Toward Solving the Medical
Mystery of MRLS
elementary school through graduate school, students are inculcated
with the scientific method as the preferred way of discovery.
To many, the scientific method seems contemplative, systematic,
thorough, and exhaustive, which indeed it usually is. For scientists,
the method is rigorous, logical, and fascinating, and maybe even
comforting because of its measured pace.
Every now and then, however, all those qualities of the scientific
method must be put to work fast, at breakneck speed, because scientific
discovery cannot wait for the niceties of time. In such urgent
times, experiments succeed and fail in rapid fashion; ideas are
proposed, tested, and pursuedand discarded in favor of more
compelling theoriesin days and weeks instead of years. In
these times of urgency, the scientists themselves renew their
understanding of their passion and excitement for the process
of science, and their appreciation of it becomes even more keen.
Such was the case in May 2001, when the number of stillborn,
weak, and dying foals and early aborted foals in Central Kentucky
mares grew alarmingly high. During the weekend of the Kentucky
Derby, Lenn Harrison, the director of the UK Livestock Diagnostic
Center, knew that his life in the near future would be directed
toward research at machine gun pace until the causeand hopefully
a prevention strategywas discovered. On Derby Saturday alone,
73 dead foals and fetuses10 times the normal numberhad
been delivered to the back door of the facility; by Monday, that
number had reached 276. It was becoming abundantly clear with
each new foal or fetus that whatever was causing problems was
doing so with a vengeance.
the same time, veterinarians Roberta Dwyer and David Powell of
the Maxwell H. Gluck Equine Research Center were fielding questions
from Central Kentucky horse breeders and local equine veterinary
practitioners who also had noticed an increase in stillborn, weak,
and dying foals as well as aborted fetuses during the last days
More than a few times that weekend and throughout the next few
weeks, when weekdays, weekends, and workdays were indistinguishable,
Harrison thought about other scientistsepidemiologists who
worked on medical mysteries such as Legionnaire's disease, the
Hanta virusas he organized a strategy to deal with the mystery.
Not only would the scientists have to be good, they would have
to be fast, because every foal or fetus lost due to the mysterious
illness represented a monetary loss of great magnitude. With each
ticktock of the clock, the cost of the disease, as well as fear
among horse breeders, grew.
Pieces of the Puzzle
The pieces of the puzzle were intriguing. The epidemic seemed
to be restricted for the most part to Central Kentucky, with few
similar cases being reported in other states, and the disease
affected all breeds of horses from ponies to Thoroughbreds to
Morganshorses that would most likely never have contact
with each otherdiscounting a bit the idea that a communicable
contagion was causing the problems. Further, the onset of the
disease was sudden, with a sharp escalation in cases. Research
had to find an answera control and preventionif not
an explanation. Harrison and the scientists from the Livestock
Disease Diagnostic Center couldn't do it alone; they needed help.
Within days of the Derby, a team of more than 100 scientists
from all over the College of Agriculture was assembled to investigate
the mysterious disease. In some ways, organizing research to find
answers as fast as possible is like playing the parlor game of
20 Questions. Instead of asking about whether it was animal, vegetable,
or mineral, team members asked whether the cause of the weak foal
and fetal losses was viral, bacterial, or environmental. If the
cause were bacterial or viral, it might well be contagious; because
of the great number of deaths and abortions, that possibility
couldn't be ruled out entirely. And if it were environmental,
what was the reason that it seemingly was confined to a very narrow
band, nearly exclusively in the Central Bluegrass? Known viral
agents, Harrison knew, would show up on necropsy and subsequent
tissue testing. (Necropsy is a term used when a postmortem examination
is performed on an animal, roughly equivalent to an autopsy in
humans.) The pathologists found no indication of known viruses.
Bacterial agents, too, would show up at necropsy as damage to
particular organs and could be cultured using petri dishes, a
growing medium, and a warm environment. Unlike viruses, however,
bacteria are found often on necropsy, and some bacteria are considered
routine invaders of dead animalssort of the coffin flies
of bacteria. Early necropsies found rare bacterial infections
in many aborted fetuses, but the scientists concluded that while
they were rareand even perhaps related to the syndromethey
likely were not the sole culprit, the smoking gun, that caused
with either viruses or bacteria, the findings from necropsy should
be pretty much consistent from accession (a fancy term for dead
animals logged in for examination for cause of death) to accession.
If, for example, the virus damaged the liverand caused death
by that damagethen the damage to the liver should be found
in every necropsy performed in theory and most in practice.
By May 14, just a hair over two weeks after the staff at the Livestock
Disease Diagnostic Center first noticed the unusual number of
foals and aborted fetuses being sent for necropsy, results of
a survey of Central Kentucky horse farms indicated that the syndrome
was widespread in the area, and it was continuing.
By this time, the mystery was occupying most of the pathologists
at the Livestock Disease Diagnostic Center as well as scientists
at Gluck Equine Research Center, the Department of Animal Sciences,
and local equine practitioners. Several faculty members at Gluck
remembered that in 1980 and again in 1981, early fetal losses
were unusually highbut not as high as the current losses.
No cause had ever been found. In both years, the mysterious syndrome
started and stopped rather abruptly.
The unexpected starting and stopping of fetal and foal losses
suggested strongly, but not absolutely, that something in the
environment was related to the syndrome, by now named the Mare
Reproductive Loss Syndrome (MRLS).
What was common about 1980, 1981, and 2001 that could be related
to outbreaks of early fetal losses and weak and dying foals?
"A similar pattern of weather conditions just prior to the
outbreak in all three years occurred," Harrison said. "March
temperatures were below normal in all three years, followed by
above-normal temperatures in April. Such a pattern could be related
to an explosive biological activity in both plants and insects."
All three years also were noted for having a frost or freeze in
the third week of April followed by a warm-up just days later.
The similarity in weather patterns was strongly suggestive of
something weather-related occurring that had an effect on pregnant
mares and their fetuses, Harrison said.
The avenue of the search now turned to biological factors related
to weather-either through plants or insects.
Organization of the research teams within and outside the College
of Agriculture was facilitated by veterinarian David Powell of
the Gluck Equine Research Center and included scientists from
practically every discipline whose knowledge could define the
scope of the inquiry.
could be linked to a variety of possible agents of the fetal deaths
and weak foal births, including mycotoxins, poisons given off
by fungi that can explode when the weather is just right, ergot-type
alkaloids (also given off by fungi), and phytoestrogens, which
are plant hormones that mimic naturally produced estrogens. At
first blush, all of these seemed among the possible suspects for
the losses. If any of these were the cause of the syndrome, they
should show up on testing. None did.
If the common culprits appeared unrelated to the losses, the
question became more intriguing. Weather and what else?
"Early on, some people had suggested that eastern tent caterpillars
might be the culprit, but it didn't seem plausible," Harrison
said. "No one had ever reported that tent caterpillars were
anything but fairly benign creatures that created inconsequential
webs in trees in early spring."
But with time ticking away and no other obvious cause on the
horizon, the scientists turned their attention to the eastern
tent caterpillar. The literature on the caterpillars did, however,
indicate that their favorite plant to feast on was the wild cherry
tree. Wild cherry leaves can release cyanide, a poison, when ingested
and were known to be deadly to livestock eating them in large
Agronomist Jimmy Henning, now a principal investigator on the
problem, noticed on visits to farms where the outbreaks had been
most severe that wild cherry treesand eastern tent caterpillarswere
also abundant. A thorough survey of farm managers with and without
losses to MRLS was led by veterinarian Roberta Dwyer and confirmed
the associations. But, as any scientist knows, simple presence
of phenomena does not necessarily imply a cause and effect relationship.
Nonetheless, the idea was intriguing and worth further exploration.
By May 20, 2001less than a month after the first known
casesthe deaths of newborn foals and spontaneous abortions
of early fetuses dropped off precipitously, just as they began.
This coincided with the drop in eastern tent caterpillar numbers.
And although losses were down to normal levels, the scientists
continued their search to prevent and explain the syndrome that
reared up in 1980, 1981, and 2001. What about future outbreaks?
With eastern tent caterpillars coincidently being linked to the
losses, the next step was to try to replicate the losses in a
controlled experiment. Up to now, the scientists had to rely on
survey techniques that helped narrow the field of causes, but
they were less than conclusive in a scientific sense.
Entomologist Bruce Webb, whose specialty is insect molecular
virology, and equine reproductive researcher Karen McDowell designed
an experiment to see if eastern tent caterpillars were linked
to the losses.
The experiment was straightforward: expose 10 pregnant mares
to high levels of tent caterpillars and their frass (excrement),
expose nine mares only to the frass, and try to minimize exposure
of 10 mares to both caterpillars and frass in a control treatment.
Within a week, the first losses were noted, and ultimately 70
percent of the mares exposed to the eastern tent caterpillars
or their frass aborted their foals. Mares in the no-treatment
group also had abortions, but significantly fewer. Webb explains
that those abortions were likely related to the fact that the
experimental facilities failed to keep all the caterpillars in
their assigned pens. Because of logistical problems, caterpillar
fencesmade of plastic pipe cut into a half-round shape so
that the caterpillars would fall back to the ground if they tried
to crawl outside the pencould not be completed until the
experiment was well under way. Webbs data confirmed that
some of the caterpillars escaped to other treatment groups. Indeed,
he found out caterpillars are harder to keep in a herd than horses.
"From this experiment, we were pretty sure that caterpillars
were associated with the fetal losses. And following our initial
experiment, we worked with local equine veterinary practitioners
to verify our findings with another experiment," Webb said.
In that experiment 15 mares were put into one of three treatments.
Those in one group were administered ground-up caterpillars directly
into the stomach in a saline solution; a second group received
frass in a saline solution; the third set of mares received the
"Eighty percent of the mares treated with the ground-up
caterpillars aborted their fetuses, while none of the other mares
did," Webb said. "With that, we were pretty confident
that whole caterpillarsand not just their frasswere
associated with MRLS." So if horse producers wanted to minimize
their losses to MRLS, they should try to minimize exposure of
pregnant mares to the eastern tent caterpillars.
The 'How' Is Still Unanswered
Okay, if caterpillars are linked to the outbreak of the syndrome,
then how? That's still under investigation by scientists.
Currently, they are pursuing three leads on the precise mechanism
by which eastern tent caterpillars cause such destruction:
- First, it might be that eastern tent caterpillars are the
vector for some heretofore unidentified pathogen.
- Second, eastern tent caterpillars could carry an unidentified
toxin, such as the blister beetle carries canthradin poison,
so lethal to horses but not other animals. Scientists are studying
the eastern tent caterpillar further to determine if this is
- Finally, something about eastern tent caterpillars themselves
may cause internal injuries to horses, which would result in
secondary pathogens getting a foothold in pregnant mares and
the first MRLS cases in 2001 to the last in 2002, scientists have
been perplexed by the many features of this syndrome," Harrison
said. "Now that a strong, scientifically-based association
has been made between MRLS and the eastern tent caterpillar, scientists
can focus their research efforts on projects that will provide
a thorough understanding of the mechanisms that cause this disease
The Power of Teamwork
While the logic of science helped the scientists ferret out the
association between eastern tent caterpillars and Mare Reproductive
Loss Syndrome, it wouldn't have happened without the complete
dedication and cooperation of more than 100 scientists in the
College of Agriculture, who worked together with equine veterinary
practitioners, and Kentucky farm managers. Every person involved
provided yeoman's service to the cause.
vigilantly tramped through pastures throughout Central Kentucky,
assessing them for a plethora of factors that might even distantly
be related to the syndrome. In addition, they spent days and weeks
investigating potential causes and some factors that were, quite
frankly, long shots. Equine veterinary practitioners monitored
their cases of MRLS and provided rich data to the UK scientists;
without their help the association between tent caterpillars and
the syndrome might still be obscure. Vigilant farm managers kept
tabs on the situation and provided complete access to their farm
records and situations, helping speed up the investigation enormously.