Emir Hodzic, a colleague of Baumgarth’s and Barthold’s at UC Davis, speaks about B. burgdorferi in almost reverential terms. He and Barthold had tracked infected mice for a year after aggressive antibiotic treatment, expecting the pathogen to persist in small amounts, as other researchers had found in shorter-term tests. Instead, he was stunned to learn the mice carried as many spirochetes as controls that had never received the supposed cure. “Borrelia is a really, really interesting microorganism,” he told me. “It has a huge brain. It outsmarts people.” These bacteria don’t just resist antibiotics, he said. “They tolerate antibiotics.”
The disheartening thing about Hodzic and Barthold’s mice, however, was this: When they removed spirochetes and tried to culture them—to grow more of them in a petri dish—nothing happened. The bugs stubbornly refused to be cultured. This is where Borrelia burgdorferi confounds and thwarts every effort to be understood. By this point in the research, the Davis team had confirmed something significant was happening. In mice, which should have been Borrelia-free, they found the bacterium’s DNA (indicating it had been there), its RNA (indicating it was replicating), and, nestled within mouse tissue, the spirochete itself—in fact, many of them. They had transplanted these spirochetes in tissue into other mice and infected them. They had also attached ticks to the “cured” mice, and the ticks became infected. Yet the bugs themselves—“viable, but uncultivable,” Hodzic called them—would not grow outside of the mouse.
To Hodzic, this was part of the character and mystery of persistent, some might say chronic, Lyme disease infection. “Having worked with B. burgdorferi for over 21 years, it is apparent that not all isolates or strains can be easily cultured,” he told me, “and this is especially apparent during long-term infection.” Barthold referred to this dynamic in his Congressional testimony. The inability to culture the spirochete, he acknowledged, was an absence of one kind of proof. But he cited all those other ways in which presence of surviving Borrelia had been confirmed repeatedly. “Naysayers refute these collective observations for a variety of reasons,” he told me, including study design, and how mice were infected and treated. The other thing the naysayers do, Barthold said, is “simply ignore them altogether.”
Poles Apart
When I first began this line of reporting in 2012, I spent an hour on the phone with a respected scientist in the study of Lyme disease. As I had with many other researchers, we hashed out the issues that have dogged this epidemic, the chief one being whether Lyme disease can be chronic, can persist. Unlike some scientists I had interviewed, this scientist did not dismiss the contentions of those with opposing views. In the end, this scientist said, “You have to decide what side you’re on.” It was a frank admission and an assessment of the science of Lyme disease, a worldwide epidemic on which there were and still are clear sides. Each has looked at the science, chosen what to acknowledge and what to dismiss, and gone in opposite directions.
“I find myself in a rather contentious field,” Stephen Barthold commented to that Congressional panel, “coming out of the mainstream of Lyme disease research into one in which I am somewhat of a pariah, in terms of the established medical opinion.” Like other scientists, Barthold had come to believe that modern medicine had it wrong on Lyme disease. Antibiotics, he had concluded, did not always kill the bug, at least as commonly prescribed.
Linda Bockenstedt, a Yale University researcher, is the yin to Barthold’s yang, an esteemed scientist with a pedigree every bit as weighty as Barthold’s (who had come to Davis from Yale) but with a very different view of Lyme disease persistence. In 2002, Bockenstedt and Barthold shared credit on an early study that dosed infected mice with antibiotics and then found spirochetes in ticks that fed on four of ten of them. But disease carrying though they may have been, the ticks did not go on to infect uninfected mice. Significantly, the spirochetes were damaged, lacking some of the basic genes related to infectivity. The two scientists concluded then that spirochetes lingered to be sure, but, of paramount importance, the changes in them meant they were not infectious. By 2012, Bockenstedt, working again with mice, was convinced of this; Barthold, working on experiments on monkeys and mice, published in 2012 and 2014, of just the opposite.
To be sure, something lingered in the joints and surrounding tissue of diseased mice that had been given antibiotics, Bockenstedt reported in a study published in the Journal of Clinical Investigation. But they were not viable, infectious organisms of the kind that lived in the mice before treatment. Rather, Bockenstedt’s team found a kind of debris, seen in fluorescent deposits near ear cartilage and within joint tissue of mice, which contained bits of spirochete protein. That detritus was enough, she and her colleagues theorized, to cause “prolonged inflammatory responses in the joint after infectious spirochetes have been eradicated.” In other words, people who suffered ongoing symptoms after Lyme disease treatment, in this case those with arthritis-like symptoms, may not have chronic disease but a prolonged autoimmune response to vestiges of illness.
“This study provides the first direct evidence that spirochete proteins can remain long after the bacterium is gone, and in places where people can experience symptoms after treatment for Lyme disease,” Bockenstedt told YaleNews. “These symptoms after treatment may not be caused by the Lyme bacterium itself, but by an immune system that is slowly removing the nonviable remains of the long-dead bacterium.”
In key ways, Bockenstedt’s latest findings were not the polar opposite of her earlier ones with Barthold. Borrelia DNA was found in five of her twelve mice after treatment with doxycycline, enough in the view of some Lyme doctors to equal infection. Borrelia was even cultured from a tick that had fed on a treated mouse, though not from eleven others. Shouldn’t that one mouse, representing 8 percent of the sample, have been cured?
A commentary that appeared with Bockenstedt’s article said the Yale team offered “compelling evidence” that residues of the Lyme bug—not the bug itself—were “continuing to cause mischief long after bacterial life has ceased.” Once again, the message was broadcast that antibiotics had done their job against Lyme infection. But, akin to research on the other side of the Lyme divide, the findings were by no means conclusive and in some ways contradictory. Yes, Bockenstedt found evidence of potentially damaging cellular debris. But she also found spirochetal DNA and, at least in one mouse, spirochetes. No matter.
“Bockenstedt et al. recognize the far-reaching consequences of claims about persistent viability,” said the commentary, written by Alan Barbour, an early Lyme disease researcher. “They come down on the side of the existence of non-viable and non-transmissible posttreatment spirochetes in their mouse model.” Hence, they favored the theory that remaining spirochetes could not transmit disease. In the end, the mainstream side warmly embraced Bockenstedt’s findings. The disagreement, like the spirochete, persisted, though just one side prevailed.
“Fuel to the Fire”
In 2012, a study in the New England Journal of Medicine repackaged an oft-repeated bromide of Lyme disease: It doesn’t come back after antibiotic treatment. In the article, several authors of the prevailing treatment guidelines reported that seventeen Lyme disease patients who had repeat Lyme rashes over a twenty-year period got them from another tick bite, rather than a relapse from their original infection. Repeat bites and recurrent rashes occur frequently in tick-ridden areas—I have had two rashes, two quickly treated infections—so this was not a startling conclusion. Nor was it news that new rashes, the basis of the study, supported evidence that people had been bitten and infected again.
So how meaningful was a study of seventeen patients who got two infections in twenty years? Did it disprove relapse? In 2013, I raised this question with two of the primary authors of the study, Gary Wormser and Robert Nadelman, for a newspaper article I was writing. Both were also authors of the Infectious Diseases Society of America Lyme disease guidelines.
I was told, through a spokesperson for New York Medical Colle
ge, where the physicians were based, that the reinfection study had appeared in a “highly respected medical journal” and they would have no comment for the “lay press.” Ironically, the study’s findings had already been widely reported in the lay press, from NPR to the New York Times. The college had even put out a press release on it—part of a public relations effort that has solidified the easy-to-treat myth of Lyme disease. I was rebuffed because I had questioned mainstream Lyme dogma. Similarly, I reached out for this book to Wormser and Nadelman and, after several tries, was told in an email from Jennifer Riekert in the medical college press office, “The Dr.’s have declined your invitation for an interview.”
One author of the reinfection study was Dustin Brisson, a University of Pennsylvania researcher and expert in disease ecology, who did kindly respond to my inquiries. He said the conclusion used basic statistics to compute the probability of reinfection or relapse given the strains found in one infection to the next. I asked him if the study had convinced him that Lyme disease was not a chronic illness. “I am not convinced of this at all,” he wrote in an email, “and it is not what the paper suggested either.” Nonetheless, the paper was widely reported as bolstering the case that Lyme disease, once treated, does not recur. Eugene Shapiro, an author of the Lyme guidelines, said in a MedScape video that the study provided “very strong evidence that the recurrences are new infections as opposed to persistence of the original infection.” Here was another study that disproved the notion of chronic Lyme disease—even if it only considered people who got the rash twice.
In his commentary on Linda Bockenstedt’s landmark article on spirochetal “debris,” Alan Barbour wrote that the Lyme debate hinged on a choice “between lifeless leftovers and viable hangers-on,” namely between spirochetes dead after treatment or alive and well. After three decades, the Lyme disease “controversy,” a word he used five times, lingered like pesky posttreatment symptoms. Yet here was a classic example of why so little had been accomplished to bring opposing sides together. On the side of lifeless leftovers was Bockenstedt, whose research—diligent and honest as it was—comported with long-held establishment views and was warmly received. On the side of viable hangers-on were findings by Monica Embers who had recovered spirochetes and Borrelia DNA from treated monkeys but whose study, a critique by guidelines author Gary Wormser said, was plagued with “important flaws in experimental design.” That lone appraisal would be footnoted by Bockenstedt two years later when she wrote that Embers’ findings had “evoked considerable skepticism.”
This is all part of the mainstream echo chamber of Lyme disease. Bockenstedt, Barbour wrote in his commentary, provided “compelling evidence”; Embers “added more fuel to the fire.” But Barbour couldn’t seem to commit because, well, you never know. He ended his commentary with a study from a half-century before that had found remnants of a bug that caused kidney infection even after antibiotic treatment. “These remains in the urine were uncultivable by routine procedures,” he wrote, “but, according to the authors, lived to cause disease again.”
Both Embers’ and Bockenstedt’s papers were published in 2012. Bockenstedt’s article appeared in a journal with four times the all-important “impact factor” of Embers’, a measure of how often a journal’s published research is cited by other scientists. This was and is symptomatic of the publishing struggles of scientists who challenge Lyme dogma. They find outlets where they can. Nonetheless, Embers’ landmark research would not be squelched. It was read more than 45,000 times on PLOS-One and dubbed a “Faculty of 1000” paper, a distinction by a clinical research service reserved for important findings. In answer to the uproar that followed her article, Embers posted a comment on PLOS-One. Her goal was to undertake “objective, well-performed experiments on antibiotic efficacy” in monkeys, she wrote, rather than to challenge the hot-button issue of treatment regimens for people. Doing that would take “solid proof of better treatment options,” she said pointedly. “These are currently not available.” This, indeed, is another outcome of the accepted model of Lyme disease care. Research is scant on better ways to treat Lyme disease because there is little impetus to look.
Lessons of Infection: How They Hide
Garth Ehrlich knew nothing about the so-called Lyme wars, as they have been described, when he began looking into the parallels between Borrelia burgdorferi and other difficult-to-eradicate bacteria he had studied since the early 1990s. Ehrlich, then an associate professor at the University of Pittsburgh, had had an “ah-ha” moment in the mid-1990s when he read an article in Science magazine by a microbial ecologist named Bill Costerton. In the 1970s, Costeron had noticed a slimy substance clinging to rocks in pools in the Canadian Rockies with high bacteria levels, finding they were essentially protective coatings for an army of bacteria. Now, Costerton was discussing how difficult it was to culture and kill bacteria beneath what he came to call “biofilms.” Ehrlich wondered: Could this explain the intractable nature of some human infections he had studied?
In 2002, Ehrlich infected forty-two young adult chinchillas, basically one-pound rodents covered in velvety fur, with Hemophilus influenzae, which is a leading cause of ear infections in children. When the animals were euthanized, Ehrlich made a groundbreaking discovery that was rooted in Bill Costerton’s work in the Rockies. Inside the rodents’ ears, beneath amorphous, impenetrable biofilms, were H. influenzae bacteria, uncultivable and resistant to antibiotics. Four years later, Ehrlich, by then a professor at Drexel University College of Medicine, directed a team of scientists that analyzed bacterial samples from the chronically infected inner ears of twenty-six children. Sure enough, in twenty-four of the children, pathogenic bacteria were found under layers of nonliving matter where, as in the chinchillas, they had found refuge until the time was right to emerge and cause sickness. “They build a little house for themselves,” Ehrlich told MIT Technology Review when his team’s article was published in the Journal of the American Medical Association.
In 2012, Ehrlich was asked to give a talk in Hershey, Pennsylvania, at a conference organized by a former Fortune 500 company consultant and champion of Lyme disease patients named Julia Wagner. The mother of three had also found herself, within two years of moving to the Philadelphia area in 2004, hit by virtually every punch the Lyme bug can land, including crippling joint pain, early dementia, and cardiac problems. After she at last found a Lyme specialist who would diagnose and treat her—“I didn’t get any help from the medical community,” she said—Wagner began to organize and agitate. She turned to Ehrlich. Ehrlich knew a thing or two about chronic disease, she reasoned, and Wagner knew that a savvy scientist named Eva Sapi had found Lyme pathogens alive and well beneath biofilms. Could Ehrlich speak at the Lyme conference? Ehrlich’s introduction to Lyme disease came in fits and starts over the next eighteen months, but he soon made connections, saw parallels, and, ultimately had another ah-ha realization.
The clincher came in October of 2013, when Ehrlich listened as a researcher from Switzerland, Judith Miklossy, offered a potential bacterial explanation for Alzheimer’s disease: spirochetes, and, in particular, the Lyme pathogen, Borrelia burgdorferi. A presentation at a conference of the American Academy of Oral Systemic Health might not be a game-changer for many people. It was for Ehrlich, who had earlier published on the link between periodontal spirochetes, namely on teeth and in gums, as a cause of chronic infections in artificial knees. “I was putting 2 and 2 together,” he told me. Spirochetes could lead to chronic infections. The Lyme spirochete often spurred lingering symptoms. It was able, in petri dishes and human tissue, to form antibiotic-resistant biofilms, just as in Ehrlich’s chinchillas. Periodontal spirochetes hid beneath biofilms, causing gum disease. A pathologist named Alan MacDonald had discovered Lyme spirochetes as early as the 1980s in the brain tissue of Alzheimer’s patients, while Miklossy had published a score of articles in the decades since on the mechanisms behind spirochetal infection in the brain.
When scientists make s
uch connections, they fall back on a huge chapter in medical history involving another spirochete and its link to dementia. Treponema pallidum, the cause of syphilis, was legendary for leading to psychiatric illness that, before the advent of penicillin in the 1940s, accounted for 20 percent of admissions to US mental hospitals. “These are some of the most famous persistent bacteria in all of human health and disease,” he told me. And they are cousins of Borrelia burgdorferi.
Ehrlich, then in his midfifties, had another reason to be drawn to Lyme disease. His sister, Susan, who resided in Connecticut, a state that is ground zero in modern times for the disease, had had perhaps five Lyme disease infections in the previous fifteen years. They had left their mark. Growing up in the Genesee River Valley in New York State, he recalled, self-deprecatingly, “I was like the village idiot.” Susan, “monstrously gifted,” he said, had been valedictorian of her high school class, with a cracker-jack ability to master and recall information. When I spoke to Ehrlich in June of 2016, he said his sister “can’t remember anything—she says she lives in a world of brain fog,” which Susan confirmed when I spoke with her by telephone from her home in Woodstock, Connecticut.
After the Miklossy talk, Ehrlich explored the Lyme disease research, discovering, as others had before him, a contentious scientific landscape, dominated by a powerful camp that denied the bacterium survived antibiotic treatment and left little room for debate. He saw this firsthand, when he served on a National Institutes of Health panel that reviewed a grant proposal to study basic mechanisms that might allow the Lyme disease pathogen to persist. He and two other primary reviewers gave it high marks, virtually assuring it would be approved. But when presented to the entire panel, he said, an infectious disease physician spoke up. “This shouldn’t be funded,” Ehrlich recalled the physician saying. “Everyone knows there’s no such thing as chronic Lyme disease.” A second infectious disease doctor agreed, and the proposal was killed. Ehrlich was stunned.
Lyme Page 15