyzed from the waist down, struggles repeatedly to use his front legs to drag the lower half of his body along behind him. Try as he might, he can’t budge an inch.

As the clip ends, the silence in the Sheraton ballroom grows eerie but for the sound of the Oz-like winds picking up again. Too many patients in this ballroom, myself included, know all too well what it feels like to muster every ounce of grit and muscle you possess in the hope your legs will hold your weight, only to lose that struggle over and over again. Everybody in this room knows just what the rat is dreaming of, if rats do dream.

The short film ends. A second begins. The same rat that, moments ago, was unable to move is now racing around a shallow-sided plastic box with the vigor of a rodent triathlete. Call him Regeneration Rat, call him Robo Rodent, call him the Rebound King. He is one of a group of thirteen rodents recently cured of paralysis in a groundbreaking stem-cell study at Johns Hopkins Medical Institutions.

The audience bursts into enthusiastic applause. One gets the impression that, if they could, the folks who are dependent on wheelchairs, walkers, or canes would be on their feet by now instead of hooting cowboylike bravos and clapping from their seats, letting their voices and hands convey the standing ovation that their bodies cannot.

The researcher they are lauding is the slightly sheepish but smiling Dr. Douglas Kerr, associate professor of neurology at the Johns Hopkins University School of Medicine, and principal investigator on this groundbreaking stem-cell study that recently rocked the scientific world. Whether by disposition or by training, Kerr is reluctant to accept the wave of admiration coming his way. He lowers his hands to stem the tide of applause, eager to explain to the crowd how, utilizing embryonic mouse stem cells in a novel set of strategic scientific steps, he has been able to regenerate the damaged axonal nerves and myelin sheaths in paralyzed rats.

“Is this the first time that paralysis has been cured in adult mammals?” a man in the audience calls out from his wheelchair, near the back of the ballroom.

“The first time,” Kerr answers, duly aware that the breakthrough offers a long-overdue gleam of hope on what often seems a bleak scientific horizon for the growing number of Americans facing multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, transverse myelitis, and a host of other neurological autoimmune diseases in which the body attacks its own nervous system, leading to weakness, numbness, and, in some cases, paralysis in the limbs.

There is a well-loved joke in scientific research in which a veteran lab researcher calls his grown son in order to share with him some astonishing news. “Son,” he says, “we are turning old rats into new rats in the lab!” His son replies, “Great dad—call me when you can turn old people into young rats.”

The point is well taken. Curing rats is a far cry from curing humans, and yet because rats, like mice, share remarkably similar neurological and immune systems to ours, it is with rodents that most medical research begins.

The story of how Kerr and his team came to cure paralyzed rats began in 1998 in Douglas Kerr’s lab on the fifth floor of the Johns Hopkins Bloomberg School of Public Health. At the time, Kerr’s meager research team consisted only of himself and two others. Today, taped across the door to his lab, along with photos of Kerr with his wife and two young daughters costumed as a beekeeper and bees for Halloween, are pictures of him with his current research staff—which has burgeoned into a team of twenty. The latter photos speak to the kind of teamwork mentality that any pioneering scientific endeavor such as this one requires. In the center picture, taken in Kerr’s family room, his lab staff poses together sporting goofy hats—straw hats with flowers, caps with cascading pink rose petals, panamas, and fedoras. One researcher holds a stuffed Elmo to his chest. They are laughing; they exude the aura of a family.

In the lab today, country music plays softly in the background. A half-consumed chocolate bar sits on a stool top. Beakers and bottles covered with aluminum foil fill the shelves of the glass and blue metal cabinets that line the walls, and a glass vase holds purple orchids. It is in this lab that the forty-year-old Kerr has developed what he likens to a step-by-step cookbook recipe on how to use embryonic stem cells to restore lost nerve function in paralyzed mammals. Kerr’s impetus to practice what he terms “science for a cure” began early on in his career when he worked as both a researcher and clinician treating many patients—especially kids—with neurological autoimmune diseases such as multiple sclerosis, a chronic central nervous system autoimmune disease that can cause blurred vision, poor coordination, slurred speech, numbness, acute fatigue, and, in its more extreme forms, paralysis. He also tended many patients with transverse myelitis, an MS-related autoimmune disease of the central nervous system that causes severe paralysis and other neurological disabilities.

In his fourth year of residency at Johns Hopkins in 1999, Kerr treated an eleven-month-old baby named Morgan Gertz, who was suffering from transverse myelitis. Kerr grew discouraged when current treatment therapies “couldn’t do a thing for Morgan.” Research into neurological autoimmune diseases wasn’t moving fast enough to help one whit. Morgan died. The loss of Morgan Gertz, coupled with similar losses, “broke my heart,” says Kerr. When Kerr became a father for the first time at the age of thirty-three, he began to appreciate even more viscerally what it was like for a disabled person—child or parent—to be unable to partake fully in the small milestones of growing up or raising children. “When I see those small moments aren’t possible for a patient because of their autoimmune disease, it becomes even more poignant,” he says.

Today, a picture of Morgan Gertz sits on Kerr’s desk, and another is on his office wall “to remind myself and every person who works in this lab why we’re here,” says Kerr. “I feel very strongly that I have to be these patients’ advocate.”

Until very recently Kerr’s pursuit to cure paralysis with embryonic stem cells—by attempting to grow brand-new nerve pathways throughout the adult body—was viewed by most scientists as little more than a pipe-dream hypothesis too far-fetched to warrant the research effort. The accepted science has long held that neural pathways can only grow during our initial development when we are still fetuses in the womb. After we finish developing in the womb, new nerves cannot grow in the body. Likewise, once those nerves are damaged they cannot be regrown—and most certainly not in an adult. Well aware that pursuing a plan to regenerate nerve pathways in adult mammals would mean skepticism from fellow researchers and years of patience, if it were to work at all, Kerr nevertheless pursued his experiments.

Step one involved taking mouse embryonic stem cells—which, at the earliest stages of development are known as “undifferentiated” stem cells—and “differentiating” them into motor neuron cells. In development, undifferentiated embryonic stem cells become differentiated as they take on the distinct, necessary roles needed to create specific organs and tissue. Undifferentiated stem cells are kind of like college freshmen who haven’t yet decided what subject they want to major in. Some go on to become heart tissue cells, others skin cells—and some become motor neurons. During our development in the womb, motor neuron cells are responsible for creating the complex nervous system that runs like a superhighway throughout our bodies, connecting our brain, cerebellum, and spinal cord to every nerve in our skin, limbs, fingers, toes, organs, and muscles. Kerr had to find a way to prompt these undifferentiated mouse embryonic stem cells to differentiate into motor neuron cells in such a way that they would go on to create axonal nerves covered with myelin sheaths—a fatty insulating tissue—that together make up the elaborate electrical highway that constitutes the nervous system.

Under Kerr’s microscope, undifferentiated stem cells don’t look like much; a group of fifty thousand appears no bigger than a speck of table salt. To the naked eye, they are invisible. But these small cells are integral to human life. When the axonal nerves and myelin sheaths become damaged we become—in simplest terms—a bit like marionette puppets without any strings: nothing connects the brain and the toes, the central nervous system and the muscles in our arms or legs. Or, imagine the body as an electrical system. If you turn on the light switch in your bedroom, the electric current races through the wiring behind the walls and around to the socket where the lamp is plugged in, then into the lamp cord, where it races up to light the bulb. If you damage that wiring or cut too deeply into the plastic coating around the wire, your light won’t turn on. Damage the myelin sheaths or axons that run from the spinal cord down into the legs and toes and your toes won’t move; you won’t feel the floor beneath your feet.

These myelin sheaths and axonal nerves are of critical importance in MS and transverse myelitis research. Much MS research is focused on an autoimmune process in which immune fighter T cells, which are only supposed to attack foreign pathogens and invaders, mistakenly attack and damage myelin. The process of demyelination interrupts the electrical impulses that run through these nerve fibers, causing weakness and paralysis. More recently, however, researchers have discovered that B cells are also involved in the autoimmune response to MS. Instead of targeting myelin, B cells—which T cells signal to attack foreign antigens—can directly attack axons. In transverse myelitis, demyelination and injury to bundles of axonal nerves occurs in focal areas of the spinal cord, often leading to permanent and severe paralysis.

Kerr knew that if he were to succeed in stimulating the regrowth of axonal nerves and myelin sheaths—the kind of growth that happens naturally during a mammal’s fetal development—he would need to give each embryonic motor neuron cell the strength, power, and precise signals necessary to tell it exactly where to go in the nervous system and what axonal nerves to redevelop once it landed there. You might call it a “smart cell.” If such a plan succeeded, one could theoretically repair the damaged nerves in MS, transverse myelitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and acute disseminated encephalomyelitis—all neurological autoimmune diseases in which the myelin sheaths and axonal nerves are compromised.

Kerr’s first step was to collaborate with other researchers at Columbia University who had succeeded in prompting mouse embryonic stem cells to become specialized motor neurons by adding growth factors—known as “retinoic acid” and “Sonic hedgehog proteins”—to undifferentiated stem cells to induce them to specialize into motor neuron cells, the same cells that, when we develop inside the womb, assume their proper place in the spinal cord and, from there, are responsible for the growth of our axonal nerves and the myelin that sheaths them.

Once Kerr’s team succeeded in prompting undifferentiated embryonic mouse stem cells to become differentiated motor neuron cells, they had to figure out a way to make these newly differentiated motor neuron cells do their natural job—to grow brand-new nerves from the spinal cord down into the legs. Kerr’s lab team took these motor neurons and injected them into the paralyzed rats’ spinal cords, hoping they would begin to grow new nerves. The experiment failed; once Kerr’s team transplanted these hard-won motor neuron cells into the rats’ spinal cords, the motor neuron cells died, without exception. “We found that if we just transplanted motor neurons into the spinal cord and did nothing else, then the surrounding neighborhood in the spinal cord—the white matter surrounding the spinal fluid, which is full of other, healthy myelinated axons—would see these motor neurons as foreign and reject them,” Kerr says. The motor neuron cells expired. Kerr had to find a way to make the neighborhood recognize the transplanted motor neuron cells as friendly so that the motor neurons would be allowed to generate new nerves.

In 2001, Kerr and his team achieved this second step by treating the newly created motor neurons with additional growth factors that told the surrounding white matter that the motor neurons emitted the kinds of growth hormones that they excrete during development—even though they weren’t. The trick, as Kerr terms it, worked—and it worked beautifully. The transplanted cells survived in the rat. Step two was complete.

But there was another problem. Although Kerr’s team had succeeded in creating new motor neurons and in getting the adult body to accept them, the transplanted motor neuron cells didn’t do what he had hoped they would once the successful transplant was completed. The transplanted cells did grow new axonal nerves, but these only ran up and down the spinal cord. They didn’t reach out from the spinal column and shoot new axonal nerves into the arms and legs, which is where they needed to go if they were going to help the rats use their paralyzed limbs again.

In order to coax the nerves to grow out into the paralyzed legs, Kerr had to introduce two last chemicals into his nerve-regenerating cocktail: chemicals that told the myelinated axons that these newly birthed nerves were exactly the same as those that wire the body during fetal development. Now, says Kerr, “We got wild growth of myelin. We looked at this in our lab animals to see whether axons could now grow out of the spinal cord and we found that they did.” Check off step three.