The double life of Christopher Hug
Splitting their time between lab and clinic,
Whitehead physician-scientists bring research and reassurance
to patients
Breathing can get a little competitive in the fourth-floor
pulmonary clinic at Children’s Hospital in Boston.
In an exam room, a lanky 15-year-old boy, his lips around
a plastic nozzle, sucks air through clear plastic tubing
hooked up to a laptop computer.
“Deep breath,” coaches the pulmonary–function
technician, watching the air flow measurements on the
computer screen. “Bigger, bigger, bigger!”
A pause. “Push, push, push, push!”
The boy exhales every last bit of air, red in the face.
Test over, the boy draws a normal breath and immediately
doubles over in a fit of thick coughing. He recovers,
and checks out his scores on the screen. Then he convinces
the technician to repeat the test and try for a better
result, as if it were a fifth attempt on a computer
game.
His doctor talks to the boy’s mother and looks
over the test results from last year. The cold end of
a stethoscope draped around the doctor’s neck
partially obscures the blue cursive stitching on the
white lab coat that spells out “Christopher Hug,
MD, PhD.”
“You would be hard pressed to say he has cystic
fibrosis, looking at these curves,” says Hug,
pointing out how closely the graphed air volume and
velocity match those of an average healthy teenage boy.
Some people with cystic fibrosis, the most common lethal
inherited disease, still die in their teens. But better
nutrition, antibiotics and mucous-clearing medicines
have helped many live well into their 50s and 60s. Yet
for all the advances in understanding the genetic mutations
and molecular mechanisms of the disease, a cure is still
elusive, and a lung transplant remains inevitable.
Nearly every day, researchers announce important new
discoveries with the potential to alleviate much human
suffering. In fact, advances in basic science are piling
up faster than other researchers can figure out how
to apply that knowledge to disease.
The future of medicine depends upon physician researchers
like Hug to close that gap. “In order for medicine
to progress there is need for physician-scientists who
understand clinical medicine and for basic scientists
who can effectively communicate and collaborate with
them,” said Irwin Arias of the Tufts University
School of Medicine in a report published last year by
the National Research Council, “Bridging the Bed-Bench
Gap.”
"In the clinic, where you are managing chronic illnesses, you can lose sight of the bigger
picture of how to prevent or cure diseases." - Christopher Hug
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Between bio and medicine
Hug, a postdoctoral fellow in the Whitehead laboratory
of Harvey
Lodish, is in the final stages of training for a
career designed to bridge the two worlds. It has been
a long haul. Hug graduated from college 18 years ago,
and at age 39 looks forward to establishing his own
lab soon, while continuing to consult with patients.
In the lab, where Hug spends most of his time these
days, the typically tedious, laborious and faltering
pace of research can be disheartening. In the hospital,
where Hug spends Mondays in the outpatient clinic and
four weeks a year in the inpatient wards, it can be
heartbreaking.
Down the hall, an anguished father asks Hug if his 17-year-old
son, paralyzed by a mysterious infection of the spinal
cord three years ago, can sign up for the stem cell
experiments that were supposed to save Christopher Reeve.
The boy can wiggle his toes and move his hands enough
to spin his wheelchair in playful circles. Today he
breathed for 15 minutes on his own without his ventilator.
But healing has been slow, and stem cell research is
still far from offering even an experimental option.
“In the clinic, where you are managing chronic
illness, you can lose sight of the bigger picture of
how to prevent or cure disease,” says Hug. “In
the lab, it’s good to be motivated by clinical
work.”
Hug ducks out of the examining room to renew the usual
medications and order the appropriate lab tests.
The science behind the prescriptions he writes reaches
back more than 60 years. In 1943, a Danish and a U.S.
biochemist shared a Nobel Prize for the discovery that
vitamin K, named for the Danish spelling of “coagulation”
(“koagulation”), could prevent severe internal
hemorrhaging in chicks.
Antibiotics for the frequently life-threatening lung
infections in people with cystic fibrosis also kill
the bacteria in their guts that produce about half the
daily supply of the nutrient. Low levels of vitamin
K, combined with lung damage, can lead to lethal pulmonary
bleeding, Hug says.
To complicate matters, people with CF have trouble digesting
dietary fat, including the fat-soluble vitamins A, D,
E and K. So Hug also prescribes pancreatic enzymes to
help their bodies absorb the supplements.
Another medication, DNase, is a more recent product
of modern science. Discovered by veterinarians in the
1970s and rediscovered by medical researchers in the
1980s, DNase became the first new drug for the management
of CF in 30 years when it was launched by Genentech
in 1994. Delivered through an inhaler, it cleaves the
DNA of dying cells in the lungs of people with CF, helping
to thin the thick mucous that builds up in the airways.
Respiratory failure accounts for about 90% of CF deaths.
The scientist in Hug has idly wondered how DNase could
be so effective. In his graduate research, Hug used
DNase in test tube experiments to bind to and count
actin filaments, the infrastructure of cells in most
organisms. Actin, which is also present in the dying
lung cells of people with CF, can interfere with the
ability of DNase to degrade DNA.
But now, the doctor’s chief concern is that the
boy take the necessary 15 minutes every morning to use
the aerosol device that delivers the life-extending
drug. This and other medicines to fight inflammation
and help clear the mucous can buy decades of life. A
lung transplant can promise only two to five extra years
for the 50% of patients who survive the operation. “He’s
used to coughing,” Hug points out. “He may
not appreciate that [the medication] will slow down
the decline in lung function we know will happen with
time.”
Hug finishes the scripts and grabs the notes on his
next two patients, a four-year-old boy whose asthma
flare-up resolved itself in the long time it took to
get an appointment at the clinic, and a 15-year-old
whose mother was worried about a pain in his chest that
a cardiologist had ruled out as a heart problem.
Fields of focus
Doctors and scientists are trained to approach biomedical
problems in very different ways, observes Bradley Bernstein,
MD, PhD, a pathologist at the Brigham and Women’s
Hospital in Boston and the recipient of a Howard Hughes
Medical Institute physician postdoctoral fellowship
in a chemistry lab at Harvard University.
“In medicine, it’s breadth,” Bernstein
says. “You need to know a little about everything.
It’s completely the opposite in science. You need
to be the world’s expert on an incredibly narrow
area.”
A day in the clinic varies from a day in the lab in
other ways, says pediatric neurologist Annapurna Poduri,
MD. She specializes in childhood epilepsy and is spending
the year in a neurobiology laboratory at Boston’s
Beth Israel Deaconess Medical Center testing the hypothesis
that localized genetic changes result in the brain malformations
that are observed in many patients with epilepsy.
“The clinic is more structured,” Poduri
says. “You have skills, an acknowledged competence,
immediate feedback from your patients, and a sense of
closure at the end of the day. In the lab, though, while
you have the freedom to organize your own time and design
your own projects, you are working without knowing the
results of your experiments for long periods of time.
You may not have a sense of conclusion for weeks or
months.”
Poduri and Hug met during their residency training at
Children’s Hospital and married two years ago.
Coincidentally, Hug’s father and mother also met
and married when both were working at Children’s
Hospital 45 years ago.
On top of the challenges of a double career in science
and medicine, physician-scientists also may be juggling
the demands of dual-career families. “Many MD/PhDs
marry another MD or PhD, because that’s the only
type of people you see when you’re training,”
says Robert Flaumenhaft, an assistant professor in hematology
at Beth Israel Deaconess.
Flaumenhaft is married to a clinical endocrinologist.
When it is time to pick up the kids from school, they
call each other to determine who is more desperately
behind in his or her work. Because Flaumenhaft is concentrating
on his research these days, it is often easier for him
to leave his test tubes than for his wife to leave her
patients.
One day, stuck in traffic on the way to the zoo, with
her parents driving and their three children sitting
on their parents’ laps in the backseat, Flaumenhaft
and his wife came up with an idea to collaborate on
a research project to analyze molecular signaling in
the blood platelets of patients with diabetes. The grant
for the project was funded.
Lives of a post-doctor
It is a light morning in the pulmonary clinic. Hug’s
last patient ends the morning on an upbeat note. The
energetic four-year-old was born prematurely at 23 weeks
weighing only one pound, his mother explains. Today,
the scale reads 34 pounds with clothes. He breathes
enthusiastically while Hug listens with his stethoscope.
The boy’s abdomen shows the scars of several tubes
that once sustained his life when he was an infant.
The lungs sound good, and Hug prescribes a different
dosing regimen in anticipation of weaning him off his
lung medication soon.
“When you pick up a baby, there is a strong, hands-on
incentive to study the problem,” Hug says.
He rushes downstairs to scavenge leftovers and catch
the end of the lunchtime talk given today by Poduri.
After lunch, Poduri and Hug compare their schedules.
Hug has an hour of dictation ahead of him. Then he will
meet with an asthma researcher to discuss a basic science
project that may tie together Hug’s pulmonary
clinical expertise with his Whitehead research on molecular
signaling in fat cells, by way of related inflammatory
processes.
Hug first met Harvey Lodish at a pool party hosted by
Lodish’s daughter, a fellow resident-in-training
at Children’s. Two years later, he chose the Lodish
lab for his postdoctoral fellowship because he wanted
to work with a preeminent cell biologist.
His research is on adiponectin, a hormone released
by fat that was discovered in the Lodish lab a decade
ago (see “Fat chance”).
Since then, researchers have linked low levels of the
hormone and the location of its genes to cardiovascular
disease, diabetes, obesity, high blood lipids and hypertension.
Large doses of the protein can reverse insulin resistance
in mice and cause obese mice to lose weight.
Last June, Hug reported discovery of a receptor for
the protein, located on cell surfaces in blood vessels
in the heart and muscle tissue. He continues to search
for other receptors that will help scientists understand
how the hormone works and how to develop a molecule
that can mimic its protective effects in patients.
At this stage, there is little connection between Hug’s
basic science and his clinical work, but Hug is confident
that his life in the clinic and the lab will converge.
After all, making novel connections is a main point
of the dual MD/PhD training, says Howard Hughes investigator
Daniel Goldberg, MD, PhD. Goldberg heads the country’s
largest physician-scientist training program at Washington
University Medical School in St. Louis, from which Hug
graduated nine years ago.
While there is a cultural gap between doctors and scientists,
“painting it in black and white is an exaggeration,”
Goldberg says. “Some people can move between them,
even if their ways of thinking are different. The best
clinicians don’t just treat the disease; they
treat the patients. PhDs who do not have a full appreciation
for the human body and everything that can go wrong
may not realize when something comes up in research
that could be important medically.”
A handful of other Whitehead researchers also are bridging
this gap. Several of these work at the Lodish lab, which
has a long history with clinician/researchers. They
include Aleksandar Babic, a clinical pathology resident
at Brigham and Women’s Hospital; Shilpa Hattangadi,
a pediatric hematology oncology fellow at the Dana Farber
Cancer Institute and at Children’s; and Andreas
Herrlich, a renal fellow at Massachusetts General Hospital.
Tonight, Hug will be back among them at Whitehead, working
with the lab’s fluorescence-activated cell sorter,
which uses light to sort cells based on their size and
color.
“If I work as fast as I can in the clinic, I can
help 20 patients a day,” Hug says. “But
if I learn something in the lab that can be used to
develop a new treatment, it will help hundreds of thousands
of patients.”
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