There’s an old story about a policeman who encounters a drunk at around midnight, down on his hands and knees searching the sidewalk under a streetlamp. When questioned, the drunk says he’s looking for a silver dollar he dropped an hour earlier at the other end of the block. “So what are you doing down here?” the officer asks. “Why aren’t you looking where you lost it?”
“Use your head, man,” the searcher replies, squinting into the void beyond the ring of the streetlamp. “It’s as black as the pit out there. What chance would I have of finding it in the dark?”
You can see that same joke repeated every day on every well-lighted street corner in medicine. Searchers by the thousands scour the same old territory for as long as the light lasts, in some rare cases just to prove the ground is fallow, but far more often for no better reason than the certainty that even when they come up empty-handed they still get paid for looking.
And what about the far fewer researchers who are actually willing to work in the dark where answers await discovery, the true scientists who are led by a hunch or happenstance to challenge a tradition or consensus that is always heavily defended by politics and myth? They can be assured of a very hard road: shunning or outright attacks by colleagues who frequently are also their rivals, little or no grant support, restricted access or no access to peer-reviewed media, loss of reputation, frequently loss of income, and sometimes loss of employment.
When the producer of “20/20” asked Tom Brown why he had written a book for the general public that challenged the conventional view of connective tissue disease after four decades of nearly constant attack by the medical establishment for those very same heresies, he answered with a tired smile, “Because I’ve finally outlived the sons of bitches.” But of course, he had not. The real reason Tom wrote the book was because he knew he was dying. If there was any doubt of the outcome, by the time the segment aired it was abundantly apparent the sons of bitches were going to outlive the pioneer. They usually do.
In 1984, Dr. Barry Marshall was serving out his residency at a hospital in Perth, Australia. At about the same age as Tom Brown and Albert Sabin had been when they began their careers at the Rockefeller Institute some half-century earlier, he too made a discovery that one day would revolutionize medicine. Suspecting that bacteria, not stress, were the cause of stomach ulcers, he and a colleague had taken samples from the stomachs of ulcer patients and were trying to culture something in a Petri dish. The standard incubation time is forty-eight hours, and like Tom Brown with mycoplasma, they had come up empty in their first several attempts to isolate a potential culprit. By chance, however, over the Easter holidays one batch was left in its dish for more than twice the normal length of time, and they returned to find a colony of corkscrew-like Helicobacter pylori swarming under the microscope. Repeating the technique, the same suspect appeared in cultures from other ulcer patients.
The obvious next step in Koch’s postulate would be to use the bacteria to induce this disease in an animal model, as Sabin had induced arthritis with his second mouse, but those attempts proved just as unproductive as their earlier tries at culturing the bug. In frustration, young Dr. Marshall decided, perhaps rashly, to try the experiment on a human subject, swilling down a microbial cocktail that he later described as tasting like swamp water. A week later he awoke in the middle of the night with severe stomach cramps, and a few days after that an endoscopic examination with a tiny TV camera revealed a gastric inflammation of the type often associated with ulcers.
Armed with these revolutionary results, Marshall hit the medical convention trail to rouse the sleeping populace—and of course his colleagues responded to the wake-up call with nudges, winks, and snickers. Who was this bothersome upstart? He came from a hospital hardly anyone had ever heard of, was still a resident, hardly even a clinician and certainly not a researcher. Everybody knew that ulcers were caused by acid triggered by stress (one way of blaming the patient, as stress is usually seen as a function of lifestyle.) There had been a longstanding myth in medicine that the environment of the stomach was too hostile to support any life forms, and many doctors still adhered to that fiction even though it had been disproven before Barry Marshall ever appeared on their horizon.
Perhaps even more to the point, there was already an absolutely wonderful treatment, Tagamet, an acid-blocker approved by the FDA less than a decade earlier that had cut ulcer surgery by a third in its first year on the market and that by 1984 had become the best-selling drug on earth. From a strictly business point of view, the real magic of acid blockers was that no matter how many times they “cured” the disease, the ulcers usually came back. No investor in his right mind would want to kill the goose that lays that kind of golden annuity, and neither, apparently, would the typical gastroenterologist for whom ulcers produced a quarter of all annual income.
The more resistance he met, the more determined Dr. Marshall became. He concocted a number of different therapies aimed at knocking out both the painful symptoms and the H. pylori, which he remained convinced was their real cause. He got a 70 percent remission rate with a combination of Pepto-Bismol and the antibiotic metronidazole, and when someone else added tetracycline to the mix the effectiveness rose another 15 points to 85 percent of all stomach ulcers treated, a number that may represent 100 percent of those with a bacterial etiology.
Unlike Tom Brown, he responded to the indifference or criticism of his colleagues by turning up the volume, often angrily scolding them at medical conventions about their obligation as healers to eradicate ulcers at their source, an exercise that increased his visibility in about the same degree as it reduced his peer popularity. But eventually his efforts began to attract a different constituency, and a far larger audience. After he published a paper in the British medical journal The Lancet, the story of his work was picked up in America by The National Enquirer, then the Cincinnati Enquirer, and eventually the Wall Street Journal. For many, his saga became a model of everything that was wrong with how the establishment responded to innovation, how the ethics of medicine had been pre-empted by the venality of big business, and how the little guy, whether a renegade genius or a helpless patient, always gets it in the neck. It was one of the best conspiracy stories since the assassination of John F. Kennedy, only this time the victim was still alive and it looked as if he finally had a chance of winning.
A decade and a half after that breakthrough in Perth, how has this process played itself out: how is Dr. Marshall viewed in the medical establishment, and how much of a difference have discovering the cause of stomach ulcers and offering an effective cure made in the way the disease is now treated?
Today it is almost universally accepted that 85 percent of all ulcers in the digestive system are caused by the bacteria he identified in 1984, and numerous clinical trials have shown that antibiotic therapy can cure them up to 100 percent of the time. Meanwhile, H. pylori have also been implicated in stomach cancer, which, in parts of the world such as Italy and Peru where the bacteria are more ubiquitous, can be a leading cause of death. In America, the NIH has officially declared that ulcer patients with H. pylori should have the bacteria eradicated.
Procter & Gamble, which had acquired Pepto-Bismol, began supporting Dr. Marshall when they recognized that his work with bismuth against H. pylori might represent an opportunity to carve out a larger share in their new pharmaceutical marketplace, and under the company’s powerful aegis the young renegade from Perth moved into a new position at the University of Virginia Medical School. Even though his work met with often blistering criticism, ridicule, and even personal attacks at every step of the way, almost all of his original critics have swung full circle, some gracefully and some grudgingly, in support of the infectious theory and antibiotic therapy. In 1995 he was honored with the prestigious Lasker Award for his work on ulcers, and three years later many people still consider him a prime candidate for the Nobel Prize in medicine.
All of which might appear to be the happiest possible ending to these two stories, both of a truly deserving innovator and of the scourge that he has devoted his career to eradicating.
But so far, that would be a false conclusion. Despite all the well-publicized evidence of its efficacy, safety, and cost-effectiveness, the number of ulcer cases actually treated by antibiotic therapy had risen only sluggishly, from zero in 1984 to a mere 16 percent in 1995, a share described by Fortune magazine as “amazingly few.” Dr. Marshall’s office at the medical school still receives panicked telephone calls from patients who are facing painful, expensive, and life-threatening surgery for a condition that the world now knows can be treated better medically, and at far less cost or risk. If the young Australian doctor ever does make it down the aisle at Oslo, it is a certainty that those plaintive calls for help will be ringing louder in his mind than anything he is likely to be hearing at the same time from his colleagues, whether their praise, their familiar but subdued snickers, or the gnashing of old teeth.
In his classic work, The Structure of Scientific Revolutions, the late MIT professor Thomas S. Kuhn sees the process outlined above—and indeed, the process described in this brief book—as being not just occasional to such change, but inevitable. “Normal science,” he writes, “often suppresses fundamental novelties because they are necessarily subversive of its basic commitments.” He describes the major turning points in the careers of Copernicus, Newton, Lavoisier, and Einstein, among many others, as dramas in which the transforming event results not just from insight or serendipity but from the resolution of the often bitter contest between personalities, between the cultures of the status quo and the revolutionary, between deeply entrenched and heavily defended traditions that no longer work and radical changes that do, between the present and the future: “. . . a new theory, however special its range of application, is seldom or never just an increment of what is already known. Its assimilation requires the reconstruction of prior theory and the re-evaluation of prior fact, an intrinsically revolutionary process that is seldom completed by a single man and never overnight.”
sixty-one, is a police clerk in De Queen, Ark. She developed symptoms of systemic scleroderma in 1989 and was diagnosed in April 1990.
Things moved fast; in a year I had severe joint pains, problems swallowing and breathing, extreme fatigue, contractures of the fingers, ulcerated joints, and hardening or tightening of the skin all over my body. I saw a series of rheumatologists, but none of them could offer a thing that helped. I finally found a doctor who put me on antibiotic therapy in January 1991.
I was pretty far along when they started me on IVs, and they had to push so hard to get the needle through my skin, there was a risk of blowing the vein. But it began to work almost from the start. The redness and soreness left my hands, the skin softened, and the ulcers healed on my knuckles. The lung and throat problems got better, along with my range of motion. The nurses giving the treatment were amazed at the difference in my condition.
Today, all I have left of this disease are contractures in one hand and some thickened tissue on part of one leg. I can do things at work, around the house, and in the garden that I never expected to do again. My life has been given back to me.
That contest can be vastly more complex when the science is in medicine, and the outcome of a medical revolution frequently depends far more on the strength of its champions than on the power of its truth.
Consider the case of Virginia Wuerthele-Caspe, M.D. (later and better known as Virginia Livingston-Wheeler), the lead author some years back, along with Eva Brodkin, M.D., and Camille Mermod, M.D., of a preliminary clinical report titled Etiology of Scleroderma. The study was based on the probable bacterial cause of scleroderma and its treatment with antibacterial agents.
“On the assumption that the organism is a mycobacterium as in leprosy and tuberculosis,” she wrote, “the senior author reasoned that it should be found in nasal ulcers, subcutaneous tissue, and sputum when there is pulmonary involvement. Accordingly material was prepared from the sputum of a proved case of scleroderma. When the slides were stained by the Ziehl-Neelson method, numerous short, thick, acid-fast rods appeared.” A cooperating team of investigators was formed to study the organism’s pathology in six patients, all but one of whom were women.
The conclusions of the study, potentially at least, were revolutionary in the true sense of the word. “An acid-fast bacillus [was] found in five cases of scleroderma examined bacteriologically. The organism [was] found in the sputum, blood, nasal and subcutaneous tissue smears, and has been grown in pure culture from the blood. All patients treated with promin (which destroys or inhibits mycobacteria) have shown definite, responsive changes. The organism . . . may be a newly recognized member of the family of mycobacteria.”
So whatever happened to these four muses, the first researchers to name mycoplasmas as the prime suspect in the disease of scleroderma and the first to point directly to antibiotics as a therapy that works?
In case you missed it, all three authors of the study are women, as is the researcher in charge of the lab work, a questionable advantage in medicine even in today’s enlightened environment. And what they are reporting, in its context, is revolutionary, which means they are also heretics.
Because the authors were deprived of virtually all the power required for effective advocacy, although their brilliant, prescient study was knocking at the door to a cure of this disease, it failed to meet the acid test of What Happened Next. It was published, not in JAMA or The Lancet or Arthritis and Rheumatism, but in The Journal of the Medical Society of New Jersey. And it appeared in print long before the term “glass ceiling” had been coined and before PC meant either politically correct or personal computer, a half-century ago, in the summer of 1947. And of course it was universally ignored.
Now, over a million scleroderma patients later, another study has been completed, this one pointing more directly to a cure for the disease; the fact that you are now reading this book means that the scientific report of The Road Back Foundation’s scleroderma study at Harvard Medical School has already been presented in a peer-reviewed medical forum. This time the revolutionary concept may have some advantage in its aegis, but it is revolutionary nonetheless and will hardly be exempted from the protracted and surely rancorous defense of the truths that it will eventually displace.
On May 8, 1998, at the Sixth Biennial Meeting of the International Society for Rheumatic Therapy in Boston—in the same forum and on the same day that David Trentham presented the results of the Harvard Medical School study of minocycline in scleroderma—a kind of requiem was offered for the long, mean war against the use of that drug in rheumatoid arthritis. Sheldon Cooper, M.D., of the University of Vermont Medical School presented a paper titled “Minocycline for RA: The Controversy is Gone.” Dr. Cooper, who ran one of the six treatment centers in the MIRA study and who is emerging as a key figure in the ascent of antibiotic therapy, was obviously deliberate in his choice of such an optimistic title, and it wasn’t hard to imagine the reaction it would engender among the majority of his profession, who remain far more faithful to ancient folly. But if the title was more prophetic than factual, it acknowledged that a foot is now firmly wedged in a door that had been nailed shut for decades, and promised that someday soon there would be enough such feet to kick it down.
Similarly, the purpose of this book is to broaden the forum in which the new truths are weighed against the old by inviting in the thousands of patients for whom this therapy can mean the difference between improvement or remission and crippling pain, and sometimes between life and death. For doctors or patients, the experience and insights of others who have traveled a similar road can illuminate personal choices that ease the journey.
At the bottom line, all patients are consumers, whatever the name of their disease, and they deserve not just to participate but to be in charge of the process by which they select the most appropriate therapy and hire the best physician to provide it.
They no longer have to take no for an answer.