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JACK REMINGTON, MD, world-renowned
as an infectious diseases expert, always wanted to be a neurosurgeon.
From the day as an adolescent that he saw a polio-stricken child
in leg braces, Remington vowed to be the kind of doctor who could
repair the nervous system to prevent such tragedies.
But this initial goal -- combined with serendipity
-- instead set Remington on the path to becoming a clinician and
researcher in immunology and infectious diseases as a professor
of medicine at Stanford.
In 1952, within weeks of beginning studies at the
University of Illinois Medical School, Remington applied for a fellowship
to study nerve regeneration in squids. When his application was
denied, he was crushed. Wandering down a hall in the medical school
in this dejected state, he attracted the attention of immunologist
Harry Dowling, MD, chief of medicine at the U of I hospital, who
stopped to ask what was troubling Remington. When Remington explained,
Dowling pointed out that the fellowship was for postdoctoral research,
and Remington had only just begun his first year of training. "But
if you're so interested in research," Dowling suggested, "why don't
you come and work with us?" Remington accepted the challenge and
began research related to the immune system.
A second turning point came in 1957, when Remington
was honored with an invitation to join the first group of research
associates at the National Institute of Allergy and Infectious Diseases
in Bethesda, Md. As he waited for an interview in the office of
the NIAID director, Remington perused an issue of Science
that featured an article on diagnosing the infectious disease toxo-plasmosis,
co-authored by NIAID researcher Leon Jacobs, MD. At NIAID Remington
had counted on continuing his medical school research on immune
system responses to antimicrobial agents, so he was distraught to
receive an assignment instead to the Laboratory of Tropical Medicine.
"But when I got there," Remington recounts, "there was Leon Jacobs
-- who had written that article -- as head of the lab. He was a
wonderful and brilliant human being, and his enthusiasm and the
description of his research program led me to decide that I would
work on Toxoplasma gondii."
T. GONDII, ALSO KNOWN SIMPLY AS TOXOPLASMA,
IS THE MICROSCOPIC PARASITE THAT CAUSES TOXOPLASMOSIS.
The single-celled organism occurs worldwide.
Nearly one-third of adults in the United States
and Europe carry antibodies to it, acquired by exposure,
usually through the consumption or handling of raw or undercooked
meat from infected animals. Though a latent infection is benign
in healthy people, immune-deficient individuals
can develop acute, life-threatening infections. And women who develop
toxoplasmosis during pregnancy can pass it on to their fetuses,
95 percent of whom, if untreated, will suffer tragic cons
equences later in life.
Remington's commitment more than four decades ago
to unlock the secrets of a then poorly understood parasite has borne
fruit on a scale neither he nor anyone else could have predicted.
Working in his laboratory at the Palo Alto Medical Foundation (where
he served until recently as chief of infectious diseases), Remington
has virtually "written the book" on the pathogenesis, diagnosis
and treatment of toxoplasmosis. He and his collaborators have extended
the frontiers of understanding about the workings of the immune
system in many opportunistic infections, developed serological screening
tests and tested drug therapies for infections in AIDS patients.
At the same time he has served as an energetic mentor to a cadre
of postdoctoral researchers who have come of age in his lab and
moved on to leading roles at prestigious academic institutions around
the world. He has left his mark on the study of the immune system,
in the United States and abroad, as author or co-author of more
than 600 articles, the recipient of more than a dozen of the most
prestigious medical research awards, and a leader in dozens of professional
societies.
Remington credits the basic discipline and dedication
that have supported him in his multi-faceted role to mentors such
as Jacobs and Maxwell Finland, the "father of infectious diseases,"
under whom Remington served as a postdoc at Harvard from 1960 until
1962, when he joined Stanford's medical faculty.
Remington had begun his work on toxoplasmosis at
NIH in the late 1950s in pursuit of answers to a controversy over
whether pregnant women could transmit the infection to their babies.
At that time, in the USSR and many other countries such infections
were blamed for stillbirths, spontaneous abortions and congenital
abnormalities, and doctors warned women whose blood tested positive
for exposure to toxoplasma not to get pregnant. Remington
experimented with chronically infected mice and found
that they could indeed pass on toxoplasma to their offspring in
utero. He went on to isolate the parasite
in cyst form from the uteruses of women who were
"Somehow I've spent a
lifetime and failed
to have the ob-gyn medical community
and health insurance industry
appreciate what it means for a
pregnant woman to deliver a destroyed or dead
baby because of
an infection that's preventable!" says
Remington.
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chronically infected but free of symptoms. These findings
did not prove that latent infections in pregnant women necessarily
led to serious problems for the fetus -- but unfortunately many
medical practitioners jumped to this conclusion and urged that women
seropositive for the organism undergo drug treatment and avoid pregnancy
until antibodies no longer showed up in their blood. As Remington
and others would show, such treatment is futile, for, once exposed,
even apparently healthy individuals carry the parasite as cysts
in their organs and antibodies in their blood for life.
He worked hard to overcome the misinterpretation
of his results. "Over the years I've tried to change medical opinion
in Germany, Mexico, South America, and elsewhere," he laments. "I've
had women flying in to see me from all over the world to ask if
they should attempt to have a child, and I've told them that there
is no proof their infection is a danger to their unborn child."
Meanwhile other clues in the toxo mystery had emerged.
At NIH Remington and Jacobs had analyzed varieties of meat commonly
consumed by humans and found they contained toxoplasma cysts, strongly
suggesting a meat-to-man transmission route for the organism. The
less thoroughly the meat was cooked, the higher were the chances
that viable cysts, which defy digestion, would cause infection.
A researcher in France, Georges Desmonts, MD, later proved the hypothesis.
Desmonts and Remington collaborated closely over the years, and
it was in France that Remington earned his title, "pope of toxoplasmosis,"
from television appear ances in which he counseled
pregnant women to eat only well-cooked meat.
Despite these successes, Remington's early mentor
Harry Dowling chided him for his tenacious interest in "an organism
in search of a disease." Remington recalls, "That smarted a bit,
but somehow I liked toxoplasma, and I stuck with it."
In 1962, when he joined the Palo Alto Medical Foundation's
research institute at the invitation of director and School of Medicine
alumnus Marcus Krupp, MD, Remington became the first full-time Stanford
medical faculty member to hold a concurrent position outside the
medical school. Remington's double appointment has strengthened
ties between the medical school and the research institute, says
Stanford professor of medicine Gary Schoolnik, MD, former chief
of the school's infectious diseases division. "It certainly has
been an advantage for the medical school to have one of the world's
best infectious diseases researchers and clinicians on the faculty,"
Schoolnik notes. "In Remington's era, physicians were encouraged
to do both clinical work and research if they were energetic and
bright. But if you really look at how many have done both at his
level of excellence, it was very, very few."
From the start, the major focus in Remington's lab
was host resistance against nonviral opportunistic pathogens. His
clinical subjects were patients in Stanford's pioneering organ-transplant
program and cancer patients at Stanford and the Palo Alto clinic.
These immunosuppressed patients -- or "compromised hosts," to use
the term Remington coined -- developed all kinds of potentially
lethal infections from bacteria, fungi and protozoans (including
toxoplasmosis when an infected organ from a seropositive donor went
to a seronegative recipient). According to Schoolnik, "Remington
and his lab were at the forefront of defining the spectrum of diseases
that could occur in these severely weakened patients and experimenting
with drug therapies for managing them."
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"As a mentor, he
is demanding and
extremely honest. I
learned research science from
one of the great research scientists
that this country has produced,"
says Conley.
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Meanwhile, the unfinished business of the impact of
toxoplasma on pregnant women and newborns continued to hold Remington's
interest. "Always on the side we were interested in working on toxo,"
he says. Since the 1940s the sole means of detecting toxoplasmosis
had been the Sabin-Feldman dye test, which measures immunoglobulin-G
(IgG) antibodies to toxoplasma in blood serum. Though highly accurate,
the test doesn't reveal whether the fetus or newborn has acquired
an infection, or if its antibodies to toxo came from the mother
via the placenta. Remington knew that another type of antibody,
immunoglobulin-M, is too large to pass through the placenta. So,
he devised a test to detect IgM antibodies to toxo in the fetus
or newborn that would provide a reliable means for diagnosis.
This led in the early 1970s to the development of
a battery of tests for detecting IgM antibodies to several infectious
agents. Dubbed "TORCH" (for toxoplasmosis; other, including rubella;
cytomegalovirus; and herpes), it is now used routinely worldwide
for diagnosis of these infections in newborns and adults. In Europe
it is known as the "test of Remington." The research associated
with the development of the TORCH screening tests and with treatment
of organ-transplant recipients contributed to Remington's serological
lab evolving into the major reference facility in the United States
for toxoplasmosis. At the same time, his growing prominence in the
field of congenital infections prompted him to co-edit (with Jerome
Klein, MD, a pediatrics professor at Boston University School Of
Medicine) a comprehensive textbook on infectious diseases in fetuses
and newborns. First published in 1976, Infectious Diseases in
the Fetus and the Newborn Infant is now in its fourth edition.
As beneficial as the TORCH screening proved for identifying
toxoplasma in newborns, it represented an "after-the-fact" diagnosis,
and Remington pressed on for a means of prenatal detection and treatment.
He and his colleagues found that anti-microbial treatments for women
who become infected during pregnancy dramatically decrease the risk
of fetal infection. And, if amniocentesis is performed and toxoplasma
is found in the amniotic fluid, the fetus can receive treatment
directly, via treatment of the mother. But by far the most proactive
measure, says Remington, would be a periodic blood test before and
during pregnancy, for swift response as early as possible. In the
United States approximately 4,100 of the 4.1 million infants born
annually have congenital toxoplasma infections. Most of these, if
not treated, will suffer epilepsy, mental and psychomotor retardation,
serious vision and hearing problems, or even death. The estimated
lifetime costs for special services for infected children born each
year are at least $222 million. Remington decries the fact that
serological testing for toxoplasma is not yet routine in prenatal
care, as it is in France and Austria. "Somehow I've spent a lifetime
and failed to have the ob-gyn medical community and health insurance
industry appreciate what it means for a pregnant woman to deliver
a destroyed or dead baby because of an infection that's preventable!"
he laments.
Over time, as Remington teased out the workings
of toxo, he saw that he could use toxo to tease out the workings
of the human immune system. Toxoplasma, as a relatively large and
easy-to-see infectious agent, was useful for studies of how the
human cellular immune system functions when challenged. "You could
see toxoplasma inside a cell," he explains. "You could tell if the
cell killed it, because you could see it disappear."
IN 1968 POSTDOCTORAL RESEARCHER JOEL
RUSKIN, MD, AND REMINGTON MADE A KEY DISCOVERY: MICE INFECTED WITH
TOXOPLASMA WERE RESISTANT TO LISTERIA AND SALMONELLA BACTERIAL INFECTIONS.
With additional studies, the list of organisms
warded off by this protective effect grew to include a range of
unrelated fungi, viruses and mycobacteria. Spurred on by these findings,
the pace in the lab accelerated.
"I had an extraordinary experience," recalls John
Hibbs Jr., MD, a postdoc under Remington from 1969 to 1971, and
now professor of medicine and chief of infectious diseases at the
University of Utah. "There was an undercurrent of excitement, as
the lab was on a true frontier in the rapidly developing field of
immunology." Hibbs and Remington went on to show that the ongoing
stimulation of the immune system in mice caused by toxoplasma infection
also enhanced their resistance to tumors. The driving question was
what conferred this powerful resistance.
The answer turned out to be macro-phages, the non-specific
"wandering cells" of the immune system that engulf and kill intracellular
invaders. Hibbs and Remington showed that macrophages activated
by infection were highly cytotoxic to tumor cells. "This was remarkable,"
Hibbs explains, "because previously it was thought that all such
anti-tumor resistance was highly specific and mediated by sensitized
lymphocytes. Ours was the first description of non-specific cytotoxity
by a mammalian cell for a tumor cell." This breakthrough set off
a flurry of investigations around the country, leading to discoveries
of other non-specific defense cells.
Neurosurgeon Frances Conley, MD, member of Stanford's
medical faculty and chief of staff at the Veterans Affairs Palo
Alto Health Care System, worked with Remington in the mid-1970s
to investigate whether the anti-tumor resistance conferred by toxoplasma
would work against brain tumors. It did. "As a mentor," she recalls,
"he is demanding and extremely honest. I learned research science
from one of the great research scientists that this country has
produced."
Remington's high standards extend to the realm where
the research discoveries ultimately count the most: the patient's
bedside. "In making infectious disease rounds, he absolutely does
not tolerate mediocrity," Hibbs remembers. "He's an uncompromising
and compassionate advocate for the patient, and if the best wasn't
being done by everyone involved in the patient's care, he would
stir up a ruckus and make sure the message got across in no uncertain
terms. One of the most important things you learned from Jack is
implicit in being a physician, but it has to be emphasized for every
generation: that first and foremost you have to be an uncompromising
patient's advocate. Jack is that par excellence."
His toughness has made him a legend among Stanford
interns, residents, and house staff, and rumor has it that in some
circles he is known as "STAT Jack." Hibbs recalls being at a professional
meeting where a group of young doctors from Stanford, sitting at
a nearby table in a restaurant, were laughing and competing in telling
"war stories" -- the subject of which Hibbs could just make out.
It was Jack Remington. "You could tell that they'd all had uncomfortable
experiences, but in retrospect found them very humorous -- and they
had a very warm attitude toward him."
In the early 1980s, when the AIDS epidemic broke,
toxoplasma took on a new significance, as the culprit that caused
encephalitis in immune-deficient HIV-infected patients. In short,
the organism "in search of a disease" had found one in a big way.
Remington pushed hard for all HIV patients to get tested for toxoplasmosis
(at least 30 percent will come down with toxoencephalitis without
prophylactic drugs). Virtually every new drug that is currently
used for toxo treatment in HIV patients was first tested in the
Palo Alto lab.
During the last decade, his lab research has concentrated
on the roles of monocytes, cytokines, and specialized T cells in
resistance to infections, primarily those of the brain. Thus he
has made, and continues to make, an immense contribution to scientific
and medical knowledge of the central nervous system, the subject
that fired his passion for medicine more than four decades ago.
And before he considers retiring, there's at least
one more contribution he's determined to make. "It's been my lifelong
ambition to derive a means of identifying acute toxoplasma infection
in pregnant women testing a single serum sample, so they wouldn't
have to abort or worry throughout their pregnancy about having an
abnormal child," he says. Given Remington's lifetime of fierce focus
on the microorganism that's caused such heartache, it won't be surprising
when he does it. SM
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