It’s 8:15 on a cold morning, and the waiting area for the Women’s Health Center on the eighth floor of the Johns Hopkins Outpatient Center is filling fast—bundled-up women ranging from their 20s to their 60s, a toddler in a stroller, one skittish-looking man. In the buttery early sunlight outside, the skyline of downtown Baltimore glows.
The patients, however, seem oblivious to the view. Their focus is inward. They've been summoned here because they have cervical disease. Among them are a handful of patients of the young, soft-spoken gynecologist Cornelia Liu Trimble, who has set out to find a cure for their disease.
Patient #1: Diane
Diane, a plump young black woman wearing a sweatsuit and stocking cap, slumps in a plastic chair beside the exam table. She studies the floor and licks her chapped lips. Trimble has just peered at her cervix through a colposcope, a vaginal microscope, at a magnification of 40x, and has taken two gasp-inducing swabs of cells from the cervix's exterior surface and canal. Diane's last Pap smear—13 months ago—contained cells indicating a high-grade cervical lesion, a precursor to cancer. But despite two letters, Diane failed to schedule a follow-up exam.
“How come I didn't see you for a year?” asks Trimble. There's a lilt of teasing in her voice, but the bass note is concern. Diane (We've changed the names of all the patients in this article) doesn't answer. Instead, she draws a ragged breath and shakes her head. Trimble's voice softens. “Whatcha thinkin'?”
Diane covers her face with her hands. Trimble lays a hand on her shoulder, and Diane begins to weep, sobs wracking her stout body. Finally she says through the gap between her palms, “Scared it's gonna turn into cancer. My grandmother died of cancer. My uncle died of cancer. My aunt just had a breast removed.” She drops her hands and stares bleakly at Trimble.
|> Premalignant HPV disease: high grade dysplasia.
“Nothing I saw looks like cancer,” Trimble assures her. “This may go away on its own. If it doesn't, I can do a minor surgical procedure to remove it. It'd feel about like what you felt just now when I took those swabs.” Diane nods dubiously. “I'm gonna take care of you. I'm gonna make you well. That's what I do. But you can't go disappearing on me again.”
The fear in Diane's eyes gives way to something that looks like relief. Maybe gratitude. She nods.
Deciding. “I'm gonna come back every time y'all need me to,” she says.
Trimble glances at the chart. “If you keep smoking,” she says, back in a brisk, clinical voice, “you triple the risk that this stuff won't go away.”
Diane looks sheepish. “I'm tryin' to quit.”
“How much are you smoking now?” “I'm down to two cigarettes a day.”
“That's good,” Trimble says. “You save money and you smell better.” She laughs at her own joke. Diane laughs too. A few minutes later, she leaves the clinic, repeating her vow to come back if today's Pap smear proves abnormal.
Over the past seven years, Trimble has seen some 10,000 variations of Diane's cervix and has surgically removed cancerous or precancerous lesions from hundreds of them. As director of the Johns Hopkins Center for Cervical Disease—a center Trimble herself created—she's keenly aware of how many Dianes there are. In the United States, roughly 50,000 women have high-grade cervical dysplasia, the precursor to cancer. Trimble's main concern is dysplasia of the cervix, the cylindrical, muscular portal between the vagina and the uterus. In Baltimore and eastern Maryland—the area where most of Trimble's patients live—the rate of cervical disease is three times the national average. As with many health issues, the brunt of the problem—that is to say, the brunt of suffering and death—is borne by poor women, women tumbling through the cracks of America's health care system.
In developing countries, where regular screening is rare, the problem is far worse. Globally, half a million women—half a million wives, mothers, sisters, daughters—will develop cervical cancer this year. The disease will kill nearly 300,000, making it the third-deadliest cancer among women, lagging behind only breast cancer and lung cancer.
The Sneak Virus
Cervical cancer belongs to an extended family of death, a hundred or more diseases characterized by runaway cell growth. Unlike other cancers, though, cervical cancer is a sexually transmitted infection. Virtually all cases are caused by human papilloma virus, HPV, which is transmitted by sexual contact. A spiky invader that bristles like a microscopic sea urchin or cocklebur, HPV lacks the name recognition of AIDS, but it's far more common, and it's spreading faster. “A 20-year-old woman today,” notes Trimble, “has an 80 percent chance of being infected with HPV sometime during her life.”
In June 2006, a giant step occurred toward reducing those odds: The FDA gave full approval to Gardasil, an HPV vaccine developed by pharmaceutical giant Merck that proved 100 percent effective in clinical trials in preventing high-grade cervical lesions. If, as Trimble hopes, girls are vaccinated with Gardasil before they become sexually active, their risk of cervical cancer could plummet to almost zero. But tens of millions of women in America and hundreds of millions around the world are already infected with the virus. For them, it's too late for Gardasil—but not for the vaccine Trimble is testing.
Once infected with HPV, a woman might be symptom free for years. If she's strong or lucky, her immune system will recognize and destroy the virus, or “clear” it. But HPV is “a sneaky virus,” Trimble says. The strain that causes most cervical cancers, HPV-16, combines with its host's DNA and tricks infected cells into releasing immunosuppressants that coax the virus into looking like “Self” to the immune system's sentinels. It's the virological equivalent of Harry Potter's cloak of invisibility.
The fight against cervical cancer has long been a Hopkins fight. Early studies of the disease were conducted by Richard TeLinde, the world-famous women's physician who became chair of the gynecology department here in 1939. Half a century later, in the late 1970s, painstaking research by Keerti Shah and colleagues at the Johns Hopkins School of Public Health showed that 99.7 percent of cervical cancers are caused by HPV, mostly strains HPV-16 and HPV-18. And finally in 1988, it was Shah's findings that paved the way for tumor immunologist Drew Pardoll to team up with molecular biologist T.C. Wu and begin looking for chinks in HPV's armor.
Wu set out to engineer a batch of mice that would sprout tumors closely mimicking the human progression from dysplasia to invasive cervical cancer. Once he had this mouse model, he and Pardoll began testing for vaccines that could latch onto antigens produced by HPV-infected cells, unmask the virus and call in the immune system's T cells for a search-and-destroy mission. “Like smart bombs or guided missiles,” Trimble says.
The two researchers' experimental vaccines proved powerfully effective. “In a decade, T.C. and Drew cured thousands of mice,” Timble jokes. Meanwhile, millions of women were dying. By December 1997, the researchers felt ready to start on the long slog toward phase 1 clinical trials in humans. But for that, they would need to hook up with a clinician with access to female patients.
“One day, Drew walked in my door,” Trimble recalls. “I had no idea who he was. Here was this guy asking, How would you like to do HPV vaccines with us?” Becoming part of such basic research, she knew, would require years of educating herself about virology, immunology and clinical-trial design. She leaped at the chance.
Trimble spent six years collaborating in the lab with Pardoll and Wu, schooling herself in their research and setting up the infrastructure for testing the vaccine in women. Still, on the spring day in 2004 when she finally stood poised to insert a needle into a 44-year-old woman with a high-grade lesion on her cervix, it was she, not the patient, who was nervous. This would be the first human to receive an HPV immunovaccine. If all went well, this injection could become the shot heard round the world.
Patient #2: Melissa
Trimble's second scheduled patient of the morning, Melissa, is due for a shot in each arm: the second of three vaccine doses she'll receive at one-month intervals. If it works in Melissa as it did in the lab mice, the vaccine will bind to antigens in infected cells, allowing her immune system to spot them and clear the virus.
The trial's nurse, Barb Wilgus, arrives from the oncology research pharmacy in another building with an insulated cooler. A thermometer is tucked in an outside pocket of the bag; a temperature probe nestles beside three tiny glass vials inside the cooler, where dry ice keeps the vaccine frozen. The trial's protocol requires that the vaccine be kept at –30 Celcius (–22 F) until just before use, so there's no chance it can degrade.
At 10:30 a.m., Melissa's appointment time, she still hasn't shown up. If she doesn't appear soon, Barb will need to return the vaccine to the research pharmacy, documenting that its temperature never rose above –30. The vaccine is a precious commodity; any dose wasted would mean one less patient's data. At 11, Barb starts trying to reach Melissa by phone.
At 11:10—40 minutes late—a flustered and apologetic Melissa arrives, explaining that she'd written down the wrong time. Barb checks the thermometer nervously and finds the vaccine's temperature still well within range. She divides the vial's contents—3 milliliters of clear fluid—between two syringes, one for each arm.
With one hand, Trimble pulls down the neck of Melissa's sweater to expose her left deltoid. With the other, she holds one of Melissa's hands. Barb eases the needle in and depresses the plunger. Melissa winces, then laughs nervously. The sequence is repeated at the right shoulder. Later Trimble examines Melissa's lesion through the colposcope. It has shrunk, she estimates, by 80 percent.
“You Look Different.”
Connie Trimble is a classic Asian-American success story. Her parents both graduated from ultra-competitive National Taiwan University before immigrating to New York in the late 1950s. Her father, a protein chemist, did postdoctoral work at the Rockefeller Institute, worked at Brookhaven National Laboratory on Long Island and finally transferred to the National Institutes of Health. Her mother attended pharmacy school in the States. Their firstborn, Cornelia—named for Cornell Hospital, where she was born—taught herself to read at age 2.
Trimble's Hopkins roots run deep. In 1973, 10-year-old Connie Liu took the SAT, as one of the first youngsters to participate in the Hopkins Talent Search. She snagged a near-perfect score. At 13 she was encouraged to enroll—as a sophomore—at Hopkins. Instead, her parents sent her to Phillips Exeter Academy in New Hampshire. “My dad gave me a lecture in the car on the way up, ” she recalls. “He said, ‘You look different. You're going to have to be twice as good as the other kids.'” But instead of feeling pressure at Exeter, she felt immense relief. “It was the most beautiful place I'd ever seen,” she says. “Two weeks after I got there—late September, blazingly beautiful leaves, a riot of color—I was walking across campus and I just laughed out loud, I was so happy to be there. It was this white-boy school, yeah, but it was the first time I'd ever felt normal.”
At Princeton, where Trimble double-majored in civil engineering and international relations, she learned to play an ensemble's worth of instruments—everything from piano to French horn—and discovered her singing voice, a pure, solo-caliber soprano.
Migrating south to Vanderbilt for medical school, she began working in Nashville's inner-city hospitals and was startled by the desperate health problems of the struggling poor—“war-zone medicine,” she calls it. “That's when I knew I wanted to try to make a difference in the world.”
During her med school Ob/Gyn rotation, Trimble began dating one of her residents, Edward (Ted) Trimble, a Baltimorean descended from a long line of Johns Hopkins physicians (see page 19). They married in 1988. The Trimble last name, she soon realized, carried special meaning at Johns Hopkins. ”Ridge Trimball passed away before I met his youngest son,” she says of her late father-in-law, a 1926 School of Medicine graduate and revered Hopkins neurosurgeon. But despite the fact that I look so different from him, people treated me like I was one of theirs.”
Medical school planted doubts in Trimble. “I wasn't sure I was supposed to be a doctor,” she says. “I was so shy.” After taking a year off to earn a master's from the Johns Hopkins Writing Seminars, her course became clear. “Medicine was a more quantifiable way to make a difference than writing.” And the patients she most wanted to cure were women. “I wanted to make it safer for them somehow.”
In 1991, after a pathology internship and residency at Cornell, Trimble returned to Hopkins for a fellowship in gynecologic pathology and then a residency in Gyn/Ob. Today, she is a diplomate of both the American Board of Pathology and the American Board of Obstetrics and Gynecology and holds faculty appointments here in Gyn/Ob, oncology and pathology.
Trimble finds herself increasingly in the limelight. She's been called the poster girl for cancer research at Hopkins, and indeed, she graces a movie-size poster highlighting how the Maryland Cigarette Restitution Fund has supported her cervical-cancer research. But she chafes at all the attention and sees herself as “a nerd—a nerd who gets my book bag caught in the elevator door.”
But her colleague Tracy Stierer, an anesthesiologist who works with her in the OR, calls her a “phenom. She treats very complex patients, and she is compulsive about their care. She's the total package.”
Martin Abeloff, director of the Kimmel Cancer Center, calls Trimble unique, “because she brings together a magnificent social conscience—a concern about societal issues like health care for these low-income women who are so many of her patients—and a real aptitude for medicine and science. She is,” he says, “clearly a rising star.”
“Everybody at Hopkins is smart enough,” says Drew Pardoll, who walked into Trimble's office eight years ago and invited her to join the HPV project. “But not everybody has her rapport with patients, her team-building skills, her vision and resolve. She knows where she wants a program to go and gets other people excited about playing their part in making it happen. T.C. and I did the key immunology, but the science is meaningless unless it gets into patients. What Connie's doing gets it into the patients.”
Patient #3: Katherine
Katherine* is a New York law student and an athlete, a young woman of discipline and iron will. She's also a fighter. In the stairwell of her apartment building, a man pressed the blade of a box-cutter to Katherine's throat and demanded that she take him to her apartment. Instead, she fought. As she struggled, he cut her mouth and hands and slashed her upper left arm before giving up and running away. Months later her smile is perfect, but a four-inch scar still angles pinkly across a tanned tricep.
|> Drew Pardoll and T.C. Wu, who developed the vaccine.
Katherine brought the same courage to her battle against high-grade cervical dysplasia. When her hometown gynecologist said she needed a cone biopsy that would remove a substantial section of tissue from the face and neck of the cervix, Katherine chose to fight. “I Googled cone biopsy on the Internet,” she recalls, “and I read that it could damage my cervix and make it difficult to get pregnant. I was in graduate school at the University of Maryland at the time, so I searched the Johns Hopkins Web site for specialists in cervical dysplasia. I found Dr. Trimble and made an appointment.”
Trimble's colposcopy confirmed that the cervical lesion was high grade. She told Katherine it had to be removed.
“I was very upset,” says Katherine. “I want to have a family someday, and I didn't want to degrade my cervix. I asked if there was any alternative to the surgery.” Trimble described a 15-week study she'd done in which—even without treatment—30 percent of patients experienced spontaneous regression of their cervical lesions, evidence that their immune systems succeeded in detecting and clearing their HPV infection. “That shows their immune system is right on the cusp of being able to clear this virus,” explains Trimble, “so our hope is that the vaccine can give the immune system that extra bit of help it needs. ”
She told Katherine about the clinical vaccine trial, which had begun a year before, though she stressed that there was no guarantee the vaccine would help. Katherine leaped at the chance to enroll. “I wanted to do it not just for myself,” she says. “Every woman who does this is helping advance the research, helping move the vaccine along.”
Katherine received three injections of vaccine, at the highest dose level, at four-week intervals. She's a second-year law student now; in order not to miss sessions of her afternoon Contracts class, she scheduled her Hopkins appointments at 8:30 a.m., which meant catching the train from New York by 5 a.m. She makes the return trip on the “Chinatown bus: 20 bucks from Chinatown in Baltimore to Chinatown in New York.”
At each appointment, Trimble rechecked Katherine's lesion, showing her on a video monitor. Three months after the first injection, the lesion had shrunk noticeably. “It was at least 40 percent smaller,” says Katherine. Trimble waited six more weeks, in hopes the lesion would continue shrinking, before removing it. “By then it was even smaller,” Katherine recalls, “like a tiny dot. ”
That was four weeks ago. Today, Katherine is back for her post-op checkup. Trimble greets her with good news. “Your high-grade lesion went away,” she says.
The words take a moment to sink in. Slowly the perfect smile spreads across Katherine's face. “It did?”
Trimble nods. “You had an itty-bitty low-grade. Your high-grade was gone.”
“So we did good!”
“We did good.” The women exchange a high five.
Once Katherine is settled on the exam table, Trimble swings the colposcope into position, then scoots in for a look. “Oh my god, it's normal,” she says. She switches on the video monitor to show Katherine. “This is as close as you can get to what God gave you,” she tells her. For comparison, she calls up images from the prior three visits. The sequence of images is a study in shrinkage. “Now I'm gonna take a picture of a perfectly normal cervix,” says Trimble, “which is so cool.”
Five minutes later, doctor and patient join Katherine's mother and younger sister in the clinic's waiting room. Trimble lets Katherine relay the news about the lesion's regression. Mother and daughter hug. Then Katherine gives Trimble a farewell hug. Katherine's mom hugs Trimble, too. Her eyes are red-rimmed. Brimming. Shining. “Thank you, doctor,” she whispers. “Thank you.”