The IV bag empties its last drips into Betty Mahoney's arm, and a buzzer beckons a nurse to her bedside.
"I think this one is done," Mahoney offers. Mahoney only has a couple more hours to go. She's in the 22nd of a 24-hour overnight infusion of trabectedin, a chemotherapy drug approved in Europe for the treatment of advanced softtissue sarcoma—but not yet endorsed by the U.S. Food and Drug Administration.
That's why Mahoney is here, in this hospital bed at the University of Iowa's Institute for Clinical and Translational Science, why she's traveled from Mount Pleasant to Iowa City every three weeks since the trial began last March. Why she dares to hope at every follow-up scan that her tumor has shrunk or at least not grown.
If her fate must include cancer, then she's at least glad to be in this place with these kind and compassionate caregivers; not only because she wants to buy more time for planting vegetables in her beloved garden and turning them into soup in her cozy kitchen, but because, like so many people, she wants to be part of something bigger than herself.
This drug she's permitted into her body for some ten months now shows real promise for sarcoma patients who have not responded well to other treatments, patients who need and deserve other options. If all goes well in the nationwide trabectedin trial, including at the UI site, the drug could soon achieve FDA approval and appear on the U.S. market for wider distribution.
Betty Mahoney is here to perhaps save a life, even if it's not her own.
"I'm no martyr," she says in her typical straight-shooter fashion, adding that cancer took the lives of both her father and mother. "So I don't want you to think I'm doing all this just for the cause...because obviously it helps me, too. But I would like to see something happen to cancer."
While Mahoney views her role with genuine humility, UI researchers such as Joel Kline, 93F, 05MS—director of the institute's Clinical Research Unit—and Mohammed "Mo" Milhem, assistant director for multidisciplinary research at the Holden Comprehensive Cancer Center and lead investigator in the UI's trabectedin trial, don't hesitate in their praise of her contributions to scientific advancement.
"The people who volunteer for these studies are medical heroes," says Kline, in the midst of his own groundbreaking asthma trial. "The human aspect is so important—we need to study real disease and real medicine in real people."
At the heart of science lies humanity; new innovations from superior minds combine with everyday people to press onward toward a greater good. The best ideas, the best medicine, and the best labs mean little without people willing to volunteer their bodies and their time and assume certain risks. Only then can life-changing discoveries emerge.
"If you come to my office, you will find a wall with pictures of people whom I consider my heroes," says Milhem, who devotes his time to clinical studies of treatments for complex, difficultto- treat melanoma and sarcoma tumors. "My patients, they teach me. They add to the science. And when new knowledge comes out, I consider it theirs."
Such discoveries are happening not only at UI Hospitals and Clinics, but across the University of Iowa campus. Not only in the medical field, but in liberal arts, law, psychology, and in other disciplines that influence, shape, and decipher the human experience.
According to the UI's Human Subjects Office, some 2,000 ongoing, campus-wide projects involve human participation. Every single one channels through this office and receives some level of review—from a quick approval to full vetting by an eight-member institutional review board. In 2006, in support of this critical aspect of research, the UI established the Institute for Clinical and Translational Science (ICTS)—one of only 60 institutions in a national consortium to improve biomedical research.
Over the past few years, the ICTS has added more staff, space, and resources to help UI researchers facilitate their projects, reducing the time it takes for discoveries to move from laboratory bench to patient bedside. Such resources include Kline's Clinical Research Unit—20,000 square feet of space in UIHC's Boyd Tower designed to meet the specialized needs of clinical investigators, from inpatient facilities and outpatient meeting rooms to areas for collecting samples and monitoring vital signs.
Although many UI researchers choose to conduct their studies independently or already have necessary support from industry-sponsored trials, Kline and his colleagues hope to spread the word about the institute's resources. Of those 2,000 diverse projects across campus, the institute supports at least 100 each year—a number Kline would like to see grow.
On a chilly December afternoon, Susan Griffith sits in an outpatient suite at the ICTS, just around the corner from the room that Mahoney left the week before. She blows into a tube that measures and records her lung function. Earlier in the month, she'd begun her role in a clinical trial to assess the long-term benefits of a revolutionary new asthma treatment that Kline has shepherded to FDA approval.
Partially sedated and with a bronchoscope down her throat, Griffith watched wordlessly via a computer monitor as doctors gently warmed the inside of her lungs to decrease the thickness of smooth muscle lining inside her airways. Although back at work at the UI Alumni Association the next day, she suffered from the aftermath of the procedure, coughing and wheezing heavily for more than a week. She kept her rescue inhaler close by, ready to take one of the many daily doses, along with a heavy course of prednisone to help her recover from the procedure.
Griffith's first asthma attack struck one summer day when she was 21 years old and helping paint a barn near her Crawfordsville, Iowa, hometown. She doesn't know whether dust from the corn harvest or farm chemicals in the air brought on the attack, but she vividly remembers the panic of not being able to breathe later that evening. She sat on her parents' porch and gasped for air.
She recalls, "They took one look at me and said, 'We're going to the ER.'"
Since then, Griffith's considered herself a mild asthmatic, managing her condition reasonably well with the typical corticosteroid treatments. But a couple years ago, she participated in a UI asthma study that revealed the truth about the severity of her disease. When this latest research trial came up, she knew she had to try it. Although the Alair bronchial thermoplasty procedure has proven safe and effective, with a 75 percent success rate in patients, the thought of such an invasive treatment was still daunting—despite the sheaf of informed consent documents she received that clearly set out the potential rewards and risks of the treatment, what exactly was involved in the trial, and the fact that she could withdraw at any time.
In the end, the potential life-changing benefits were too important to ignore. Griffith wanted to attempt strenuous agility competitions with her two dogs, to participate more fully in her life. She was tired of the chronic, potentially debilitating health condition that interfered with daily activities and exercise—also leaving her vulnerable to infection, with minor colds inevitably developing into serious illnesses that required yet more courses of drugs.
The study in which she now participates investigates the long-term benefits of the Alair treatment from Asthmatx, a Boston-Scientific company. Approved for patients whose asthma is not well controlled with inhaled corticosteroids, Alair uses heat energy to reduce the amount of smooth muscle in the lungs—the tissue that contracts and blocks airways during an asthma attack. Earlier studies have proven its ability to reduce asthma attacks and improve symptoms among patients with severe, persistent asthma.
For this trial, Griffith agreed to three bronchoscopy procedures, follow-up telephone calls every three months, and yearly research visits for the next five years. Thirty centers in the U.S. and Canada have enrolled 300 participants, who will receive free treatments worth $60,000, the best medical care, and $600 for their trouble.
Griffith's positive experiences in her previous UI study were a big reason she decided to enroll in the Alair investigation. Her nerves eased further when respiratory therapist Janet Keating promised to hold her hand throughout the thermal bronchoplasty. "Despite some discomfort and challenges with the anesthesia," Griffith says, "I'm comforted at the thought I'm in good hands."
Beyond personal health benefit, Griffith wants to support the university's important research enterprise. Plus, it's exciting to be involved with a project that could take management of asthma—a devastating chronic illness that affects millions of people—to an unprecedented new plateau.
Like Kline, Mo Milhem uses the ICTS for his studies. Milhem works in the UI's National Cancer Institute-designated cancer center, which wants to increase clinical trial enrollment by 15 percent over the next three years. The ICTS helps by providing resources including the infusion suite where he administers trabectedin to patients like Betty Mahoney.
A longtime educator, Mahoney retired to her garden and kitchen in 1998. In 2009, she learned she had a sarcoma in her uterus; after unsuccessful surgery and chemotherapy, the cancer metastasized through her blood stream to her lungs. Unwilling to give up despite a grim prognosis, Mahoney asked about research options—which eventually led her to Milhem, who specializes in formidable cancers like sarcoma and melanoma. In pursuit of answers, he currently focuses on an exciting, largely unexplored field in cancer research called "epigenetics," which addresses the biochemical mechanisms that alter how genes operate. If these mechanisms direct genes to mutate into cancer, then Milhem wants to find a therapy that will interrupt the process.
Since his arrival at the UI in 2007, Milhem has initiated 39 trials and believes most cancer centers should focus on clinical research. "We don't have the answers to cancer; the toxic treatments are horrible and they hurt patients," he says. "I want better, gentler drugs for my patients so they can live comfortable, high-quality lives."
Wherever Milhem spots gaps in treatment, he designs a trial.
Initially, Mahoney had enrolled in another sarcoma trial, responding well to treatment for about six months—before her tumors started growing again. The good news was that she then qualified for the trabectedin study, which so far has kept her cancer stable. She'll keep taking the drug as long as her scans show good results, and if she comes to the end of this road, she's willing to explore other avenues. Luckily, Milhem and others like him will try to keep coming up with ideas.
"Individuals with a history of gambling are invited to participate."
"The FaceBase repository is recruiting individuals without a history of facial birth defects."
"Healthy volunteers ages 18 to 80 are invited to determine the most effective method of testing side vision."
"We need preschool-aged children to learn words in different settings."
While Mahoney and Griffith found their trials through seeking treatment for their conditions, many participants decide to volunteer after seeing a subject line like this in an email or recruitment campaign. The UI's research efforts are so diverse, there's a study for just about anyone. The current range includes tinnitus, the relationship between smell and cognitive functioning in Alzheimer's patients, dental implants, flu vaccine, and even a pharmacy project that feeds participants chocolate in a study about food preferences and tastes. As researchers explore such a wide variety of subjects, they need a correspondingly diverse group of subjects: men and women of all races, healthy and unhealthy, young and old, addicted and non-addicted, mentally well and unwell.
"Different people respond differently to therapies, so we need all kinds of participants to help us know how well treatments work," says Pat Winokur, 88R, 91F, a UI professor of internal medicine who concentrates almost exclusively now on clinical studies of public health vaccines.
In fact, the UI is one of eight National Institutes of Health-sponsored Vaccine Treatment and Evaluation Units (VTEUs) in the U.S. able to respond quickly to national priorities like bioterrorism and pandemic flu. Through her work with the UI's VTEU, Winokur tackled the 2009 H1N1 panic with trials to develop vaccine. Since then, she's worked on safe dosage levels of the smallpox shot; the best ways to administer rotavirus vaccine to babies and protect the elderly from pneumococcal pneumonia; and how to prevent troops in Afghanistan and the Middle East from contracting painful and potentially fatal leishmaniasis. In the ongoing battle against influenza, she's also working on a vaccine for H3N2V (another variant virus that jumped from swine and slipped into the human population this past summer), as well as a study of an innovative vaccine that uses the DNA from flu virus to stimulate an immune response.
Regardless of their focus, all trials involving human subjects treat safety as a paramount concern. All the UI researchers are acutely aware that should the study go wrong, volunteers may pay with their lives. As recently as last August, Bristol-Myers Squibb halted the development of the potential hepatitis C drug "Inhibitex" after nine trial participants were hospitalized and one died from heart failure (although the drug's link was not definitively established). Perhaps more widely known, an NIH-sponsored asthma study at Johns Hopkins in 2001 resulted in the death of an otherwise healthy participant after she inhaled a lung irritant. Yet another tragic story came in 2006 when a pharmaceutical-company-sponsored study of an immune stimulant brought six patients in England to death's door. Although they survived, the horrifying experience included headache, chills, nausea, uncontrollable pain, and almost total organ failure for some subjects. By the time it was all over, the trial had raised grave concerns about patient safety in the quest to move drugs to the marketplace.
"Some projects will never be completely safe, and there's always a chance for human error," says Andy Bertolatus, a Johns Hopkins graduate and director of the UI's Human Subjects Office, which exists to ensure the safety and ethics of all research involving people. Of the tragedy that occurred at his alma mater and led to the suspension of 2,400 federally funded Hopkins trials, he says: "In this case, it appears there wasn't enough consideration given to the risks of what they were doing."
To guard against such incidents happening at the UI, the Human Subjects Office works with the university's three institutional review boards that oversee biomedical projects, social/behavioral studies, and studies conducted by the Iowa City Veterans Administration Health Care System. Each board consists of faculty, staff, and members of the general community who meet up to six times per month to consider new studies and assess ongoing ones. Ultimately, their priority is to check that human research complies with strict federal regulations, established in the 1970s after what Bertolatus describes as a series of fiascos that regarded certain human beings as dispensable. Prisoners, African-Americans, children with disabilities—it was not so long ago that the medical community treated such groups as throwaways.
"There was a time in American medicine," Bertolatus explains, "when some physicians thought they had the absolute right to involve people in medicine without their consent."
In 2001, the University of Iowa even apologized for its own role during times when different standards prevailed. The apology meant to make amends for damage done during UI Professor Wendell Johnson's 1939 psychological exploration of stuttering, a project that became known as "The Monster Study." This experiment involved 22 orphans from Davenport who believed they were going to speech therapy sessions. Half did indeed receive positive speech therapy, but the others were belittled for every speech imperfection and told they were stutterers—until they eventually developed some difficulty with their speech. (Johnson intended to discover whether stuttering could be induced and whether telling stutterers their speech was fine might produce a change.) In 2007, the State of Iowa awarded the six adults subjected to the negative experiment as children a $925,000 settlement for their emotional torment.
Similar projects took place across the country. In Staten Island, from the mid-1950s through 1970, doctors deliberately injected hepatitis virus into children institutionalized with intellectual disabilities to investigate the disease's development. Just recently, the U.S. government revealed and apologized for the 1946-48 actions of American doctors who infected Guatemalan prisoners, soldiers, and the mentally impaired with syphilis and gonorrhea to study these sexually transmitted diseases.
But it was the U.S. Public Health Service's Tuskegee Study that led directly to new federal laws and regulations for the safety of human subjects—including the establishment of the Office for Human Research Protections and the national requirement for institutional review boards. In the Tuskegee Study, which ran from 1932 until 1972, government researchers enrolled impoverished black men in Alabama to participate in a long-term study of syphilis. They wanted to study the disease's evolution over time, and lured their subjects with what appeared the promise of free health care for their "bad blood," as well as other perks like burial insurance. The study persisted even after the establishment of penicillin as a cure for syphilis, a cure the Tuskegee subjects never received. Instead, they were kept under observation in an incomprehensible failure of moral standards for which President Bill Clinton formally apologized in a 1997 White House ceremony.
In the end, these unknowing participants transformed modern research practice into an endeavor that puts ethics and transparency first. "We owe a tremendous amount to all research subjects throughout time," Bertolatus says. "We wouldn't be where we are today without them."
Likewise, today's participants define tomorrow's progress.
In the years to come, the need for human subjects will only grow. With the speed of research and discoveries ever-increasing, scientists estimate that by 2020, new developments will impact the medical field every two months. Therapies offered in February could become obsolete when April rolls around.
Every time she's confined to a hospital bed for hours on end, fulfilling her commitment to the research trial, Betty Mahoney sometimes lets her mind wander to what her future holds. Mostly, she just tries to feel grateful for the moment at hand, even though she can't resist thinking about spring—that most optimistic of seasons. She daydreams about snow receding to reveal her garden and the feel of earth in her hands. She ponders the planting of daisies, her favorite flower, and imagines that this new medicine will allow her to feel good enough to enjoy the coming spring—and maybe live to see the one after that.
Like countless others who give of themselves this way, Betty Mahoney allows herself the luxury of hope.
For more on how the UI's Institute for Clinical and Translational Science can help get trials off the ground, read this Iowa Now interview with research support specialist Jessica McConnell at http://tinyurl.com/ cfc4plq.
For specifics about ongoing clinical research at the University of Iowa, visit www.uihealthcare.org/clinicalresearch.
On the medical front, U.S. News & World Report ranks the UI Carver College of Medicine 11th in the nation among public medical schools. With an overall research enterprise of $209.5 million, it's also one of 12 medical schools nationwide selected for the Doris Duke Clinical Research Fellowship Program, which enables medical students to explore careers in clinical research.