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Cell
biologist wins Lasker prize
Alumni Faces
Alumni Notes
Juanita Merchant says the mentoring she received as
a student in Yale's M.D./Ph.D. program exerted an important influence
on her career. She now fills the same role for students at the University
of Michigan, where she is an associate professor. “We have little
training sessions: How do you write an abstract? How do you present a
10-minute talk? … I could just hand them a stack of examples, but
it's not the same as having me sit next to them explaining how to do it.”
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Gut
feeling
Gastroenterologist Juanita Merchant followed her intuition
to a new view of how the stomach deals with acid.
By Nancy Ross-Flanigan
Photographs by George Waldman
Temperatures hit the 100-degree mark and just kept climbing on the summer
day when Juanita Merchant tackled Lava, the most challenging rapid on
her 8-day rafting trip through the Grand Canyon in 1993. Only the occasional
splash of chilly river water offered relief as her oar dipped in and out
of the churning froth. But the heat was hardly her main concern. Stroking
in synchrony with her raft-mates, Merchant could only hope that they would
slide into Lava at precisely the proper point and paddle at just the right
moment to avoid crashing into boulders or flipping over. There was no
turning back, no second-guessing. It was a matter of trusting their instincts,
believing that the river would eventually smooth out and take them where
they wanted to go.
Trusting one’s instincts is as important in research as in roiling
rapids, says Merchant, a 1984 graduate of Yale’s M.D./Ph.D. program
who is now an associate professor at the University of Michigan. Her recent
work on stomach ulcers is a case in point. Ultimately, she and her co-workers
showed last year that suppressing stomach acid with prescription drugs
called proton pump inhibitors can allow bacteria to flourish, triggering
inflammation and ulcers that may lead to cancer. But before they could
reach that conclusion, the scientists had to rethink almost everything
they had been taught about stomach acid secretion, and to trust clinical
observations and experimental results that seemed to fly in the face of
conventional wisdom.
The standard textbook explanation of how acid secretion is regulated revolves
around the hormone gastrin, which is produced by specialized cells in
the stomach when acid levels are low. Gastrin acts on acid-secreting cells
to induce and maintain the proper level of acidity; then a feedback mechanism
turns off further gastrin production and acid secretion. But this time-honored
view doesn’t square with what Merchant and other gastroenterologists
see in patients infected with Helicobacter pylori, the bacterium
implicated in ulcers. Somehow, Helicobacter thwarts the feedback
response, and the stomach just keeps pumping out acid, which eventually
leads to ulcers. To better understand the process, Merchant’s research
team developed a strain of mice that couldn’t produce gastrin. The
plan was to infect these mice with Helicobacter and see if they
would still develop inflammation and ulcers. The researchers ran into
a snag that again challenged their assumptions: mysteriously, infecting
the mice with Helicobacter was virtually impossible, and yet the
uninfected animals were showing signs of inflammation, just as if they
had bacteria in their guts.
“We could have just said, ‘Well, this isn’t working, so
let’s chuck this model and move on to something else,’”
says Merchant. “But I knew we had technically executed this experiment
correctly, so I reasoned that the data must be telling us something. I
always tell my postdocs that it’s almost like there’s a secret
door waiting to be uncovered. If you sit down and really organize your
data and look at it without tunnel vision, without being bound by assumptions,
you’ll find a way to move through that door.”
By scrutinizing their data and carefully performing a series of experiments,
the researchers figured out that low acid levels in the gastrin-deficient
mice had allowed a variety of other bacteria to flourish in their stomachs,
preventing Helicobacter from gaining a foothold. But far from protecting
against the effects of Helicobacter, these other bacteria, such
as Staphylococcus and Pseudomonas, were themselves triggering
inflammation.
“It seems that the stomach is almost like a rheostat, with acid levels
controlling which organisms end up growing there,” says Merchant.
Helicobacter thrives when acid levels are high; when levels drop,
other bacteria take over. The finding that these other bacteria can stir
up their share of trouble overthrows the notion that Helicobacter
is the only bug behind the kind of chronic stomach inflammation that can
lead to cancer.
But the implications of Merchant’s research don’t end there.
If low acid levels allow bacteria to run rampant, what does that mean
for the millions of Americans who seek relief from heartburn and ulcers
by gulping down acid-controlling pills every day? Merchant can’t
say for sure, but another set of experiments in mice suggests that long-term
use of such drugs may do more harm than good. In these experiments, Merchant
and colleagues at the University of Michigan treated normal mice for two
months with a proton pump inhibitor, a type of drug that blocks acid secretion
(Prilosec and Prevacid are examples). Sure enough, the mice developed
inflammation that subsided only when the burgeoning bacteria were controlled
with antibiotics. Merchant isn’t telling patients to dump their pills,
but she cautions against taking high doses over years or decades.
She plans to follow up the findings with studies of patients. “Mice
obviously can’t tell you when something hurts or feels better,”
says Merchant, a former Howard Hughes Medical Institute investigator who
sees patients on rotation as an attending physician in the U-M Health
System. “So we really need to correlate the inflammatory changes
due to these other bacteria to symptoms that patients have.”
Though she never set out to overturn the view that Helicobacter
is the sole culprit in ulcers or to question the use of popular acid-reducing
drugs, once the results were published—in the January 2002 issues
of Gastroenterology and the American Journal of Physiology/Gastrointestinal
and Liver Physiology—Merchant felt prepared to stand behind her
conclusions. She had braced herself for criticism, but says that so far
it hasn’t come. In fact, in an article in the April American Society
for Microbiology News, Martin J. Blaser, M.D., whose earlier work
uncovered the Helicobacter-ulcer connection, agreed that getting
rid of Helicobacter can allow other bacteria to colonize, with
potentially harmful results. And in a commentary in the November 2002
issue of Gastroenterology, the journal of the American Gastroenterological
Association, Richard M. Peek Jr., M.D., concurred with Merchant’s
hypothesis that other bacteria can induce and perpetuate the inflammation.
Even if peers had been critical, Merchant probably wouldn’t have
wavered. Wavering just isn’t in her makeup. That confidence comes
in part from her scientific and medical training, she says, but also from
earlier influences.
“My mother was a teacher, and she raised my brother and me by herself,”
she explains. “My father left when I was in fourth grade, and seeing
my mother struggle at such a young age made a lasting impression. She
also instilled in us the importance of getting an education and not letting
anything deter us.” That resolve, in turn, traces back to Merchant’s
mother’s childhood on a small farm in Oklahoma, where her
mother was determined to help the family get ahead. “It was a family
of 13, and everyone was expected to work on the farm,” says Merchant,
46, who now has a daughter of her own, 3-year-old Olivia. “I remember
my mother telling me that her mother used to take her place in the field
so that she could go to school.”
Determination does run deep in Merchant’s lineage, but she would
be the first to acknowledge that sheer will and ability aren’t always
enough. Sometimes you need an expert guide to show you the way, she says,
again drawing parallels between whitewater rafting and negotiating the
career challenges of a physician-scientist.
“As a novice rafter, there were times when my well-being was completely
dependent on the skill of the guide calling out orders from the rear of
the raft,” she recalls. Similarly, she would have been adrift without
mentors who guided her, from her undergraduate days at Stanford through
her time at Yale, where she studied with Russell Barrnett, to her faculty
position at Michigan. It was in Barrnett’s lab that she learned “how
to think about science” while working on membrane biogenesis in the
duck salt gland. Her very first mentor as a sophomore Stanford pre-med
student was Renu A. Heller, Ph.D. ’69, who suggested she obtain both
a doctorate and a medical degree at Yale. She’s also grateful to
her first clinical mentor, Rosemarie L. Fisher, M.D., FW ’75, professor
of medicine at Yale, who helped her stay focused on her goals and showed
by example that a woman could succeed in a male-dominated subspeciality.
Now in the mentor’s role, Merchant is the one at the rear of the
raft, offering guidance to her students and postdocs. It’s not enough
simply to expect them to follow her lead, she believes. To make sure they’re
adequately equipped for their future careers, she meets with each person
in her lab individually. “We have little training sessions: How do
you write an abstract? How do you present a 10-minute talk? How do you
present an hour-long talk? How do you write a five-page grant? How do
you write a 10-page grant? I could just hand them a stack of examples,
but it’s not the same as having me sit next to them explaining how
to do it.” But unlike the whitewater guide, you won’t hear Merchant
barking orders.
“I believe,” she says, “in a gentler approach to bringing
people along.”
Nancy Ross-Flanigan is a freelance writer in Belleville, Mich., and
a former science writer for the Detroit Free Press. George Waldman
is a photographer based in Detroit.
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Familiar Faces
Do you have a colleague who is making
a difference in medicine or public health or has followed an unusual path
since leaving Yale? We’d like to hear about alumni of the School
of Medicine, School of Public Health, Physician Associate Program and
the medical school’s doctoral, fellowship and residency training
programs. Drop us a line at ymm@yale.edu or write to Faces, Yale Medicine,
P.O. Box 7612, New Haven, CT 06519-0612.
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Fenn
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Almost a century after mass spectrometry was first used to analyze small
molecules, a Yale doctoral alumnus and former professor has shared in
the 2002 Nobel Prize in Chemistry for his pioneering efforts to apply
the technique to large molecules, such as proteins.
His discovery, electrospray ionization (ESI), allows scientists to gauge
the weight of large molecules and determine quickly and accurately what
proteins are in a sample. John B. Fenn, Ph.D. ’40, professor
emeritus of chemical engineering at Yale, described his technique in a
paper in Science in 1989. Evidence of his method’s significance
is clear: last year alone more than 1,700 scientific papers that relied
on ESI were published.
“What really gave it a kick in the pants was the advent of proteomics,”
Fenn said when reached by phone three weeks after he heard the news. “It
turns out that ESI is one of the most sensitive ways of getting accurate
values of the mass of protein molecules. With the right instruments it
has got such tremendous resolution that you can distinguish individual
protein molecules even though they are in with a whole bunch of others
in the sample.”
In its citation, the Royal Swedish Academy of Sciences said Fenn’s
work has led to “increased understanding of the processes of life,”
quickened the pace of drug development and led to faster diagnoses of
cancer.
Fenn received the news of the award at his home in Virginia, where he
is a professor of analytical chemistry at Virginia Commonwealth University
in Richmond. He shared the award with two other researchers, Koichi Tanaka,
an engineer from Japan, and Kurt Wüthrich, Ph.D., of Switzerland.
Tanaka worked on other applications of mass spectrometry and Wüthrich
used nuclear magnetic resonance to determine protein structures.
“It’s like winning the lottery,” Fenn says. “I’m
still in shock.”
The technique he described in his 1989 paper solved a problem that had
bedeviled scientists since 1912, when mass spectrometry was first used
to analyze small molecules. Mass spectrometry worked only for molecules
that weighed up to 1,000 times as much as a hydrogen atom. Using ESI,
Fenn turned large molecules into smaller ions, without causing them to
decompose. He created charged droplets by spraying molecules with water
in an electrical field. As water evaporated from the droplets, only protein
ions remained. Their mass could be determined by setting them in motion
and measuring how long they took to travel a set distance.
Fenn, who received his doctorate in chemistry from Yale in 1940, returned
to his alma mater in 1967 as a professor of chemical engineering, after
stints in the chemical industry and on a U.S. Navy jet propulsion project.
In 1978, with colleagues in chemistry and medicine, he began the work
that led to the development of ESI.
Fenn left for Virginia in 1994, after his wife’s death and disagreements
with the university over lab space. (His daughter, Barbara Fenn Reif,
retired in December as director of student and alumnae affairs at the
School of Nursing.) He’s still teaching and doing research, concentrating
on the “conformation problem” of proteins. “How they fold
and why they fold and what they fold to are extremely important problems
because they determine what chemical reactions they do,” he says.
“We are trying to pursue that.”
And, of course, his main tool is ESI.
—John Curtis |
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Harrison
Harrison’s father, Ross Granville Harrison, chaired Yale’s zoology
department.
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Elizabeth R. Harrison, M.D. ’26, one of the first women to
graduate from the School of Medicine and pediatrician to three generations
of New Haven children, celebrated her 103rd birthday on November 2.
A medical career seemed a natural choice for a young woman growing up
with a father who did research in embryology. “I was just immersed
in all this,” Harrison says of medicine, during an interview at the
Whitney Center in Hamden, Conn., where she lives. She was the daughter
of Yale zoologist Ross Granville Harrison, M.D., Ph.D., known for developing
an early method for growing animal cells in vitro in the early
1900s. Having been exposed to her father’s work, Harrison had no
qualms about performing her first human dissection in medical school.
“All you did was take a scalpel and move the muscle and isolate it
and report it on the chart. There wasn’t anything to be squeamish
about,” she recalls. “My father had taken us tadpole hunting
and we’d worked with live animals, so I didn’t think anything
of it.”
Harrison was born in Baltimore in 1899. Her German-born mother spoke five
languages, and Elizabeth Harrison grew up speaking German and English.
According to her nephew, Ross Granville Harrison III, Harrison was visiting
Germany on the eve of World War I and found herself trapped there by war
for three years. She returned to New Haven to graduate from Hillhouse
High School, began college at Smith, then transferred to the University
of Chicago.
When asked if she faced prejudice as a woman in medicine, Harrison says
that whatever problems she encountered, she kept to herself. “If
I had shot my mouth off, I never would have gotten anywhere. I was very
reticent about my experiences.” Her nephew says Harrison has spoken
obliquely of feeling ostracized or passed over during medical school and
in her early years in practice, but “as she would say, she doesn’t
like to be a crab.”
Harrison lived above her Bradley Street office. Never married, she maintained
a very busy practice. “She was a spectacular diagnostician,”
her nephew says. “She would take one look at a kid and tell you what
was wrong with him. She had instincts that were bigger than life.”
He says Harrison still saw patients into her 90s. When he took her to
celebrate her 102nd birthday with a dinner at Mory’s, she was not
just visiting a Yale landmark but also returning to her childhood home;
what is now Mory’s was faculty housing when her father was named
chair of Yale’s zoology department, her nephew said, and the family
lived there from 1907 to 1911. Harrison still very much enjoys music (although
she claims she “flunked” piano). She hummed along when a group
of Whiffenpoof alumni sang at the Whitney Center last fall.
—Cathy Shufro
We are sorry to report that Dr. Harrison died on January 5, as this
issue of Yale Medicine was going to press. A memorial service at
Battell Chapel is planned for February 15.
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Suphapeetiporn
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When Kanya Suphapeetiporn, M.D., Ph.D. ’02, finishes her pediatrics
residency in Brooklyn and heads home to her faculty position in Thailand,
she hopes to send some of her best students back to Yale for educational
exchanges. If they do come, it will be nothing new: the link between Yale
and Chulalongkorn University, where Suphapeetiporn is both alumna and
junior professor, has a long history.
It began 20 miles from New Haven, more than 30 years ago. In the late
1960s, Nicholas P.R. Spinelli, M.D. ’44, served as a mentor to a
young doctor from Thailand doing an internship at Bridgeport Hospital,
a Yale-affiliated hospital where Spinelli was director of medical education.
That man, obstetrician Supawat Chutivongse, M.D., went on to become dean
of Chulalongkorn’s medical school in Bangkok. Since then, he and
Spinelli have worked together to bring a dozen of the school’s strongest
graduates to Yale to hone their skills.
Spinelli helped Suphapeetiporn apply to Yale’s doctoral program in
the Department of Genetics, where she did research in cancer genetics.
Suphapeetiporn plans to set up a basic research lab when she gets back
to “Chula,” the university named in 1917 after the beloved Thai
King Chulalongkorn, King Rama V. (His father, King Rama IV, was portrayed
by Yul Brynner in The King and I.) Spinelli met Suphapeetiporn
at the airport when she arrived in 1996, invited her to his home, attended
her thesis presentation and watched her graduate last May. Suphapeetiporn
enjoyed listening to Spinelli’s stories from a career in medicine
that included private practice as an internist, overseeing the Bridgeport
residency program and directing alumni affairs for the School of Medicine.
Reached by telephone after a long night on call at the State University
of New York Medical Center in Brooklyn, Suphapeetiporn says that Spinelli’s
dedication to former students is exemplified by the fact that he’s
kept in touch with her dean at Chula for more than 30 years. “I am
so impressed that they still keep in touch,” she says.
While at Yale, Suphapeetiporn spent most of her time in the lab and the
library, but she also enjoyed New Haven’s first-rate pizza and New
England’s hiking trails. Two years ago, Yale’s community of
Thai students, numbering about a dozen, gained a new member: a colleague
of Suphapeetiporn’s from Chula, Atapol Sughondhabirom, M.D. He is
doing a postdoctoral fellowship in psychiatry, studying the genetics of
drug addiction. Sughondhabirom and his advisors have a grant to train
Thai students in the genetics of psychiatric disorders, further strengthening
the connection between Yale and Chula.
Spinelli says he is impressed that every Thai student he has known has
returned to Thailand. Planning to follow suit, Suphapeetiporn is eager
to get home. “I think,” she says, “that I can do something
useful.”
—Cathy Shufro |
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