Health Sciences Report Fall 2004

"BIRCH" Scholars:  Women Researching Women's Health
By Susan Sample

Photos by: Sean Graff

Robin Marcus, Ph.D., P.T., sees the trajectory of her career taking off in a new direction that looks surprisingly familiar.

"I'm working backwards," mused the assistant clinical professor of physical therapy in the College of Health, as she watched a 58-year-old grandmother, one of the subjects in her research project, work out on an eccentric ergometer by pedaling backwards.

"I've been working 20 years as a clinical physical therapist. I've treated many women with hip fractures. Most falls occur when you go down stairs. They're the result of a loss in bone density and decreased muscle mass, or sarcopenia," explained Marcus, her voice picking up speed. "But, if you have muscle strength and function, you may never fall. The way to improve muscle mass is exercise. Eccentric exercise produces high forces of resistance and is a potent way to stimulate muscle growth. If we can train women with eccentric exercise, maybe we can reduce the number of falls."

That was the original focus of her research when she applied to be a Scholar in the Building Interdisciplinary Research Careers in Women's Health Program (BIRCWH, pronounced "birch") at the School of Medicine. Then, after conferring with her mentor, she added a critical component to her hypothesis: the exercise regimen also may have a positive impact on women's metabolism.

"Much of the food you eat is converted into glucose, an energy source, and is stored in muscle. If you lose muscle mass, you lose some of this storage space. This can have a negative impact on your metabolism and can contribute to the development of type 2 diabetes," said Marcus, with the disclaimer: "This is a very simplistic explanation." But she hopes that her research with Donald A. McClain, M.D., Ph.D., chief of the Division of Endocrinology, Metabolism, and Diabetes at the School of Medicine, may help improve insulin sensitivity in postmenopausal women who are at high risk for developing type 2 diabetes.

"My task is to help figure out the basic science portion of this," said Marcus, just named Physical Therapist of the Year by the Utah Chapter of the American Therapy Association. "This takes me as a clinical P.T. and puts me in the research world. It's been great! It's changed my career path. I want to improve the lives of the people I see with physical problems, but I want to know why the problems occur and, hopefully, make the clinical side even better."

That is precisely one of the aims of BIRCWH, a new project funded by the National Institutes of Health (NIH). The U medical school was one of 24 centers selected nationwide to participate in the program, which pairs junior faculty, women and men, with mentors to guide them in pursuing interdisciplinary studies in women's health. The grant provides $2 million over five years, enabling the women to devote 75 percent of their time to research.

"Hopefully, it gives five women in Utah who otherwise might not be funded--and who otherwise wouldn't be researching women's health--a lifelong direction to do exactly that," said Eli Y. Adashi, M.D., principal investigator. "They will constitute a cadre of individuals who will in time become leaders in women's health."

As chair of the Department of Obstetrics and Gynecology at the U medical school, Adashi not only promotes women's health, but also supports women in their professional roles as physicians and scientists. Ninety-five percent of the U of U ob-gyn residents are women, mirroring national statistics. "We don't think of it as an issue in our sphere," said the presidential professor and holder of the John A. Dixon Presidential Endowed Chair in the Health Sciences. "We balance professional aspirations with personal aspirations any way we can."

He conceded, though, that the federal government has not always been seen as equally supportive. "Funding for BIRCWH, and programs like it, was the consequence of political pressure. About 10 years ago, the National Institute of Child Health and Human Development was subjected to criticism by the women's health community that it didn't do enough for the discipline of obstetrics and gynecology by way of developing academically committed physician-scientists. It is surprising," he noted, "that there is no federal agency dedicated to women's health."

With BIRCWH, Adashi feels that he is not only fulfilling the mandate he received when he took over as department chair, "to be guardians of women's health in the Intermountain West," but also helping boost the health sciences center's academic reputation and financial base.

"My hope," added Leigh A. Neumayer, M.D., U professor of surgery who serves as BIRCWH program director, "is that Utah will be seen as a place where women's health research matters and that there will be a critical mass of people doing the research. It's very exciting."

A longtime advocate of women in medicine who has been recognized nationally for her efforts, Neumayer credits Adashi as "a huge proponent. He's been striving to build an interdisciplinary center of excellence in women's health. We do need a critical mass beyond ob-gyn," said the surgeon. "There's a narrow focus on women's health research in medical school. It's covered to the extent required, but more could be done."

When gender is considered, it's often in relation to "women's diseases," such as breast or ovarian cancer. "I didn't think about gender in neurology," acknowledged Kathryn J. Swoboda, M.D., research assistant professor of neurology, adjunct assistant professor of pediatric neurology, and BIRCWH scholar. "But medicine is not one-size-fits-all. Men and women do respond differently to treatment and interventions."

Their symptoms may differ as well. For her BIRCWH project, Swoboda is investigating the effect of gender on a group of inherited neuromuscular disorders. The most common is dopa-responsive dystonia. Symptoms can include an involuntary twisting of limbs, tremors, stiffness, pain in the legs, and a cerebral palsy-like gait.

"The disorder is more severe in females, and girls are disabled much earlier than boys," said Swoboda. "We don't understand exactly why this is. Some of the questions I want to answer are: Is the disorder a result of circuitry in the brain or hormones? Were there symptoms during the mother's pregnancy?"

Interestingly, she's found that some families with the disorder also may be prone to depression and anxiety. "Some men seem to be protected from the motor disabilities, but their moods are quite affected," said the neurologist/geneticist. One mother, for instance, is severely disabled. Her son has no motor problems, but does have a history of suicide attempts.

While Swoboda finds it rewarding from a researcher's perspective that NIH is committed to studying how gender differences impact medical care, she has a personal stake in the issue as well: "I have a history of Parkinson's disease on both sides of my family. I may need the information we eventually find out."

Patients with dopa-responsive dystonia are treated for their entire lifetime with L-dopa. The treatment is thought to be toxic to certain neurons in patients with Parkinson's disease, who also receive this treatment. By studying L-dopa in patients with dopa-responsive dystonia, Swoboda hopes to learn more about the medication's impact on brain development, which could benefit Parkinson's patients as well.

To help guide the young researchers in their investigations, the BIRCWH program specifies that they are mentored. "That's the biggest strength," said Mary Beth Scholand, M.D., an instructor in the Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine. "Trying to fly alone when you start out is challenging, to say the least."

After practicing several years as an internist in a small Colorado town, Scholand decided to specialize. She completed a pulmonary fellowship at the U medical school, then joined the University's Genetics of Nicotine Addiction and Consequences Project, researching chronic obstructive pulmonary diseases (COPD), such as emphysema and chronic bronchitis.

"I thought it would be a great population to explore gender differences in. The literature is controversial. There's thought to be a difference, and not to be. It's debatable and seems to depend upon which particular aspect of each group is being studied," explained Scholand. "Epidemiological studies seem to support that women have more COPD than men and that it develops faster. But it may be that women start out with smaller airways, so the disease progresses more quickly. Or, it could be that women smoke cigarettes differently than men. Maybe there's a difference in their pattern of satisfaction? In addiction?"

As she investigates each possibility, Scholand appreciates the guidance of her mentors: John R. Hoidal, M.D., chair of the Department of Internal Medicine, and Mark F. Leppert, Ph.D., co-chair of the Department of Human Genetics. "I'd never really been in research before," she noted. "John and Mark have been incredibly patient and encouraging. It's amazing to have their time. BIRCWH has done a good job of making sure mentors are involved. That's critical to the success of academic medicine."

BIRCWH scholar Marga F. Massey, M.D., added two women to her list of mentors: Jane Shelby, M.D., director of the U Surgery Research Laboratories and associate professor of surgery, and Leigh Neumayer, M.D., BIRCWH program director and professor of surgery. "Being a surgeon and doing research at the same time is exceedingly difficult, especially with the time constraints," said Massey, assistant professor in the Division of Plastic and Reconstructive Surgery. "To have female leadership is so helpful."

Guy A. Zimmerman, M.D., director of the U Program in Human Molecular Biology and Genetics, and professor of internal medicine, is her official mentor. He is instrumental in helping Massey carry out the basic science aspects of her research, which involve tissue engineering. "I have a passion about breast reconstruction," said Massey, who specializes in the surgery at the University's Huntsman Cancer Hospital. "My ultimate goal--when the sky's the limit--is to see if we can use fat tissue to grow a breast implant for a woman using her own cells."

In the lab, she has developed an animal model for simulating a form of breast reconstruction in which to study tissue transfer and blood flow. She also is developing a model for examining genomic and proteomic changes in fat cells that are used in different types of breast reconstruction.

In the operating room, Massey works with Neumayer, who specializes in skin-sparing mastectomy in which the incision to remove a tumor from the breast is made just around the areola. Massey, who is trained in microsurgery, uses tissue from different sites on the woman's body to create surgical flaps with which to reconstruct the breast. One method, Transverse Rectus Abdominus Myocutaneous (TRAM) flap, uses muscle and fatty tissue from the abdominal wall, which results in a simultaneous "tummy tuck." The Inferior Gluteal Artery Perforator (I-GAP) flap uses fatty tissue from the lower buttocks and thighs, which best simulate the soft tissue characteristics of the breast.

In addition to working closely with her surgical mentors, Massey meets with other BIRCWH Scholars and Neumayer for a weekly seminar, where they discuss journal articles and review progress they've made. "If anyone's at a stumbling block," noted Neumayer, "it's a good time to bounce ideas off of each other."

"I'd never realized," said Massey, "how important it is to have a support group to help you."

"It's nice to be with a group of ambitious women," concurred Colleen D. Hough, Ph.D. "It's instant networking. You immediately have connections."

That's been especially helpful to Hough, who stepped away from academics first to work as a forensic biologist in the Utah State Crime Lab, then in the biotechnology industry. "I came to the U because of BIRCWH. I was at an in-between stage. I was beyond a postdoc, but I couldn't compete for a tenure-track position. BIRCWH gave me a chance to get back into academics," she said.

After completing a postdoctoral fellowship at the National Institute on Aging, Hough stayed on and discovered several genes involved in ovarian cancer. For her BIRCWH project, she is using some of those genes in developing a mouse model using both transgenic and knockout techniques. She is looking for metaplastic and neoplastic changes on the surface of epithelium cells that might progress to cancer.

"Ultimately, what I really want to do is to develop a retroviral delivery system, so I can express genes and knock out genes simultaneously in the surface epithelium," said Hough, who is working with Eli Y. Adashi, M.D.

"NIH is like a researcher's dreamland," said Hough. But BIRCWH is not far behind: "It gives you protected time." It's also given her the opportunity to join a group of women researchers who share not only a passion for research, but the determination to overcome any professional barriers.

"Leigh's a real advocate," said Hough. "She's very in tune with the issue of women in the workplace. She understands what it's like to be a mother with a career."

Between Neumayer and the five scholars, they have a total of nine children. If these youth should ever decide to become medical researchers, they will have role models in addition to their own mothers.

"I have an undergraduate working with me who wants to be an ob/gyn researcher. She's getting the benefit of BIRCWH, too," said Swoboda, who feels strongly that "there still aren't as many women role models out there as there should be."

Marcus, who is assisted in her physical therapy research by a young woman pursuing her doctorate, agreed. "BIRCWH is enriching graduate studies now. It's beyond any opportunity I had in my Ph.D. work."

Next June, when BIRCWH holds its annual seminar, Neumayer anticipates extending an invitation to medical students, as well as any U researcher studying women's health, to submit abstracts and podium presentations. "It's my hope," she said, "that, within the next year, BIRCWH will be a widely recognized name on the U campus."


Robin Marcus, Ph.D., P.T.
Assistant Clinical Professor
Division of Physical Therapy
College of Health

Mentor:
Donald A. McClain, M.D., Ph.D.
Professor and Chief, Division of Endocrinology, Metabolism, and Diabetes, School of Medicine


Research: "Impact of Eccentric Ergometry on Muscle Size and Insulin Sensitivity in Postmenopausal Females"
We want to determine if exercising on a special stationary bicycle--an eccentric ergometer where one resists pedals moving in reverse--has an effect on sarcopenia, or low skeletal muscle mass and strength. We're also interested in knowing if this exercise can positively impact insulin sensitivity by improving the body's ability to bring glucose to its tissues. Older women are at an increased risk of developing type 2 diabetes, because their rate of muscle loss increases rapidly after transition into menopause. Muscle loss is associated with decreased insulin sensitivity, which suggests that postmenopausal women may significantly benefit from this type of exercise.


Kathryn J. Swoboda, M.D.
Research Assistant Professor, Department of Neurology
Adjunct Assistant Professor, Division of Pediatric Neurology
School of Medicine

Mentors:
James P. Kushner, M.D.
Distinguished Professor and Chief, Division of Hematology/BMT, School of Medicine
Program Director, Clinical Research Center

Mark F. Leppert, Ph.D.
Professor and Co-chair, Department of Human Genetics,School of Medicine

Research: "Effect of Gender on Motor Manifestations, Mood, and Sleep in Catecholamine and Indolamine Neurotransmitter Deficiency Related Disorders"
The focus of our work includes both phenotype and genotype studies in families with two forms of dopa-responsive dystonia: GTP cyclohydrolase deficiency and tyrosine hydroxylase deficiency. Both are neurologic disorders resulting in specific neurotransmitter deficiencies. In GTP cyclohydrolase deficiency, it appears that women are about four times more likely than men to express a motor disability and tend to have earlier onset and more severe manifestations of motor symptoms. They also have a higher rate of co-morbid psychiatric disease. We hypothesize that this also may be true of patients with tyrosine hydroxylase deficiency. We also are interested in whether there is a distinct gender effect on mood and sleep manifestations, and whether both motor and psychiatric manifestations are modified by hormones.


Mary Beth Scholand, M.D.
Instructor
Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, Department of Internal Medicine
School of Medicine

Mentors:
John R. Hoidal, M.D.
Professor and Chair, Department of Internal Medicine, School of Medicine

Mark F. Leppert, Ph.D.
Professor and Co-chair, Department of Human Genetics, School of Medicine

Research: "Genetics of Nicotine Addiction and Chronic Obstructive Pulmonary Disease-Specific Gender Studies"
We are combining comprehensive phenotyping with multiple genetic approaches to answer questions related to the genetics of nicotine addiction and chronic obstructive pulmonary diseases, and to evaluate gender differences. In the smoking topography study, we will investigate whether men and women smoke cigarettes in different ways using the CreS System, which measures puff duration, puff volume, maximum puff flow, inter-puff intervals, inter-puff variability, and number of puffs. In candidate gene studies, we are investigating the differences among smokers and control subjects in their ability to taste phenylthiocarbamide (PTC), a particular bitter taste that is an inherited trait. It has been suggested that the inability to taste PTC could be a risk factor for heavy smoking and nicotine addiction. We are specifically looking for evidence of a gender effect.


Marga F. Massey, M.D.
Assistant professor
Division of Plastic and Reconstructive Surgery, Department of Surgery
School of Medicine

Mentors:
Guy A. Zimmerman, M.D.
Program Director, Human Molecular Biology and Genetics
Professor, Department of Internal Medicine, School of Medicine

Leigh A. Neumayer, M.D.
Professor, Department of Surgery, School of Medicine

Jane Shelby, Ph.D.
Associate professor, Department of Surgery
Director, Surgery Research Laboratories, School of Medicine

Research: "Composite Tissue Transfer for Soft Tissue Reconstruction"
Breast reconstruction has become an integral component of treatment for women diagnosed with breast cancer. The technically most difficult form of breast reconstruction uses Deep Inferior Epigastric Artery Perforators (DIEP). The breast mound is reconstructed entirely of subcutaneous adipose (fatty) tissue and variable amounts of overlying skin, which has been shown to best simulate the soft tissue characteristics of the breast. The next advance in breast reconstruction likely will involve tissue engineering. To this end, we have developed an animal model of composite tissue transfer, which simulates a form of breast reconstruction, and we have tested the blood flow in the transplanted flaps. We also plan to work with a different animal model to study cell-to-cell interactions in the composite tissue transfer and to perform molecular investigations.


Colleen D. Hough, Ph.D.
Research Instructor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, School of Medicine Investigator, Huntsman Cancer Institute

Mentor:
Eli Y. Adashi, M.D.
Presidential Professor and Chair, Department of Obstetrics and Gynecology
John A. Dixon Presidential Endowed Chair in the Health Sciences

Research: "Creating a Mouse Model of Epithelial Ovarian Cancer"
Ovarian cancer is the deadliest of gynecological cancers with a 60 percent mortality rate that has not changed in 30 years. A better understanding of epithelial ovarian cancer, the most common form, would aid in the search for an accurate diagnostic tool and more effective treatments. To develop these, we must better understand the molecular mechanism responsible for the cancer. My goal is to help identify the genes involved and their roles by developing a mouse model of human epithelial ovarian cancer. I will use both transgenic and knockout techniques, as well as generate a new system to introduce genetic lesions in the ovarian surface epithelium. I expect these lesions to develop metaplastic or neoplastic changes, ultimately leading to ovarian carcinomas with metastatic spread from which I can identify the genes involved.

Committed to Women's Health

Patricia Murphy, C.N.M., Dr.P.H., joined the U College of Nursing faculty last August as the first holder of the Annette Poulson Cumming Presidential Endowed Chair in Women's and Reproductive Health.

A nurse-midwife and nurse practitioner whose clinical focus has been contraception, family planning, and reproductive health, Murphy served as an assistant professor at Columbia University School of Nursing prior to coming to Utah. She also was an associate research scientist in the Department of Obstetrics and Gynecology at the university's College of Physicians and Surgeons. Her research focused on evidence-based approaches to helping women use contraception more effectively, in addition to complementary and alternative medicine in women's health.

Murphy holds a master's of nursing degree from New York Medical College/Pace University; a master's of science in maternity nursing/nurse-midwifery from Columbia University School of Nursing; and a doctorate of public health from Columbia University School of Public Health.

At the U of U, Murphy is teaching research courses at the doctoral and master's levels. She is responsible for developing a multidisciplinary program of research, clinical care, teaching, and mentoring students, and will serve as a public policy advocate for improving health care and reproductive choices for women. She also will oversee outreach, public policy, and service activities relating to women's health issues.

The nursing college's new endowed chair in women's and reproductive health is supported by a $1.25 million endowment honoring Annette Poulson Cumming. She and her husband, Ian Cumming, are longtime benefactors of the U of U.

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