• • •
For more than twenty years, Andrew Wakefield has published work in which he’s claimed to have uncovered new ways of looking at old problems. This pattern began in the late 1980s, when Wakefield, a Canadian-trained surgeon then in his early thirties, challenged the conventional thinking about a debilitating and incurable inflammatory bowel disease (IBD) called Crohn’s disease. Already, Wakefield was a seeming contradiction of brash self-confidence and unrealized potential. He was a former amateur rugby player who’d earned his doctorate when he was only twenty-five years old—but according to medical databases, he’d published a total of just three research papers during the first decade of his career.
In focusing on Crohn’s, Wakefield had chosen a disease whose precise etiology has never been established, although then, as now, the vast majority of evidence indicated that it is an autoimmune disorder that causes the body to incorrectly identify partially digested food as invasive matter. When the immune system attacks the perceived threat, white blood cells build up on the walls of the small intestine, resulting in painful, and occasionally deadly, inflammations. This way of understanding Crohn’s, Wakefield speculated, was all wrong: The disease’s trademark inflammations were not the pathological features of an immune system malfunction, they were the result of clogged blood vessels in the wall of the gut. If true, Wakefield’s theory stood to completely change the way Crohn’s was treated—but, as would be the case repeatedly in the years to come, Wakefield’s data did not justify his conclusions. “[It was] an interesting idea,” Thomas MacDonald, the dean for research at the Barts and London School of Medicine, said later. “But just wrong.”
Such appraisals did not prompt Wakefield to reexamine or revise his theory; if anything, they seemed only to reinforce his belief that he was correct and his critics were mistaken. In the early 1990s, building on his earlier work, Wakefield began to focus on measles as a likely cause of the IBD-causing stomach inflammations. In later years, Wakefield would say that the genesis of that insight was neither lab research nor collaboration with infectious disease specialists: His “eureka” moment occurred one winter night when, while flipping through an old virology textbook, he happened upon a description of how the measles virus had, on occasion, been shown to cause ulcers. “You could have been reading an account of Crohn’s disease,” he said. “It was very exciting.”
Those years also marked the point in his career during which the focus of Wakefield’s work increasingly converged with public health concerns. According to an investigative journalist named Brian Deer, it was around that time that Wakefield began contacting high-level officials at the British Department of Health, requesting face-to-face meetings to discuss financial backing for his work. His entreaties seemed to go beyond a sober recitation of the value of his research: In an October 1992 letter to David Salisbury, who at the time was the head of the British vaccine program, Wakefield wrote, “My concern is that although measles, and in particular the vaccine, may have no association with Crohn’s disease whatsoever, what will be picked up by the press is the apparent association between the increasing incidence of disease and the vaccine.” It was an odd point for a researcher to make. Instead of arguing the merits of his work, Wakefield seemed to be warning about the possible public fallout of his conclusions.
By the beginning of 1993, Wakefield, having failed to obtain government funding, was fully immersed in the work that would dominate the rest of his life. That spring, he and several co-authors submitted a paper to The Journal of Medical Virology that claimed to have found evidence that “the measles virus is capable of causing persistent infection of the intestine” and that Crohn’s disease “may be caused by a . . . response to this virus.” That study created such a furor that Britain’s Medical Research Council (MRC), which oversees and promotes health-related research, convened a panel to examine the data that Wakefield had relied on—and found that it had such significant problems as to render the study’s conclusions all but meaningless.
Wakefield’s next attention-getting paper was published in 1995, not long after the government’s measles vaccination campaign: Now, he was “examin[ing] the impact of measles vaccination” on “the rising incidence of inflammatory bowel disease”—and in doing so, fulfilling the prophecy he’d made to Salisbury three years earlier. By that point, the nascent concerns about Wakefield’s early research were appearing with increasing frequency. In the years to come, teams in Japan and the United States would try, and fail, to replicate the 1995 paper’s results. That was not a surprise: The shortcomings of Wakefield’s research were so serious that they all but negated his results. In one instance, the chemical solutions he’d used to identify the presence of measles in intestinal tissue were not specific for the virus, which meant that positive reactions could have signified almost anything. In another, the results that Wakefield claimed were indicative of the presence of measles actually stemmed from contamination by a clone of the virus that had been provided to Wakefield’s lab for use as a positive control. Even if his data had been more reliable, his conclusions were oftentimes contra-logical: If measles infections did, in fact, cause Crohn’s in some subset of the population, why had there been an increase in Crohn’s diagnoses over the previous two decades, a period during which measles infection rates had plummeted?
By 1997, the emerging consensus about Wakefield was, as Thomas MacDonald explained later, that he often neglected to carry out “important things that a credible, decent scientist would feel duty bound to do.” But if Wakefield had an increasingly checkered reputation within the insulated worlds of medicine and academia, he was a rising star in the public sphere, where his skill at public relations endeared him to a London press corps willing to hype results first and check reliability later, if at all.
CHAPTER 9
THE LANCET PAPER
On February 26, 1998, journalists from London’s dailies were invited to a press conference at the Royal Free Hospital School of Medicine. The occasion was the publication of a dense academic paper in The Lancet, the august medical journal that is one of the most cited scientific publications in the world. The paper’s title didn’t make it an obvious candidate for articles in the next day’s broadsheets; even the most creative headline writers would have trouble coming up with a pithy leader for a piece about “Ileal-Lymphoid-Nodular Hyperplasia, Non-Specific Colitis, and Pervasive Developmental Disorder in Children.” But the Royal Free’s PR team gave hints that this was no ordinary paper: They’d put together a twenty-minute promotional video for the occasion and assembled a panel of five of the hospital’s researchers to address the report’s implications. Andrew Wakefield, the paper’s lead author and its “senior scientific investigator,” was the star of both.
It didn’t take long to figure out what all the fuss was about. Contrary to the paper’s title, the main thrust of the press conference was not the possible connection between intestinal and developmental disorders—it was Wakefield’s supposition that the MMR vaccine, which had been used in the United States since the early 1970s and in Great Britain for the previous decade, could very well be responsible for the dramatic rise in rates of autism. In order to support this theory, Wakefield piggybacked on his claim that he’d found the measles virus in the intestinal tracts of IBD patients—a claim that had already been discredited by other studies. Now he said he’d come up with a potential biological pathway that linked the MMR vaccine with IBD and autism. Some children, he speculated, had immune systems that, for some unknown reason, were unable to handle the combination of the three vaccines at once. As a result, the measles component of the vaccine took root in the lining of the small intestine, causing a “leaky gut.” The next step in Wakefield’s hypothesis was dependent on a widely discredited “opioid excess” theory of autism, which drew parallels between autistic children and doped-up lab rats: After the opioid peptides that are naturally produced during digestion escaped through the gut’s newly porous walls, Wakefield argued, they bre
ached the blood-brain barrier and overwhelmed developing children’s brains. The result was autism.24
Knowing that the paper’s findings would be controversial from the start, the five experts who addressed the media had agreed beforehand that regardless of their individual interpretations, they’d deliver one overarching message: Further research needed to be done before any conclusions could be drawn, and in the meantime, children should continue to receive the MMR vaccine. Once the tape recorders began to roll, however, Wakefield went dramatically off-script: “With the debate over MMR that has started,” he said, neatly eliding over the fact that he was, at that very moment, the person responsible for igniting the debate, “I cannot support the continued use of the three vaccines given together. We need to know what the role of gut inflammation is in autism. . . . My concerns are that one more case of this is too many and that we put children at no greater risk if we dissociated those vaccines into three, but we may be averting the possibility of this problem.”
Almost immediately, the press conference descended into near chaos. Even if Wakefield’s study had been more comprehensive and his data more robust, it was virtually unprecedented for a research scientist to advocate wholesale changes to health policy. After stressing that the MMR vaccine had been given to millions of children around the world and had saved untold numbers of lives, Arie Zuckerman, the dean of the Royal Free Hospital’s medical school, became so agitated he began banging on the lectern. “If this were to precipitate a scare that reduced the rate of immunization,” he said, “children will start dying from measles.”
Zuckerman’s frustration was understandable. As scientists around the world already knew, there were ample reasons to view Wakefield’s latest effort skeptically. After an initial peer review raised questions about the quality of Wakefield’s research and the soundness of his reasoning, Richard Horton, the editor of The Lancet, demanded the paper be rewritten in such a way that made clear the speculative nature of the work and slapped an “Early Report” label above the title and on the header of each page. Horton also took the even more unusual step of asking Robert Chen and Frank DeStefano, two American vaccine specialists at the CDC, to prepare an evaluation of Wakefield’s paper that would appear in print. “Usually, when they publish a commentary, it’s to extol the study, or show how it’s advanced the field,” DeStefano says. That was obviously not the case here. When he first read the paper, DeStefano says, his reaction was, “There really didn’t seem to be that much there. It was kind of like, Why were they publishing the article?”25
You did not need to have advanced scientific training to share DeStefano’s confusion; in fact, knowledge of basic principles of experimentation were all that were needed to understand why Wakefield’s work was so unimpressive. Broadly speaking, there are three ways scientists collect data to test new theories. The best possible method is through a randomized clinical trial, in which researchers take a sampling of a population and arbitrarily test their hypothesis on one half while leaving the other half untouched. This is preferred because by engineering the test population, it is possible to control for other potentially mitigating factors.26
Unfortunately, randomized clinical trials are not always feasible. Sometimes this is for ethical reasons: You can’t determine what quantity of a given substance is toxic in humans by administering doses that could prove fatal. Other times, it’s because of logistical problems: It’s impossible to test the lifelong effects of living in a given environment by transplanting half the population. The second-best option is a case control study, where investigators analyze a group that has been naturally subjected to the issue under examination. There are a number of reasons case control studies provide less definitive proof than randomized trials. Many of those reasons stem from their retrospective nature, which means the population under review hasn’t been randomly determined and there is no way to control for other factors that may have influenced the result.
The least convincing data comes from the type of study Wakefield had conducted: a simple case series. These are oftentimes nothing more than an interesting phenomenon someone happened to notice. Generally speaking, case series are starting points for new hypotheses—and most of the time, what at first blush looks to be significant is nothing more than the result of the random nature of the universe.
To understand why a case series is a tenuous place to hang your hat, take the example of gender. Even though the population as a whole is split almost evenly between boys and girls, there are numerous examples of individual families with all boys or all girls, and there are many more examples of families where a series of children born in a row are of the same sex. Now, imagine that an alien is sent to earth to learn about what types of human offspring are born to parents living in different states. The first couple he meets, Alexander Baldwin and Carolyn Newcomb of New York, has four children: Alec, Daniel, William, and Stephen. Based on that set of data—which is the equivalent of a single case series—the alien would assume that all earthling children born in New York were boys (and that they all were actors with a penchant for appearing in the tabloids). If the second couple the alien meets was George W. Bush and Laura Bush, he’d assume that all children born in Texas were, just like Barbara and Jenna Bush, twin girls. Those conclusions would, of course, be incorrect—but the only way to realize that would be to collect more data.27
As Chen and DeStefano demonstrated with their 839-word evisceration, the shortcomings of the Lancet paper went far beyond the limitations of the way its data had been collected. There were serious problems with its entire premise: Hundreds of millions of children had received the measles vaccine since it was first introduced and the vast majority of them had no chronic bowel or behavioral problems; the “syndrome” Wakefield purported to have discovered was already well documented and was nonspecific to patients with autism; autism was a well-known condition long before the MMR vaccine became available; and despite hypothesizing that the MMR vaccine led to IBD led to autism, in most of the cases Wakefield cited, the behavioral changes preceded the bowel problems. There were methodological problems, the most glaring of which was selection bias: The parents who came to Wakefield, who was not a pediatrician and had never been clinically trained to work with children, did so because he was known as someone interested in connecting the MMR vaccine with inflammatory bowel disease. There were concerns about the reliability of the paper’s data: Wakefield was dependent on parents’ post-facto recollections about the temporal connection between vaccination and onset of their children’s symptoms, and in the three years since Wakefield first reported finding the measles virus in patients with IBD, “other investigators using more sensitive and specific assays, have not been able to reproduce these findings.” Finally, and most damningly, there was “no report of detection of vaccine viruses in the bowel, brain, or any other tissue of the patients in Wakefield’s series.” The entire report wasn’t built on a house of cards—there weren’t any cards to begin with. Several years later, when the dean of research at the London School of Medicine called the study “probably the worst paper that’s ever been published in the history of [The Lancet],” he was merely acknowledging what many scientists had thought all along.
In the coming days, as his study came under increasingly intense fire, Wakefield took advantage of the fact that public opinion wars are not won through the use of dry, academic language. While his detractors were explaining that “the most striking and consistent endoscopic feature, lymphoid nodular hyperplasia in the terminal ileum, is not unusual in children,” Wakefield was trotting out what had become a standard response of vaccine denialists to accusations of unreliable or inaccurate data: He condemned his critics for caring more about their standing in the scientific community than about sick children. “[Advocating the discontinuation of the MMR vaccine] is a moral issue for me,” Wakefield told The Independent, going on to describe the frantic phone calls he was fielding from desperate parents. “These are the people to whom we are answerable
,” he said. And Wakefield had answers: Parents should insist their children receive separate measles, mumps, and rubella vaccines, and that there be a minimum of a year’s break between each one. The fact that every child who delayed vaccination would be at risk was beside the point, as was the lack of availability of single-dose vaccines—if the pharmaceutical companies cared more about patients than profits, Wakefield implied, they’d figure out what to do. In the meantime, Wakefield’s office set up a dedicated phone line to field calls from frantic parents. When they called, they were offered a fact sheet Wakefield had put together and were told to direct any further questions to their doctors. Even when Wakefield was called on to defend his work in the March 21 issue of The Lancet, he relied on emotion instead of scientific rigor to buttress his conclusions:
Our publication in The Lancet and the ensuing reaction throws into sharp relief the rift that can exist between clinical medicine and public health. Clinicians’ duties are to their patients, and the clinical researcher’s obligation is to test hypotheses of disease pathogenesis on the basis of the story as it is presented to him by the patient or the patient’s parent. Clearly, this is not the remit of public-health medicine. The approach of the clinical scientists should reflect the first and most important lesson learnt as a medical student—to listen to the patient or the patient’s parent, and they will tell you the answer.
Accordingly, we have now investigated 48 children with developmental disorder in whom the parents said “my child has a problem with his/her bowels which I believe is related to their autism”. Hitherto, this claim had been rejected by health professionals with little or no attempt to investigate the problem. The parents were right. They have helped us to identify a new inflammatory bowel disease that seems to be associated with their child’s developmental disorder. This is a lesson in humility that, as doctors, we ignore at our peril. In many cases, the parents associated onset of behavioural symptoms in their child with MMR vaccine. Were we to ignore this because it challenged the public-health dogma on MMR vaccine safety?
The Panic Virus Page 12