The Autoimmune Epidemic: Bodies Gone Haywire in a World Out of Balance--and the Cutting-Edge Science that Promises Hope (No Series) (30 page)

Clearly, making use of prediagnostic biomarker technology to determine who will eventually be struck with an autoimmune disease will only be useful if that technology is not only foolproof, but if we possess fail-safe and side-effect-free interventions to offer to those who are informed by their doctors that they sit at the precarious edge of disease. No one should ever take a relatively healthy patient—such as Anita Louise Smith—and give to her a drug that might cause a fatal complication.

Still, should funding dollars increase for these diseases, helping scientists to achieve treatments that target specific molecular processes precisely and safely, the ability to scourge out disease before it wreaks destruction would allow 23.5 million Americans to live their lives without the devastating lifestyle changes that come with the onset of autoimmunity. Over time, such technology would also eventually mean savings in health-care dollars; no small matter given that autoimmune diseases now represent a yearly health-care burden of more than $120 billion, compared to the yearly health-care burden of $70 billion for direct medical costs for cancer.

THE DIABETES CURE: TURNING OVER PARADIGMS

At Massachusetts General Hospital, Dr. Denise Faustman, associate professor of medicine at Harvard Medical School and director of the Massachusetts General Hospital Immunobiology Laboratory, may well be on the verge of developing just such a cure for type 1 diabetes. Humor has helped Faustman along what has proven to be a rocky road over the past several years as she developed a revolutionary approach to targeting and destroying errant immune cells in laboratory mice.

In 2001 and 2003, Faustman published two highly controversial studies in top journals. One paper in the journal
Science
demonstrated that a forty-day treatment targeted to kill off only the very specific defective cells that cause the autoimmune destruction of healthy beta cells in the pancreas could effectively stop type 1 diabetes in its tracks. In Faustman’s experiments, 75 to 85 percent of mice were permanently cured of type 1 diabetes—an unheard-of outcome for any autoimmune disease research of its kind. The finding was remarkable: mice suffering from end-stage type 1 diabetes were not only permanently cured, their pancreases spontaneously regenerated and their blood-sugar levels returned to normal. The research would pit scientist against scientist and cause many researchers to reexamine their long-held assumptions about how autoimmune-disease treatments might be revolutionized in the future.

Faustman first decided to pursue research after years of working as a clinician treating patients with type 1 diabetes. In her seventh year of residency, she realized that she spent most of her time delivering a laundry list of bad news to patients about the progress of their disease: bodily systems that were breaking down, amputations that needed to be performed, and other grim tidings that it was her personal daily duty, as resident, to deliver. She wanted to be able to tell those suffering something good and was disturbed by the uneasy feeling that she wasn’t “making a dent” in anyone’s disease. By 1987 Faustman had done an abrupt about-face and was heading up a program to try to cure diabetes in lab mice at Harvard Medical School.

Over the next fifteen years, Faustman struggled, with a dedicated crew of eleven PhDs, to identify the exact group of pathological T cells that were misbehaving in type 1 diabetes and destroying islet cells in the pancreas. These errant T cells, she found, produced completely different proteins within their cells than did normal cells. In fact, these rogue T cells ought not to have been circulating in the body in the first place.

Normally, our bone marrow and thymus produce millions of T cells, which are the foot soldiers that work diligently to serve the immune system. All of these T cells have different random receptors on them that are equipped to recognize millions of pathogens that might enter the body—and destroy them. But many T cells are “born” faulty when they are first produced in the bone marrow; they mistakenly react to the body itself, rather than to outside pathogens: they are “autoreactive.” In normal circumstances 99 percent or more of these friendly-fire-prone T cells are killed off quite efficiently; the body recognizes them as autoreactive—long before they escape out of the bone marrow—because they have a protein sequence on their surfaces different from the good kind of T cells that help to defend us from invading foes. This faulty protein sequence on errant T cells is a signal to the immune system that these T cells should be destroyed before they have a chance to turn on us.

The specific group of dangerous T cells that Faustman discovered were mistakenly escaping the bone marrow weren’t being read as autoreactive when they should have been. Instead, they eluded discovery and snuck into the blood along with other healthy T cells.

The fact that Faustman was able to uncover and identify this specific group of flawed autoreactive T cells escaping out of the bone marrow was hugely promising. She began to wonder: What if she could kill only the misbehaving T cells in the pancreas and in the bone marrow—thus eliminating them from the body—in the same way that antibiotics would kill bacteria? Antibiotics are able to kill off bacteria in the body because the antibiotic interferes with different proteins that are unique to the bacteria, causing them to die—without interfering with any other cells. Faustman was determined to find a way to interfere with only the misguided T cells, singling them out and killing them off by recognizing the protein sequence unique to them and leaving the other T cells intact, creating something akin to an antibiotic for autoimmune disease.

Faustman’s approach offered a distinct advantage over much of the current treatment in autoimmunity, which is usually more broadly immunosuppressive—meaning it tinkers with all T cells or all B cells in order to try to keep the autoimmune reaction from occurring. The problem with such broad-spectrum therapies, Faustman knew, is that they suppress the good cells as well as the bad, which often meddles with other important functions of immune cells in the body, causing other diseases.

Faustman wanted to avoid that by being more selective. Luckily, the same defect that allows autoreactive T cells to escape from the bone marrow also results in a flaw on the surface of these T cells that allows them to be singled out and destroyed. Autoreactive T cells are more susceptible to the action of a signaling protein, known as TNF-alpha, which initiates the process of cell death only in defective T cells. Faustman’s lab was able to use TNF-alpha to kill off only those cells. This was an entirely novel concept: many drugs on the market used to treat autoimmunity are aimed at inactivating TNF-alpha. But Faustman’s data suggested the opposite. Perhaps select forms of autoimmunity, including type 1 diabetes, needed more TNF-alpha to eradicate these erratic T cells.

The thing that astonished Faustman and her team the most, however, was that when you killed off just the incorrectly functioning T cells, it not only stopped the disease, it allowed the body to regenerate the insulin-producing islet cells, reversing the disease entirely.

The very idea that by killing off the fugitive T cells that cause type 1 diabetes damage you could encourage a healthy pancreas to regenerate was considered so far-fetched that Faustman’s team was met with scathing skepticism from most of the scientific community. Scientists throughout the world openly questioned her claims. Despite her breakthrough, Faustman could not convince drug companies or major diabetes foundations to offer research funding. In 2003, two fellow colleagues at Joslin Diabetes Center—not on Faustman’s research team—sent a letter to the
New York Times,
which had run an article describing Faustman’s work, deeming the claim that she was the first scientist to cure diabetes in mice “patently false.” The researchers also apologized to patients with diabetes “on behalf of Dr. Faustman” for “having their expectations cruelly raised.” Although the
New York Times
did not publish the letter, it was posted on the Joslin Diabetes Center website and distributed by e-mail by the Juvenile Diabetes Research Foundation. Ironically, three competing lab teams from the University of Chicago, Washington University in St. Louis, and Joslin Diabetes Center were provided with Juvenile Diabetes Research Foundation grants to try to duplicate Faustman’s data, while Faustman, who had also applied for funding to continue her work, received none. Faustman’s research hung on by its fingernails.

In 2004, the three other labs set out to test the validity of Faustman’s finding that severely diabetic mice can recover on their own if researchers squelch the immune-system attack that is causing the disease through this very specific destruction of only defective T cells. All three labs followed Dr. Faustman’s procedures and, after three years of work, each study came up with similar results to Faustman’s: you could cure diabetes in mice using the protocol of killing only the autoimmune-disease-causing T cells in the pancreas. In every experiment a significant proportion—slightly less than half of the mice in these three studies—were cured, suggesting that even severely diabetic mice who have experienced significant damage to the pancreas over time still have the capacity to regenerate new beta cells if the autoreactive T cells can be eliminated.

CAN THE MOUSE CURE BE APPLIED TO HUMANS?

Faustman—like most mavericks who manage to create a new paradigm—has learned to be tough and sanguine in the face of years of scientific opprobrium. She smiles, recounting that when her original 2001 paper was first published, “We were not allowed to use the word ‘regenerate’ because it was not accepted that regeneration could happen. People thought that you are born with one pancreas and it can’t regenerate—therefore we had to be wrong. But in science, if you dig hard enough, you can find something new.”

Faustman jokes about having had to develop what she calls “scientific maturity” about the “sibling-like rivalry” scientists display in order to compete for funding. She feels that this adversarial approach to getting research dollars only serves to circumvent progress. “I thought when we developed this breakthrough that people would be excited,” she laughs. “But I learned the hard way that if you break open a new avenue in science you won’t be invited to every cocktail party. National and international research is not set up for sharing and promoting each other’s ideas and helping each other along. It’s set up so that researchers fight for limited funding, which does not allow for the kind of collaborative thinking that accelerates the delivery of new ideas to the public. But we in our lab wanted to share our work with every lab that was interested in doing follow-up studies to ours, to help them along in duplicating our protocol—with the hope that we might go further faster in curing this disease.”

Indeed, there is now considerable evidence that the same T-cell defect found in diabetic mice is physiologically identical to that found in diabetic humans. Moreover, worldwide research has found evidence of similar cell errors in a number of human autoimmune diseases similar to those seen in type 1 diabetes—meaning this target-the-fugitive-T-cell approach has the potential to impact the treatment of other autoimmune diseases, including multiple sclerosis, Crohn’s disease, scleroderma, Hashimoto’s, Sjögren’s syndrome, and lupus.

Faustman, along with Harvard colleague David Nathan, will soon launch a clinical trial in humans, funded by a private $11.5 million grant—provided by Lee Iacocca’s Iacocca Foundation. Iacocca, Faustman says—with words bathed in the kind of laughter that comes only on the heels of hard knocks—“likens this to what happened in the transportation industry when the car threatened to replace the horse and buggy. When the paradigm is changed in a way that affects others in the field negatively, it upsets a lot of people. Industry calls it ‘disruptive technology.’” She laughs more deeply. “Our work in diabetes has turned out to be disruptive technology.”

Faustman and Nathan’s clinical trial will involve three components. First, they are working to develop a laboratory test that will allow them to determine the level of defective cells in a patient’s blood rapidly and accurately. This test will enable physicians to identify patients who are most likely to benefit from treatment and can also be used to provide evidence of the success of the treatment. If the number of defective cells is lower after treatment, then researchers will know that they are succeeding in eradicating defective cells from the pancreas. In a second phase of the study, researchers will inject diabetic volunteers with a compound called BCG, which, like the compound given to mice to kill off errant T cells, stimulates the human immune system in a way that eliminates only the faulty T cells that attack beta cells. The study, which will include forty patient volunteers, will be double-blind—patients will either receive a placebo (no drug) or BCG. The researchers will evaluate whether BCG reduces the number of defective cells that attack and kill the insulin-producing cells in type 1 diabetics. Using blood tests to determine how many defective cells are still active, Faustman and Nathan will be able to see whether the mouse cure is working in humans. The clinical trial is already approved by the FDA. Faustman hopes that by 2012 her lab will have enough data to enable them to launch multicenter clinical trials around the country. Her goal in such a wide-scale clinical trial will be to find the exact dosing that can best kill off the renegade T cells that cause type 1 diabetes in the average patient. By 2017, she says, she hopes to have a “good therapeutic window” on what would be a standard dose to cure type 1 diabetes in your local doctor’s office. She smiles. “Better yet, by then I will hopefully have come up with even better ideas.”

W
hen Gerard Mullin was forty-three years old, he was already a who’s who in medicine. He was head of the Gastroenterology and Hepatology Division at North Shore University Hospital in Manhasset, New York, and had contributed scores of papers to top medical journals on two particularly difficult-to-treat autoimmune diseases of the digestive tract, Crohn’s disease and ulcerative colitis. Mullin was an expert on both of these inflammatory bowel diseases—which afflict 1 million Americans, one hundred thousand of whom are children—and patients lined up to see him for the kid-glove care he gave to their cases. The obligatory ten minutes most physicians spend per patient often became an hour of discussing drug strategies and counseling patients on how to manage life-derailing symptoms, including abdominal pain from severe inflammation of the digestive tract, diarrhea, and rectal bleeding. It was nothing for Mullin to call a patient over the weekend to see how he or she might be faring on a new medication.

Then, in September 2003, without warning, the unexpected happened: Mullin went from being an autoimmune-disease specialist to being a forty-three-year-old patient with a roaring autoimmune disease of his own almost overnight.

During the summer leading up to that September, Mullin had been unusually stressed out. In addition to working grueling hours because of hospital staffing shortages, he was caring for two dying parents. He began to experience minuscule muscle twitches in his arms and legs. A colleague suggested that Mullin have a spinal tap to rule out multiple sclerosis—although the likelihood of MS, given his atypical symptoms, was remote. Still, hospital doctors often over-test colleagues; it is not unusual for one doctor to send another for a wide battery of potentially unnecessary hospital tests “just to rule everything out.”

During the spinal tap, or lumbar puncture, a terrible medical mishap occurred: the lumbar puncture was made into what physicians refer to as the danger zone—the cauda equina—a group of nerve roots that send and receive messages to and from the lower abdominal organs and down into the legs. When these nerves are damaged, sensation to the legs can be seriously impaired. Not yet aware of what had happened, Mullin left the procedure experiencing excruciating pain. The puncture into his spine began bleeding. Something was terribly wrong. His brother drove him to the emergency room at New York Presbyterian Hospital/Weill Cornell Medical Center where he was hospitalized until the bleeding stopped. Physicians treating him told him that they could only hope that the pain would lessen with time as the area began to heal. There was nothing more they could do.

But a new problem developed while he was in the hospital. The puncture began seeping spinal fluid, and Mullin developed debilitating headaches. In October 2003 he underwent a procedure to have the leak patched. But in a second corrective procedure in February 2004, blood was mistakenly injected back into the spinal fluid while he was being treated under local anesthesia, sparking a rapid autoimmune reaction that would nearly cost Mullin his life. Since blood does not normally enter the cerebrospinal fluid, the body viewed these new, circulating blood proteins as potentially dangerous invaders that they needed to destroy. Mullin’s immune system sent out autoantibodies to wipe out these blood proteins—but in the process these same autoantibodies also targeted the innermost layers of the sac that surrounded Mullin’s spinal cord and the already inflamed nerve root of the cauda equina. Known as arachnoiditis, this devastating autoimmune disorder can lead to paralysis in the legs and turn life threatening as it attacks nerves throughout the lower organs of the body, even shutting down the bladder and bowels. (If the name arachnoiditis makes you imagine “land of the spiders,” that’s no coincidence: the nerve network that the immune system begins to demyelinate looks something like a spider web’s intricate fibers spanning out from the lower spinal cord.)

Mullin’s case was no exception. The burning pain down the back of both legs was constant. He was too dizzy to stand. He had poor control over his bladder and bowels. On April 18, 2004, two months after having had the leak patched, his heart began to beat irregularly and he began to bleed heavily through his gastrointestinal tract. Doctors started him on a third course of extremely high-dose steroids in hopes that it would help to stop the bleeding and the damage to his nerves. But he continued to worsen. He was put on a ventilator in intensive care. Mullin’s blood pressure fell so low the hospital staff couldn’t get a reading. Doctors managed to resuscitate Mullin with injections of cardiac medications and massive plasma and blood infusions. That evening he was told that his heart was so weak he might not live through the night.

But he did. The following day, doctors were finally able to stop the gastrointestinal bleeding and regulate Mullin’s heartbeat and blood pressure. He was released one week later on heavy doses of oral steroids. The pain remained untenable. His arachnoiditis—which keeps most sufferers in a wheelchair—was so severe he couldn’t walk across a room without feeling as if his back and legs were aflame, yet there was nothing more that modern medicine could do for Gerry Mullin. He was bedridden, on full disability, and the future was bleak. “I had become just another hard-to-treat patient that doctors didn’t know what to do with,” he says, looking back. “They’d run out of answers. I was unmarried, disabled, living alone, unemployed, and for the first time staring at the colder, uncaring side of modern medicine that patients so often complain about.”

Those seven months of hell taught Gerry Mullin a lot. Like many physicians who find out in an all-too-chilling manner what it’s like to be lying helpless in a hospital bed rather than standing in a white coat over bedridden patients, Mullin became a changed man. There had to be something more—beyond conventional medical approaches and drugs—that he could do to help himself. Meanwhile, his father had passed away, and his mother, who lived an hour and a half away, was very near to dying. Mullin was unable to get to her bedside, but he talked to his mother often. Growing up, she had owned a health-food store in the small town of Pompton Lakes, New Jersey, which had offered an array of health foods and supplements decades before health-food stores became part of mainstream America. She had been well known in their community for her vast knowledge about how a healthy diet and dietary supplements can affect overall wellness. Over the years she had often chastised her son for focusing only on pharmaceutical drugs when treating patients. “You’re going too medical on me, Gerry,” she would warn him, encouraging him to offer patients more holistic treatment options. She believed in the wisdom of Sir William Osler, the Canadian physician revered as the father of modern medicine, who said that “the good physician treats the disease: the great physician treats the patient who has the disease.” Diet and nutrition were, she felt, essential.

DISCOVERING THAT FOOD IS MEDICINE

Over the next several months—his laptop perched on his bed—Mullin prodigiously researched how a carefully manipulated diet along with dietary supplements has been shown in some studies to lessen the autoimmune reaction by helping to dampen down the production of cytokines—the signaling molecules that tell the immune system to react to an invader and that, if they become uncontrolled, can prompt the production of autoantibodies which attack in a friendly-fire assault, resulting in autoimmune disease. As a physician, Mullin was able to sign up for online conferences and courses in an emerging field of research being called “integrative medicine.” He became, he says, “very educated” on what a food-as-medicine approach can do to affect autoimmune activity in the body. He consulted several other like-minded physicians who specialized in alternative and complementary care. Together, the medical experts devised a carefully thought out dietary and supplementation plan to augment the conventional therapy with steroids that Mullin was using. Mullin began to consume a completely whole-foods diet coupled with nutritional supplements, with the hope that it would help to temper the autoimmune response that was raging through the nerves in the lower half of his body.

Over the next eight months Mullin’s constant pain and weakness began to ebb. His near-constant dizziness and heart-rate swings diminished. By December 2004, Mullin was able to get into a car and drive for the first time in fifteen months. His first priority was to see his mother, who had been hospitalized. He shared with her his belief that a holistic approach to his illness had allowed him to take back his life. He had decided, he told his mom, to pursue a PhD in nutrition to augment his medical degree. “She never said, ‘I told you so,’” Mullin recalls. “She just said she thought it was about time.” A few weeks later, she died.

Today, Mullin appears to be the portrait of health. It is hard to believe, watching him make in-patient rounds at Johns Hopkins Hospital, where he serves as director of Integrative GI Nutrition Services, that he spent more than a year disabled from a neurological autoimmune disease. He now regularly employs a holistic method to help keep his own autoimmune disease in check and feels it’s critical to offer the autoimmune-disease patients he sees each week complementary approaches to treatment in addition to traditional drug therapies. His papers on how vitamin D helps to prevent autoimmune disease are as likely to appear in
Nutrition in Clinical Practice
as his papers on T-cell activity in Crohn’s disease have been in
Inflammatory Bowel Diseases.
He now serves as a fellow at Dr. Andrew Weil’s program in integrative medicine at the University of Arizona.

“The idea that we should rely solely on drug therapies to help autoimmune-disease patients is antiquated,” Mullin posits as we enter his Hopkins office, where photos of his nieces and nephews sit on the windowsill and complementary health tomes line bookshelves. He sits down at his desk, his large hands clicking on the keyboard and moving the computer mouse with lightning speed, taking me on a virtual tour of research papers linking special diets and supplements to better outcomes for autoimmune-disease patients. “Drugs alone should no longer suffice as quality care,” he sighs, rubbing his hand over his three-day stubble of beard. “We know so much about the potential for special diets and supplementation to help modulate autoimmune disease and we have to help patients reap those benefits.” Still, the majority of doctors do not understand the role that diet plays in helping to ameliorate autoimmune disease. “Even in the field of inflammatory bowel disease the firm belief is that diet plays no role,” Mullin says, his fingers steepled in front of his face in a gesture that belies his frustration. “Yet we have clear data showing that changing an autoimmune-disease patient’s diet and adding in simple supplements can dramatically change the course of his or her illness.”

Not surprisingly, in the medical world, Mullin is still something of a lone ranger—though the landscape of traditional American medicine is slowly changing. Today, complementary and alternative medical centers are being developed at several top medical institutes—Hopkins, Harvard, Duke, Yale, and Stanford among them—largely driven by consumer demand. Many patients who suffer from autoimmunity are already trying dietary, supplement, and herbal approaches. Today, 21 percent of patients with autoimmune inflammatory bowel disease use complementary and alternative approaches to treat their disease. Consumers in general in the United States spend nearly $21 billion annually on nutritional supplements alone—$4 billion more than what they spend each year on going to the movies and video rentals combined.

Even so, the vast majority—61 percent—of American patients don’t feel comfortable discussing the alternative therapies they use with their physicians. Nor does the typical physician probe about diet or supplements when seeing a patient during a routine visit. Few physicians are well versed in cutting-edge nutritional research or are comfortable stepping outside of the traditional drug-the-disease box of treating patients. In what is known as allopathic medicine, physicians are trained to seek out “the differential diagnosis”—a disease name that alerts the doctor to what disease the patient has from a larger group of disorders with similar symptoms. Often, the doctor doing the diagnosing is a specialist—trained to look specifically at the neurological, gastrointestinal, or rheumatological aspects of disease—but certainly not all bodily systems together. Once the disease has a label, specific disorders and overt symptoms can be treated with pharmaceuticals that may or may not have their own symptom-producing side effects. The goal is to match symptoms to a specific disease and then prescribe the most appropriate drug.

Having a specialist is a good thing—it’s usually an experienced specialist who can diagnose more quickly and accurately and ensure a patient has the best that modern conventional medicine has to offer. But on the downside, specialists are less likely to think of the body as an interconnected, holistic system. Physicians who focus solely on a drug-the-disease approach often miss the interrelationships of the patients’ genetic background and predispositions, their history of infection, the burden of environmental chemicals and heavy metals that they may carry within, and their eating habits. In fact, a 2007 study of fifty-six second-year gastrointestinal fellows from top academic institutions in the United States bears this out all too well: 70 percent of the fellows reported having had no rotation in inpatient nutrition at all, and 87 percent had never been assessed for competency in nutrition. And yet these were subspecialty doctors in training from the nation’s top hospitals who would be specifically treating those with diseases of the gut. Counseling autoimmune patients about helping to quiet the inflammatory response through nutrition, in addition to drug therapies, necessitates a paradigm shift in medicine—toward seeing a patient’s complex biology as a dynamic, fluid, interlocking system where small and seemingly insignificant changes to the system, including shifts in diet, can dramatically influence the well-being of the whole patient.