The double life of Christopher Hug

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.”

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.”

This article first appeared in the Spring 2005 issue of Paradigm magazine.