By Andrew Schwartz
In October 2006, the National Institutes of Health (NIH) awarded UCSF more than $100 million to establish a Clinical and Translational Science Institute (CTSI) in the next five years. The CTSI will catalyze and integrate clinical and translational efforts across campus, as well as at affiliated institutions and in participating communities. In doing so, the CTSI thrusts clinical and translational work into an unfamiliar position at UCSF: sharing the center spotlight with the bench research upon which the campus has built so much of its reputation.
According to a recent article by J. Michael Bishop, MD, chancellor and Arthur Rock and Toni Rembe Rock Distinguished Professor, in the San Francisco Chamber of Commerce publication Health Care and Biotech in the Bay Area
, the seeds for the new prominence of clinical and translational work were sown 1999, when the campus first broke ground for its Mission Bay campus. Because Mission Bay would concentrate so many bench scientists in one location, it would clear the way for UCSF to become a much more significant player in clinical and translational research than it had been historically.
Over the next seven years, the seeds were fertilized by nationwide excitement about the mapping of the human genome (and other scientific discoveries) and nationwide concern that a shortage of clinical researchers and inadequate support for clinical research would slow the application of breakthrough knowledge. The NIH's recent focus on clinical and translational work is a response to those concerns. UCSF was one of 12 academic medical centers the NIH selected in 2006, all of which are part of the goal of, by 2012, creating a nationwide consortium of departments, centers and institutes focused on translational work.
Unsurprisingly, the CTSI has generated considerable excitement across UCSF. At the School of Nursing, much of the excitement revolves around the hope that the institute is a rare opportunity to highlight the value nursing science has long brought to the process of safely speeding scientific discovery to the people who need it most.
A Multidisciplinary Approach
For some, the current emphasis on clinical and translational research - and the frequent discussions it engenders - is the source of irritation or amusement at what they consider to be a matter of semantics. This group notes that the entire research community has always been focused on clinical discovery and that patient care has always been the endgame.
Others, however, believe the discussions are timely and important because there is a desperate need. "The recognition that too much basic science has not made it to the clinic suggests that we're missing some links," says School of Nursing Professor Christine Miaskowski. For Miaskowski and others, the discussions fostered by the NIH emphasis can help identify those missing links.
While some of the disagreements seem to be about the definitions of the terms, consensus definitions do exist. For example, in May 2006, an American Academy of Medical Colleges report published detailed definitions of both clinical and translational research. UCSF's own CTSI website highlights a simple graphic depicting an iterative process that moves back and forth between bench and beside, and then extends discoveries out into the community. And in speaking about the goal of the new institute, CTSI principal investigator Joseph "Mike" McCune, MD, PhD, has cut right to the chase: "We hope that the CTSI will serve to bring better health care to more people more quickly."
More of the discussion, then, seems to be about how to reach McCune's stated goal of speeding the process. At UCSF's CTSI, one of the core beliefs is that speed depends on multidisciplinary work. "We've had strong involvement from all four deans, all four schools," says Deborah Grady, MD, MPH, who co-directs the CTSI and is the grant's administrative link to the School of Nursing.
Bench to Bedside: Seeing Links That Others Cannot
Nurse scientists, of course, are steeped in a tradition of multidisciplinary work and in the bench-to-bedside process, or T1 in the parlance of NIH grants. "Nursing's role is to assist in characterizing the phenotypes - to assess patients and look at the subtle variations that help inform the bench research," claims the School of Nursing's Miaskowski.
To demonstrate this, Miaskowski offers the example of a patient she saw in a clinic some 15 years ago. The woman could not move her arm - her shoulder was frozen - and told Miaskowski that the pain had begun and gotten progressively worse since a mastectomy six years prior. Yet each time she saw a physician, the woman said, the physician dismissed the pain as impossible and attributed it to a psychosomatic reaction. At one point, the woman had even spent time in a psychiatric institution because she had become suicidal while trying to live with the pain.
A nationally recognized expert on pain and symptom management, Miaskowski knew that some women did indeed experience neuropathic pain after breast cancer surgery, though no one had ever identified why. She began a 15-year research journey, ultimately winning a grant to do descriptive research on the problem, which managed to establish various phenotypes. Then, after attending a summer genetics institute in 2006, she and geneticist Brad Aouizerat won a second grant to understand how genetics might play a significant role in determining who will experience this type of pain and who will not.
Miaskowski believes that it is unlikely anyone besides a nurse would have pursued this type of work. "Our training allows us to see links that others cannot," she says.
An Opportune Moment
The work Miaskowski and Aouizerat have done together on neuropathic pain has already produced one paper, which grouped people by the way they reported symptoms, and found that those who reported higher symptom levels typically have worse outcomes. As they explore whether there is a genetic component in how people respond to pain and, if so, whether those mechanisms can be used to create therapies, both Miaskowski and Aouizerat seem remarkably energized by the way their different skill sets mesh.
"The process of working with a geneticist helps address one of the biggest challenges in clinical practice: individual variability in response to disease and treatment," says Miaskowski, who is also Aouizerat's mentor on what is known as a K12 mentoring grant. "Genomics has made clear why one size does not fit all."
"The benefit to one another's research is that it travels in both directions," says Aouizerat. "Chris is using her clinical knowledge and experience to identify and classify patients, while together, we've been looking at the basic literature to see if we can develop hunches about new candidate genes."
The partnership clearly leverages both the NIH's new funding focus and numerous bench and clinical research advances of the past few years. "In the past, everyone understood that symptoms such as pain have important clinical applications, but seldom studied its mechanisms because of a belief that it was too fuzzy to get at the underlying biology behind it," says Aouizerat. "Now, however, on the genetics side, the tools have improved to the point that we can deal with a bit more noise on the phenotypic side."
And on the phenotypic side, researchers are getting much better at creating and validating instruments and surveys that provide crucial pieces of information. "A lot of these improvements are due to the efforts of nursing science," says Aouizerat. "They don't just think about a limited set of clinical signs; they see the entire individual."
Genetics and Sleep Disorders
Like Miaskowski, Acting Assistant Dean for Research Kathy Lee is working with Aouizerat in an attempt to speed the bedside-to-bench-to-bedside cycle. Widely known for her work on sleep disorders, Lee is characterizing patients with those disorders (including restless legs syndrome, a type of sleep disorder that may be difficult to distinguish from neuropathic pain in a routine clinical assessment), and bringing DNA samples from these patients to Aouizerat.
In turn, Aouizerat has begun to search for genes that might play a role in these clinical sleep problems, as well as in obesity linked to short sleep durations and disorders of fat and glucose metabolism. Aouizerat's arrival at the School of Nursing is particularly fortuitous for both Lee and Miaskowski because previous work he has completed on lipidemia and fat metabolism has been linked with sleep disorders and neuropathic pain.
Lee is excited about this work, but also notes that the nurse scientists' role in translational research goes beyond characterizing phenotypes. "Nurses who work in the clinic also have an important role in shaping therapies as they're designed," she says. What distinguishes the nurses' contribution is their unique perspective on the whole patient, which delivers insight into what might actually work within the context of a patient's life and what will likely not work.
Lee offers two examples. When a new drug is being developed, consulting with nurses who are experts in symptom management can play a major role in understanding what types of side effects are likely to affect adherence to drug regimens. Similarly, when an industrial engineer is in the process of creating a mask for sleep apnea, it is nurse scientists who have the best, research-based perspective on what elements of the design might stop a patient from actually using the device, whatever its biophysical advantages.
"Translational research is an iterative process," says Lee. "It takes a team. No one can be in a lab, a clinic and in the community all at the same time. What nurse researchers bring is our understanding of the whole patient - and that matters in ensuring the success of any proposed new therapy."
The Biology of Exercise
Researcher and clinician Roberta Oka also believes that nurse scientists play a key role in translational research - and that their experience working with all elements of the continuum is crucial to successful translational work. In a series of multidisciplinary studies, Oka and colleagues have looked at how exercise and dietary supplements (arginine to help dilate vessels and improve blood flow) improve symptoms and functional capacity in patients with cardiovascular disease. More recently, she became principal investigator of a five-year randomized, controlled trial that will study the effect of comprehensive risk factor management on exercise capacity and vascular health for elderly patients with peripheral arterial disease.
"At the moment, studies have shown that most patients (with peripheral arterial disease) are not optimally managed because of a number of different factors, including lack of public awareness about the serious consequences of this disease," says Oka. "The idea in this study is to incorporate lifestyle change, including diet and exercise, and optimizing medications as outlined in all of the current clinical practice guidelines to improve clinical outcomes, and to explore the biological mechanisms that may be responsible for the beneficial effect of the treatments."
Oka and her colleagues' work would appear to be a vital link between an optimized intervention and disseminating best practices throughout the community. "Once we demonstrate that an intensive intervention (rooted in a whole body of research) improves patient outcomes, the important question then becomes, 'How can this be done realistically in primary care?'"
Bedside to Community
That link to the community is a significant piece of the CTSI grant - and one that may prove to be among its biggest challenges.
"T2 (bedside to community) is UCSF's major weakness," Grady told a gathering of nurse scientists in February. "Once we prove something works, how do you get people to translate that evidence into broad clinical practice in the community?"
Here again, nurses and nurse researchers play an important role.
For example, Jyu-Lin Chen's work, which examines how the childhood obesity epidemic is affecting the Chinese American community, seems to bridge bench, bedside and community. After establishing that 25 percent to 35 percent of Chinese American children in a San Francisco Chinatown school were overweight, Chen decided to see whether there were ways to effectively address the problem. Working with local health organizations and health care providers - as well as with a trio of UCSF mentors - she developed preventive interventions that are rooted in biological discovery and social-cognitive theory, and tailored to Chinese culture and practices. "Nurse scientists often develop or adapt theories designed to operationalize real issues," she says.
During a four-week intervention with both overweight and normal-weight Chinese American children, Chen and her colleagues found that the interventions caused children to eat healthier and avoid the types of weight gains that characterized the children in her earlier descriptive study. Now, Chen and colleagues are conducting an eight-week, randomized, controlled trial with healthy overweight and non-overweight kids, which aims to improve children's health behaviors and reduce unhealthy weight gain.
While Chen's work in this case is very much a community intervention, the interventions themselves are multidisciplinary and informed by everything from bench science on weight gain to child development theory. Key perspectives in her work belong to her mentors in a K12 grant: Robert Lustig, who is among the most prominent physicians looking at the biological causes of people being overweight, with an emphasis on the role of insulin; Melvin Heyman, a physician with an expertise in child nutrition; and Sandra Weiss from the School of Nursing, who provided the child development expertise.
Making the Unexpected Links
Sociologist Howard Pinderhughes would argue that in some cases, straight community-based work that applies theory to prevention and health promotion must also figure into any entity that calls itself a translational research institute. Pinderhughes is a leading researcher on violence prevention.
"Violence is a health problem in and of itself, but it is also a risk factor for other health problems and a symptom of social-structural problems that put people at risk," he says. As just one example, he notes that violent communities affect levels of physical activity; when people feel vulnerable, they get out less, putting them more at risk for cardiovascular disease, exacerbation of diabetes and various stress-related conditions.
Few would argue, but the difference is that Pinderhughes then translates and applies theories he and others have developed about the most effective ways to prevent this root problem. In ambitious projects in Alameda and San Francisco counties, he is now testing a comprehensive approach - one that addresses all types of violence (youth, domestic, child abuse) and many of the root causes. His prior work has convinced him that this is likely a much more effective approach than attacking the problems piecemeal.
"The strategies integrate programs and policies aimed at individuals, family and communities," he says. Family support systems, programs to engage young people in educational enrichment, changing the ways in which agencies collaborate, and putting systems in place for monitoring and ongoing planning are all part of the approach - the hope being that significantly rolling back violence will be the most powerful method of prevention for many illnesses that disproportionately afflict residents of the country's poorest urban communities.
Understanding Translational Work
For Pinderhughes, Chen and many others at the School of Nursing, the CTSI could not be a more natural fit. "As a nurse," says Chen, "we're always doing translational work because we're always working with individuals and families."
In addition to those profiled herein, Dean Kathleen Dracup (heart disease), Susan Janson (asthma), Nancy Stotts (wound care), Barbara Drew (emergency cardiac care), Catherine (Kit) Chesla (family and cultural factors in illness management), Catherine Waters (health behaviors in underserved communities) and many others are all doing important work that adds defining elements to the translational research continuum.
"The key," says Miaskowski, "is getting the right people together to speed and improve the process." Miaskowski is particularly enthusiastic about the multidisciplinary emphasis because she believes that if people begin thinking about medical problems in this way, then the CTSI can truly speed the application of scientific discovery to patient care.
Her enthusiasm is palpable as she rattles off a dream team of UCSF colleagues to address her area of concern, neuropathic pain: a basic biologist, a nurse scientist, an oncologist, a molecular biologist, a molecular pharmacist, a neurobiologist, a dermatologist, a psychologist or psychiatrist, and someone from complementary medicine.
The benefit, says Miaskowski, is this more comprehensive approach would produce more refined questions, as well as more refined interpretations of the data. Studies would address more issues more rigorously, thereby heading off the years of controversy and follow-up that characterize less comprehensive work.
As she speaks, it's clear she is thinking of her patient of 15 years earlier, of the world of physical pain and psychological trauma her patient had to traverse. She seems to be saying that the CTSI and efforts like it offer hope that by different disciplines working together in coordinated ways on high-priority problems, such pain can soon be averted.
Mentorship, Career Advancement and Beyond
The CTSI recognizes that to speed theory and scientific discovery into real patient and community health benefits, you need a full complement of people trained well in clinical research, and there have to be adequate career paths, so these people will stay in the field.
"Today," says Grady, "Clinical and team-based researchers are at a disadvantage." Clinical researchers often struggle to balance their clinical work and their research, and many leave the field to concentrate solely on practice. That problem is exacerbated by the conflict between the team-based nature of clinical research and the way individual academic advancement is highly dependent upon being lead author or principal investigator of a project. The CTSI, the approach the NIH is taking, and some changes in how academic medical centers offer tenure present some hope that it will soon become easier for people to pursue clinical research careers. Mentoring is one step in making that happen.
Both Chen and Aouizerat have seen enormous benefits from the mentoring process. For example, Chen's three diverse mentors - Lustig, Heyman and Weiss - give her the opportunity to design comprehensive interventions for preventing childhood obesity. In theory, this approach will enable her work to more quickly advance community-based solutions and more effectively withstand scientific scrutiny.
"And it's not just about getting better in the field of clinical research," says Aouizerat. "As a junior faculty member, you have all these demands on your time, and Chris [Miaskowski] has been invaluable in helping me learn how to navigate that time."
Aouizerat believes that if this type of mentoring is replicated at institutions across the country on an ongoing basis, eventually there will be a growing pool of researchers capable of doing better and broader studies that will shorten the wave of transitional research and achieve the goal that McCune has so clearly stated for the CTSI: bringing better health care to more people more quickly.
CTSI at UCSF
To date, much of the work on the CTSI at UCSF has involved setting up the necessary structures: formation of functional teams, detailed program planning and tracking (14 programs are in various stages of development), the creation of an administrative office, and the formation of advisory boards.
Programs under development include:
This story originally appeared in the spring 2007 research issue of Science of Caring.
UCSF Set to Transform Itself into Engine of Translational Research
- • Clinical and Translational Sciences
- • Network for Novel Clinical and Translational
- • Biostatistics, Research Ethics and
- • Biomedical Informatics Program
- • Translational Technologies and Resources
- • Regulatory Knowledge and Support Program
- • CTSI Clinical Research Center
- • Community Engagement Program
- • Global Health Program
- • Health Policy Program
- • Strategic Opportunity Support Center
- • Career Advancement
- • CTSI Virtual Home Program
- • Research Evaluation and Allocation
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UCSF in the 21st Century: Translating Scientific Discovery to Patient Care
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Studies in Transformational Research: Bench to Bedside
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UCSF Leaders Reflect on Significance of Clinical and Translational Science Institute
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Professor Describes Goals of Clinical and Translational Science Institute
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Clinical and Translational Science Institute (CTSI) at UCSF
UCSF School of Nursing