A novel solution for an invisible enemy
Saul Tzipori, director of the Division of Infectious Diseases
Photo: Ed Malitsky
Earlier this year, 18 people died in Walkerton, a rural community
in Ontario. The catastophic event is thought to be the worst case
of a waterborne outbreak reported so far in North America.
It is also just one of the recent outbreaks of illness from food
products or contaminated water with the virulent strain of the bacterium
Escherichia coli, or E. coli O157:H7. While all animals and humans
have natural colonies of E. coli living in their intestines, E.
coli O157:H7, discovered in 1982, ranks among the most-fearedfood-borne
These bacteria liberate toxins that are absorbed from the intestine
into the bloodstream, where they cause kidney failure and often
brain damage, which can be fatal. The outcome is known as hemolytic
uremic syndrome or HUS, the leading cause of kidney failure in children.
An estimated 100,000 cases of E. coli, mostly O157:H7 with some
similar but non-O157:H7 strains, occur annually, with 2,100 hospitalizations
in the United States resulting in three to five percent deaths.
According to the Centers for Disease Control and Prevention (CDC),
disease-causing microorganisms like E. coli are difficult public-health
enemies that are invisible, furtive and gaining in strength and
At Tufts, scientists at the Division of Infectious Diseases at
the School of Veterinary Medicine have developed what may be the
first effective defense against the toxin producing E. coli O157:H7
and similar E. coli. After five years of study, researchers have
developed an antitoxin therapy that inactivates the toxins in the
bloodstream and will most likely prevent kidney failure and death
in affected children.
"Since the treatment is directed against the liberated toxins
and not the bacteria," says division director Saul Tzipori, "the
bacteria will not be able to develop resistance as they do against
antibiotics. These are human antibodies, which were produced in
transgenic mice and are very safe to use in children at risk of
developing kidney disease. Their efficacy has recently been demonstrated
in animals infected with the E. coli O157:H7."
After some initial evaluation the human antitoxins are now ready
for production for phase I and phase II clinical trials in humans.
They will be administered to children at risk of HUS and to those
who come in contact with them. Typically, within two to four days
after consuming contaminated food or water, individuals may experience
the onset of bloody diarrhea, which in some may lead to anemia,
kidney failure and sometimes death. Researchers postulate that E.
coli bacteria injure the intestinal tract, which causes diarrhea,
and the toxins are absorbed into the bloodstream through the injured
lining of the gut.
Tzipori says the development of this product promises to be the
first effective solution to a "nasty disease" that tends to strike
in clusters and in certain geographic locations.
"Food safety is a deep concern, and people are becoming more aware
of precautions needed to handle meat and other animal products,"
he says. "There is growing hypersensitivity around meat monitoring,
but it is not an easy thing to do. You can monitor a bulk of meat
and not detect contamination. We believe that this treatment will
be a significant contribution toward greater protection. It is certainly
the best option available at the moment for treating and protecting
exposed children against HUS."
Such progress, he adds, offers hopeful signs that more advances
will be made to treat this significant but yet untreatable disease.
"We got our first grant in 1996 from the National Institutes of
Health (NIH) for five years," he notes, "and we just were awarded
a second NIH grant for another five years for $1.7 million to develop
molecular techniques to amplify these antibodies for large-scale
commercial production. We are encouraged by the strong NIH support
we have received for this project."
The advancements with E. coli also mark a milestone for the Division
of Infectious Diseases, a little-known aspect of the Veterinary
School and, indeed, of Tufts, but whose brief ten-year history is
marked by impressive growth and vitality. It began inauspiciously
when Gerald Keusch, chief of the Division of Geographic Medicine/Infectious
Disease at the New England Medical Center (NEMC), persuaded Tzipori,
then associate director of the International Centre for Diarrheal
Diseases Research in Dhaka, Bangladesh (ICDDR,B), to come to the
Veterinary School as a visiting professor.
Tzipori's international reputation in the investigation, diagnosis
and treatment of infectious diseases in animals and humans made
him a natural choice. Tzipori graduated with top honors in veterinary
medicine from the University of Queensland, Australia, where he
also earned a Ph.D. From 1975 until 1985 he directed the microbiology
section at a Melbourne research institute, during which time he
identified important enteric infectious agents previously either
unknown or ill-defined in Australia and elsewhere; he also developed
two new veterinary vaccines. From 1985 to 1990 he directed the Department
of Microbiology at the Royal Children's Hospital in Melbourne from
which he was eventually recruited to Tufts.
When his four months were up, Tzipori was offered a joint appointment
to initiate a program in infectious disease, a position funded initially
by the Veterinary School and NEMC. In January 1991 he was made full
"I had an established career in Australia and some of my colleagues
thought I was taking too big a risk in moving to the highly competitive
and unfamiliar U.S. biomedical environment," says Tzipori. "The
reputation of Tufts and NEMC for interdisciplinary biomedical research,
however, particularly in the field of gastroenteritis, was well
recognized and potentially could draw resources. I figured the challenge
was worth the risk."
That challenge soon began to pay off. In less than three years,
drawing entirely on external funding, Tzipori expanded his research
staff to 15, and the group was recognized as an official division
within the Veterinary School. Today, the staff has grown to nearly
35, including 20 scientists, ten of whom are faculty. Now occupying
the entire second floor of Building 20 and part of 21 at the Veterinary
School, the division is the largest single research entity at the
University, and Tzipori the largest funded individual at Tufts.
Grant writing has secured some $15 million to fund current research
and over the next five years from sources such as the NIH, the U.S.
Department of Agriculture, the CDC, the Federal Drug Administration
and the Environmental Protection Agency.
Still, Tzipori is quick to point out that the success is not measured
in dollars alone. Members of the division are charged with the task
of directing and teaching immunology, molecular biology, microbial
pathogenesis, parasitology and public health at the Veterinary School.
This year Tzipori also was instrumental in helping launch the first
Ph.D. program at the school.
"In a relatively short time we've created a highly productive
and integrated group," says Tzipori. "It took a lot of hard work,
but as it turned out, it was worth it." The E. coli program is only
one pioneering effort by the division, noted for its multidisciplinary
approach to science.
One major initiative, also funded by NIH, investigates Cryptosporidium
parvum, a waterborne protozoa that causes diarrhea in both humans
and animals, and can be fatal to malnourished children made weak
by diarrhea, and to people whose immune system is compromised, including
the elderly and those with AIDS. Tzipori was one of the first to
demonstrate in 1980 that Cryptosporidium was a serious cause of
diarrhea in animals and humans and that humans can be infected from
contact with animals.
"When I came across this protozoa while working in Scotland, not
much was known about it. It became clear that this may turn out
to be a serious cause of disease in calves," he says. "Then, surprisingly,
when we started looking for it in other domestic animals, we found
it in every species we looked at, including humans."
There is no effective treatment for Cryptosporidium, but scientists
at the division, who have received an award to sequence the nucleotides
of the entire Cryptosporidium genome, hope to help identify molecular
targets for development of therapeutic agents.
Other key research programs include a collaborative investigation
in Uganda to identify links between Cryptosporidium and Microsporidium,
another microorganism associated with chronic diarrhea and immune
impairment due to malnutrition and chronic diarrhea and wasting
in young children. Together with the Tufts School of Medicine and
the New England Primate Center, the division is involved in defining
the contribution of nutritional factors, direct effect of the AIDS
virus on the gut, and opportunistic infections to wasting and metabolic
disorders associated with AIDS.
"We are very excited about the newly developed and funded programs
in our division," says Tzipori. "With the drive to recruit three
new talented faculty members, the division is entering its second
growth phase. Our division has come a tremendous distance since
it began, and we look forward to the next decade, which we hope
will be just as scientifically rewarding and productive as the first."