Nantucket Fever: Entomologist Andy Spielman's Search for the Creeping Carrier of Babesiosis, Ehrlichiosis and Lyme Disease
by Peter Wehrwein
Andy Spielman admits he was not the obvious candidate for the job. An entomologist and a member of the school's prestigious tropical public health department for 14 years, he had built his career primarily on mosquito research. Babesiosis, it was well known, was spread by ticks.
To the casual bug avoider, the difference between insect and arthropod might
seem slight, but scientifically speaking they are worlds apart. But when Spielman's
friend, George Healy, a researcher at the Centers
for Disease Control, helped diagnose a second case of human babesiosis on
Nantucket in 1973, Spielman was intrigued. Although a handful of human cases
had been reported worldwide, babesiosis was known, for the most part, as an
animal disease. Here was a chance to tackle a problem that was scientifically
enticing and perhaps of major public health significance.
Over the next several years, Spielman would throw off conventional wisdom and become one of the world's foremost authorities on tick-borne diseases and the environmental forces that shape them. His research solved the puzzle of babesiosis on Nantucket. He identified a new species of tick, Ixodes dammini, which is responsible not only for the emergence of babesiosis in the United States, but for a whole new group of tick-borne diseases, the best known of which is Lyme disease. Sam Telford III, a young colleague in Spielman's lab, identified a third tick-borne pathogen three years ago and has a paper in the works that will finger a fourth. And Telford and Spielman have recently played a key role in the preliminary testing of a Lyme disease vaccine. Yet Spielman says to marvel at how chance favored a Harvard mosquito expert with such a productive career as a tick researcher is to misunderstand his particular brand of research and perhaps public health research more generally.
"I am not a mosquito specialist. I am not a tick specialist. I am a transmission specialist," says Spielman. "I am interested in the etiology and mode of transmission of vector-borne infections. That is what public health entomology is all about."
Dr. Andrew Spielman
Looking back now, Spielman says with a broad smile and laugh that "God, I had no idea what I was doing" as he boarded the ferry for Nantucket one chilly morning in the fall of 1973 for the first of many times. But actually, Spielman did know a good deal. For starters, because of Healy's brilliant diagnostic skills, he knew he was dealing with a protozoan called Babesia, a blobby, single-celled parasite that comes in 70 or so different varieties. It was no coincidence that the Nantucket index case was initially misdiagnosed as malaria. The periodic shaking chills and drenching sweats of malaria are very much the same as in babesiosis. And the underlying parasites of the two diseases have the same nasty habit of destroying red blood cells. But unlike malaria, babesiosis had been known mainly as a disease of animals, primarily cattle. In fact, almost a century earlier, legendary Harvard researcher Theobald Smith had made the watershed discovery that a protozoan (now known as Babesia bigemina) could cause disease in a warm-blooded animal and be spread by an arthropod (the Boophilus cattle tick) while investigating a cattle disease in Texas. [Smith was a faculty member for about 20 years in the Comparative Pathology Department at Harvard Medical School, which later divided into HSPH's Department of Tropical Public Health and the medical school's Department of Pathology.] Because of Smith's discoveries, and other work that followed, Spielman could be reasonably sure that a tick was the culprit behind Babesia on Nantucket.
Another important piece of historical evidence that Spielman had in mind as the ferry churned across Nantucket Sound was that the ticks would probably have a hearty appetite for rodent blood. In 1938, Ernest Tyzzer, who succeeded Smith as Harvard's George Fabyan Professor of Comparative Pathology, published a rather obscure paper in Parasitology that mentions a Babesia infection of voles (a mouse-like creature) on Martha's Vineyard, an island near Nantucket and another treasured vacation spot. Moreover, his detailed drawings showed that the kind of Babesia that Tyzzer found in the voles on Martha's Vineyard looked to be very similar to the Babesia making people sick on Nantucket. Tyzzer was something of a misanthrope, according to Spielman, but his quirky personality paid scientific dividends as he pursued an interest in animal diseases. Spielman says he knew about Tyzzer's paper "from way back." "There was a collection of old departmental papers and reprints in our lunchroom at that time," he explains. "While I was in there having lunch, if there was nobody else around, I would look at those old papers just out of curiosity." So from Smith, Spielman knew he would be dealing with ticks. From Tyzzer, he had the clue that rodents would be involved.
Spielman headed out to Nantucket not only with mouse traps, but with bulky raccoon traps that he had cadged from Massachusetts's eastern equine encephalitis research station. His research assistants were not seasoned field biologists but a slightly jittery Vietnam veteran (Spielman thinks he may have been suffering from post-traumatic stress syndrome) and his girlfriend. On the island, the trio depended on bicycles for transportation, and when they rode down Nantucket's cobblestone streets, the raccoon traps tied to the backs of their bikes came tumbling down. And somehow Spielman had gotten confused about their destination. It was the UMass biological field station they were looking for, not the Max Planck field station. "We had no idea what we were doing!" Spielman says once again, for emphasis.
But Spielman was finding that the Nantucket voles were largely Babesia free. Instead, it was the red blood cells of the white-footed mice that were choked with Babesia. That mice, not voles, turned out to be the reservoirs for Nantucket fever was a lucky break for Spielman. The maintenance and mowing schedule of the UMass field station had inadvertently created the "edge" habitat ideal for mice. Ecologically, edge is the boundary area between two habitats, which in this case were meadow and brushy, covered terrain.
Homing in on the white-footed mouse put Spielman on the path to his crowning achievement, identification of the Ixodes dammini tick as the vector of Nantucket fever. When he returned to Nantucket the next year he began looking for the Babesia-carrying creatures in earnest. At this point, if Spielman had paid too much attention to what other experts were saying, he might have missed out on the discovery. Partly because the kind of Ixodes ticks he was seeing on Nantucket had not been previously observed north of Georgia, Spielman was told that the ubiquitous Dermacentor variabilis, or dog tick, was probably spreading Nantucket fever. Dog ticks also made sense because Rocky Mountain spotted fever was on the rise at that time on the East Coast, and dog ticks spread Rocky Mountain spotted fever. Spielman recalls talking to one Massachusetts tick expert early in his investigation: "He kept rattling on about how obvious it was, that it wasn't interesting, that it is the dog tick and that is all you need to know." A group at Ohio State even went as far as to publish a paper (later retracted) that identified the dog tick as the Nantucket fever vector.
Yet Spielman kept on seeing the speck-sized deer ticks, not dog ticks. And where he saw them was especially interesting: on the skin of white-footed mice. Plucking the ticks off by hand, Spielman counted roughly 19 deer ticks for every dog tick on the mice. That ratio was reversed when it came to the voles. Because vole blood was hardly ever infected with Babesia, and mouse blood was, it didn't make sense that the dog tick, which favored voles, was the vector. No, thought Spielman, the Ixodes ticks found on white-footed mice had to be what was spreading babesiosis on Nantucket.
For a century, the standard of proof for causation in infectious disease research has been fulfillment of Robert Koch's famous postulates. First, isolate the organism from an infected animal. Second, reinfect another animal with that organism. And third, recover the original organism from the animal just infected. If Spielman was to nail down the case against the deer ticks, it would mean leaving the lovely Nantucket field station and getting down to work in the lab.
Using Babesia isolated from a human patient, Spielman infected a hamster with the protozoan. Immature lab-reared deer ticks feasted on the infected hamster. Once they were sated and presumably loaded with carrying Babesia, Spielman set the ticks loose on 11 non-infected hamsters. Spielman waited three weeks and then drew blood from the hamsters. Ten of them were infected with Babesia. Koch himself would have approved.
The work was described in November 1976 in the American Journal of Tropical Medicine and Hygiene. In that paper and others, Spielman identified the culpable tick as Ixodes scapularis, a variety of tick that had been identified way back in 1805. Three years later, Spielman officially proclaimed the Nantucket tick a new variety of arthropod, naming it Ixodes dammini after Gustave Dammin, a prominent pathologist at Brigham and Women's Hospital. Naming a disease-spreading tick for someone might seem like a dubious honor, but ever since Carl Linnaeus set up the current taxonomic classification system in the 18th century, naming a new species for someone has been a way for biologists to immortalize themselves, mentors, or loved ones. Spielman chose to honor Dammin because he had helped him with his research and was a property owner on Nantucket (Dammin's wife came from one of Nantucket's most prominent families). Spielman built his case for I. dammini being a separate species from I. scapularis on the observations that the two ticks had very distinct ranges (I. dammini in the Northeast, I. scapularis in the South) and that I. dammini was morphologically different, especially at the nymphal stage. He also marshaled DNA evidence to make his case.
Since then, Spielman has been fighting a protracted, but probably losing, battle for I. dammini's identity as a separate species. Siding with researchers in Georgia, the editors of the Journal of Medical Entomology have officially ruled that, taxonomically speaking, Ixodes dammini is no different from Ixodes scapularis and therefore the two species should be "synonymized" under the Ixodes scapularis name. Spielman disagrees. Aside from any pride and politics (Lyme disease research has become highly politicized in recent years) Spielman says maintaining I. dammini's separate identity is key to understanding the ecology and epidemiology of tick-borne diseases. Southerners don't get Lyme disease. And it is immediately clear why that is so, says Spielman, if you understand that the South doesn't have the I. dammini tick that spreads the disease.
One hundred and twenty miles west of Nantucket, in Lyme, Connecticut, just a couple of years after the outbreak of babesiosis, Anne Mensch and Polly Murray were seeing an equally odd, but more alarming, outbreak of disease in their community. The disease was arthritis, and the victims were young children. By 1975, Mensch and Murray had gotten a young rheumatologist at Yale named Allen Steere involved. Steere says he and his colleagues saw the hallmarks of arthropod-transmitted disease nearly from the beginning of his investigation into Lyme arthritis, later named Lyme disease: the cases clustered in a rural area, the hit-and-miss pattern, and symptoms generally showing up in summer and fall when arthropods are most active. In fact, one of Steere's brilliant strokes was to focus his epidemiologic investigation not on arthritis, which turned out to be one of the many symptoms of Lyme disease, but on patients' recollections of an unusual reddish, bull's-eye-shaped rash. As it turned out, this condition was reminiscent of erythema migrans, an obscure skin condition seen in Europe that was known to be caused by a tick bite. In the summer of 1977, one of Steere's subjects saved a tiny tick that had recently bitten him. Yale researchers identified it as an Ixodes dammini tick, the same kind of creature Spielman identified on Nantucket. The connection between Lyme disease and babesiosis had been made. It would be, however, another five years before Willy Burgdorfer, a researcher at the National Institute of Health's Rocky Mountain Laboratories in Hamilton, Montana, identified exactly what the ticks were spreading that was causing Lyme disease: a squiggly bacterium, or spirochete, that has since been named Borrelia burgdorferi.
In November, 1994, a 68-year-old woman came to the Nantucket Cottage Hospital after five days of fever, mental confusion, and headache. Initially, doctors thought she might be another victim of babesiosis or Lyme disease or both. The woman recalled having been bitten by a tick five days before getting sick. But blood tests showed no sign of either Borrelia burgdorferi or Babesia microti. It was Telford, again drawing on Tyzzer's 1938 Parasitology paper as a reference, who figured out that the woman was infected with third pathogen, Ehrlichia bacteria. Thus, a third disease, human granulocytic ehrlichiosis (HGE), was added to the roster of ills wrought by deer ticks. Now Telford has identified a fourth pathogen, this time a virus, lurking in the guts of deer ticks. So far, he has only isolated it in ticks, and deer tick virus (as Telford is calling it) has not yet been linked to any human disease.
Lyme disease is by far the most common of the deer tick diseases with about 15,000 cases reported to the Centers for Disease Control and Prevention last year, according to David T. Dennis, MPH '74, the coordinator of the CDC's Lyme disease program. Those cases were concentrated in 80 counties in 8 states--Connecticut, Rhode Island, New York, New Jersey, Pennsylvania, Maryland, Wisconsin, and Minnesota. Annual babesiosis and HGE cases number less than 100, though lack of reporting and missed diagnosis seriously undermine the reliability of the statistics on all the tick-borne diseases. Though culling the deer herd has worked on an experimental basis in island situations, Dennis says in most situations controlling deer and mouse populations is not a feasible way of controlling Lyme disease. Because most people get bitten by deer ticks near their homes, simple things like clearing away leaves can help control the disease by making backyards less accommodating to mice. Dennis said one of the most exciting experiments in tick control involves deer feeding stations designed so that when the deer eat, they rub up against some material soaked with insecticide that kills the ticks but doesn't harm the deer. Spielman tested a similar system for mice.
Meanwhile, SmithKline Beecham and Connaught are pushing ahead with development
of a Lyme disease vaccine. Spielman led the Phase II testing of the SmithKline
Beecham vaccine among residents of Nantucket, Martha's Vineyard, and Block Island.
Steere is the investigator in charge of the larger Phase III trials. "This is
a disease that is likely to be conquered, but we are not exactly there yet,"
says Steere. Dennis and other public health officials are wary, however, about
the eventual marketing of a vaccine. "Selectively used, it could be attractive,"
he says. "But without good education, there could be a huge demand for this
kind of protection when the cost may exceed the real benefit."
Photo by Richard Chase
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