Princeton University - Council of Science & Technology

POPE PRIZE

Essay 1
Should I Give my DNA away?"
Lara C. Atwater

Essay 2
Excerpts from novella: "Dreams of Ingrid Capac-Nolasco"
Nicholas R. Lilly

Essay 3
From Greening to Curing: Cornelia Liu Trimble, M.D.
Monica H. Wojcik

Honorable Mention
Neir Eshel

From Greening to Curing: Cornelia Liu Trimble,M.D.

I first met Connie Trimble by way of a professor who taught both of us, Connie in ’84 and myself in ’05 – a writing teacher with a knack for introducing me to friends and former students without informing me of their prestige. On her first return to Princeton since graduation, Connie had sent me an email - “Give a yell,” she said, if I was interested in meeting. I eagerly yelled. “Don’t go looking for a Trimble phenotype,” she admonished in her reply. “I don’t know if John told you I am Chinese (ABC).” He also did not tell me that she is in the midst of developing the first therapeutic vaccine for Human Papillomavirus (HPV), and has founded an HPV screening center, or that she has been called “a rising star,” “a phenom”, and has achieved “headliner status” for her work on cervical cancer. In Princeton we talked less about medicine and disease than we did about writing. Now, a month later in Baltimore, things pick up where they left off. “Writing reflects the way you think,” Connie explains, in her office at Johns Hopkins University School of Medicine, where she holds triple appointments - in the Oncology Center, the Department of Pathology, and the Department of Gynecology and Obstetrics. Both good thinking and good writing are crucial for receiving the coveted grants through which top-level research can be measured: Connie is currently supported by five federal grants worth millions of dollars, and another grant is on the way. Two are SPORE grants, designed to recognize research applicable to the treatment of human patients as opposed to basic research most therapeutically beneficial to the nation’s rodent population. Since only ten percent of grant applications are approved nationwide, Connie states matter-of-factly, “You have to write the most beautiful writing in the world to get funded.” In this world, beauty is in simplicity. ‘It’s very Hemingwayesque.” She remembers well an exercise called “greening” in John McPhee’s writing class at Princeton. “He’d give us a page of prose: ‘Green five lines,’ he’d say.” This meant that the writing students would have to reduce the piece of writing, by a commonly-known author, by five lines without losing any content. They’d start with the Gettysburg address, an easy green. “For Hemingway, it was ‘Green two,’. And it was hard.” Connie pauses and smiles. When writing a grant, Connie is greening Hemingway, culling already spare verbiage for the most important points, whittling the verbal flesh down to skeletal form. “The data has to speak for itself,” Connie says. “Never write ‘It’s important’ or ‘It will be interesting.’ Make readers think they thought of it themselves.” Spending time with Connie Trimble does not make me wonder why a scientist should care about writing, but, rather, if it is even possible to be a scientist without being a writer. “If you don’t know how to write, you can’t…” Connie trails off and searches her desk, handing me a page printed on both sides in Arial font – even serifs are superfluous to this text. “I bet you could understand this.” It is a grant application for Connie’s next vaccine investigation. Vaccines can be prophylactic, administered to prevent disease, or therapeutic, designed for patients who are already infected. Connie works with therapeutic vaccines. Her vaccine therapies are rooted in basic immunology: the human immune system operates via search-and-destroy: recognize foreign invaders, or “non-self” cells, and destroy them. “But HPV is sneaky,” Connie explains, as she pulls up a PowerPoint file on her computer, and starts clicking through the slides. “I’m such a nerd,” she smiles happily. “That’s HPV.” HPV is a spherical sunburst, a molecular cocklebur that looks as though it would be sneaky. The most virulent strains of this virus, HPV 16 and HPV 18, combine their own DNA with that of the infected human host’s cells to prevent them from identifying themselves as “non-self”, thus rendering the virus unrecognizable to the immune system’s guerilla warriors. Two Hopkins Ph. D. scientists, Drew Pardoll and T.C. Wu, discovered a way of making HPV visible. Normally, foreign or infected cells display molecules called antigens to identify themselves as “non-self” and tag them for destruction by the immune system. Pardoll and Wu engineered a DNA segment whose product in host cells would not only alert the immune system to recognize HPV antigens, but also send out “danger signals”: warning the host’s immune system to search out and destroy those cells presenting the HPV antigens. When this DNA was injected into infected mice, it was able to activate the immune system that should have recognized and cleared out HPV-infected cells in the first place. Connie joined them to help turn their scientific success story into an actual therapy. Research suits her well. “I like sitting,” she says. “When I was little I’d sit and rearrange my baseball cards by league, by team, by position…I’d keep rearranging.” Now Connie sorts through slides of tissue samples, looking at the patterns. “Now I have really wonderful nerd-friends,” she says. This team of two Ph.D.s and an M.D. has been referred to as an “unlikely trio.” “Yeah, we’re crazy,” Connie says, laughing. Connie laughs often when discussing her work, not because she takes it lightly or finds humor in human papillomavirus. Her laughter expresses the exuberant joy she finds in her work as in other things that she loves. She looks around her desk. “I can’t find my pin. It says ‘If I were a mouse, I would be cured.’ I tease Drew about that all the time.” The point of the pin, however, is not to be taken lightly – the point that clinical practice lags behind scientific progress, that it takes years for a discovery such as Pardoll and Wu’s to be translated into something that will help patients. Pardoll and Wu worked on mice for years before publishing their first paper on an immunological vaccine in 1994 and Connie joined them 1997. The first injection was performed in 2004, more than a decade after Pardoll and Wu established the mouse model. In a scientific community weakened by fractionated forces, it is unfortunate that Ph.D.s and M.D.s have become unlikely bedfellows. “It’s all about the hot, hot science,” Connie says. “Physicians who treat patients are like second-class citizens.” It is much harder for clinical physicians than laboratory scientists to publish the “sexy paper,” she goes on, growing agitated with excitement. “Basic research has controlled situations, in-bred mice. Do your experiment, measure the response. People are a damn mess. They’re out-bred! They sleep with people! When I see a patient the experiment’s already done! I don’t ask people to come here and I’ll give them cancer, it’s already done!” Since there are so many variables that can affect clinical outcome in human patients, in this chaotic system “if you actually see a pattern, and it correlates to clinical outcome, it is very likely to be real. It is very likely to be important.” One pattern that Connie has already found was that in a group of nearly 200 women with high-grade HPV lesions, a precursor to cervical cancer, one-third spontaneously regressed – that is, healed on their own. It was this discovery that strongly suggested to Connie the potential power of an immunological vaccine for this disease: if so many women can cure the infection on their own, there must be many women on the cusp of spontaneous regression who need only an additional push. Her vaccine provides the push. Although clinical trials have been extremely encouraging, showing, after vaccination, an increased immune response leading to the clearing of lesions, Connie’s investigation never stops. Connie pulls out various slides, displaying slices of stained human tissue one-cell thick, each like a gangly brick-wall-patchwork of cell membranes enclosing black spots (cell nuclei). Of one, she says, “I call this ‘the Wall’.” Depicted is a cross-section of cervical tissue, clearly marked with HPV lesions. There are also lymphocytes, circulating cells that work for the immune system destroying foreign invaders. “But do you see this? They stop right here!” The spread of blackened lymphocytes, stopping at a certain point in the tissue suggests an invisible wall. Something is suppressing the immune system, preventing its fighters from attacking the lesions. Connie’s therapeutic vaccine would do no good for this patient. Her next project, therefore, is to combine the vaccine with another reagent so that not only will the HPV be detected by the immune system, but the HPV can also be reached and destroyed. Of her patients, Connie says, “People are scared to come see someone like me,” bowing her head slightly. The slides on her desk are samples taken from such patients. “They see me when they’re already infected, and they’re scared.” Cervical cancer is the second leading cause of cancer-related death in women around the world, yet it is one of the easiest to cure. A simple test, the Pap smear, detects in the cervical tissue high or low-grade lesions (termed cervical dysplasia) that are the hallmark of HPV. Asymptomatic in nearly everyone, HPV is not uncommon. “You basically get it as soon as you have sex, and everyone’s having sex!” She gestures to a chart showing the rates of sexual activity among children: many report having had four sexual partners while still in high school. By the age of twenty, a woman today has an 80% chance of being infected with HPV at some point in her life. Once detected, the lesions are carefully tracked. Surgery or radiation therapy are the current options for treating those who do not clear the infection on their own. Connie’s vaccine could replace both. Yet developing a therapeutic vaccine is only half the battle, because the vaccine is effective only in the early stages of HPV-related cervical cancer. The most important thing is regular testing. “People just don’t look,” Connie laments. “They don’t go down there.” Connie Trimble is the founder and director of the Center for Cervical Dysplasia at Johns Hopkins, established to address Baltimore’s cervical cancer problem. In Baltimore, as with many urban areas with a high concentration of low-income residents, the rate of cervical cancer is three times the national average. The center is especially useful for targeting minority patients, low-income patients – the patients who “fall through the cracks,” as Connie says. She once studied the prevalence of HPV in women who were inpatients at the Johns Hopkins Hospital, half of them non-white. She found that these women were twice as likely as non-hospitalized women to be infected with HPV. “Some people said we just showed that sick people are sicker,” Connie says, but they missed the real point of the paper: the targeted and efficient coverage resulting from testing people who are already at the hospital. “I like that paper, that’s a policy paper,” Connie says. In the path towards eradicating cervical cancer, “getting people into screening is the rate-limiting step.” This is a disease of the poor and disenfranchised, and Connie is one of their greatest advocates. “It’s all about making a safer place,” she says. “In more ways than one.” Cornelia Liu came to Princeton as a civil engineer. “I just did it ‘cause I thought I had a math gene,” she explains with a smile. Born to two Chinese immigrants (hence the ABC for American-Born Chinese), she was named Cornelia for the Cornell University medical center in New York City, where she was born. She attended Phillips Exeter Academy in New Hampshire, where she was happily surrounded by “nerds”. Princeton was different: she found classmates “for whom other things were important.” By senior year she was bored with engineering, and wrote her senior thesis advised by Professor Uwe Reinhardt in the Woodrow Wilson School of Public Policy and International Affairs, earning herself a double-major. “They didn’t know what to do with me,” she says of the Civil Engineering Department, “They said, ‘Oh, Reinhardt’s really smart. Do whatever he says.’” Connie used mathematical modeling to prove that a 1980 report by the Graduate Medical Education National Advisory Committee (GMENAC), which predicted a “physician glut” – namely 70,000 excess physicians by the year 1990 – was “essentially, wrong.” Smiling wryly, she adds, “We proved it was an assumption about how white guys practice medicine.” Connie was not always certain that she herself would practice medicine. “Did I ever tell you I was rejected by Columbia twice?” she adds, laughing. After her first rejection, she received notice that Columbia had had a change of heart, and Columbia offered her an interview. After the interview, she received a second rejection letter. Connie Liu went to Vanderbilt, where she met her husband, Edward Trimble, and was married before beginning her first residency in Pathology at the medical college of Cornell University – her namesake. Connie Trimble’s first degree from Johns Hopkins was a Master’s in writing. When Pardoll and Wu were just beginning to cure mice, Connie was elsewhere at the university, writing a series of stories from her medical-school days in hospital wards. She described an autopsy performed on one of her patients, during which Connie held the uterus in her hand and felt as though she were holding the woman’s soul, the seat of life. A piece entitled “Tyrone” described a young boy brought to the hospital, ostensibly for choking, who was later found to have suffered abuse so severe that his ribs were cracked, his brain was bleeding, and his liver was split in two. Her observations in these stories are direct and incisive, and her writing does not force the story forward, but lets the experience speak for itself. Already enthralled with pathology, she writes of the “spare truth immortalized” on slides of tissue samples, like those that sit on her desk today. She notes the precise descriptive skills of the pathologist – greening at it’s finest. She may as well be speaking of her own writing, where hardly a sentence is wasted. Connie is in her element at Johns Hopkins, an institution valuing both dedicated physicians and “hot, hot science” to an extent that other institutions do not. It is a place that has amassed a “density of wacky-ass smart people”, free from the oppressive hierarchy characteristic of many medical schools. In her office, Connie sits at the inner elbow of two perpendicular desks. A ceramic jar near her two computers reads: “Ashes of Problem Patients.” The desk also houses her CD collection: Rod Stewart, Joni Mitchell, Annie Lennox, Prince, and friends. Connie has noticed my interest in her music collection. “Rolling Stones when I’m in the OR,” she contributes. She loves the operating room. “I love curing,” she says with a shrug. Connie is in a class of her own – least of all because she is one of only fifteen physicians nationwide in her field. She picks up a tiny glass vial. The first time I saw Connie was on the cover of Promise and Progress, a Hopkins publication, in which Dr. Trimble stares at the reader, with her unassuming frank gaze and a wry smile, holding a vial the size of a peanut between two fingers. Dozens of these vials now line a shelf in her office. “The NIH took so long to make these, it seemed a shame to throw them out.” She hands one to me. “Want one?” Will it break? “Nah,” Connie says. “An elephant could step on it.” The vials once contained vaccine doses used for her clinical trials, which Connie is conducting without support from a pharmaceutical company, a situation almost unheard of in drug development. “I am not in bed with the private sector!” she declares. The money to treat the thousands of patients required for a phase III clinical trial comes solely from grants, which, often enough, she will sleep in her office to finish. This self-proclaimed “shy” doctor says, with a shake of the head: “Damn it, nobody tells me what to do!” Connie knows that pharmaceutical companies are after more than increased health. They have backed out of cervical cancer partnerships before, since cervical cancer patients are typically not wealthy. She remembers what Uwe Reinhardt once told her: “Some are more interested in doing well than doing good.” In a video about the promise of cancer research, produced by Johns Hopkins, Connie speaks of making cervical cancer a history lesson, like polio. Just at the thought of it, she is consumed by excited, girlish laughter. Here in her office, Connie pulls out a notebook. “I’m like Harriet the Spy,” she says, reading her note on the three greatest health contributions since the 1940’s: sanitation, antibiotics, and vaccines. “Our parents are the first generation where they think it’s their birthright to see their grandkids.” She laughs in amazement. “I feel lucky, I really believe in what I do.” As I leave Connie Trimble’s office, a woman in a business suit walks in, wearing a pin that says “Cancer Sucks”. Connie’s eyes light up. “Hey! I like your pin!”