Take a Different Approach

Take a Different Approach

Study Your Garden

British-born Alexander Rickard loves growing plants and crafting his garden. He coordinates fruits, vegetables, herbs, and ornamentals and does his best not to overuse pesticides. "I try to go for a healthier approach to allow a decent homeostasis, to prevent different components of the garden from harming each other," he says.

One day Rickard had an idea. What if he applied the same strategies he uses in his garden to human health? In the garden, for example, he plants mint to ward off mosquitoes and has weeping willows to protect shade-loving plants. Could he do something similar with bacteria in the human body - could he effectively manipulate organisms into doing good?

In particular, could Rickard, an assistant professor of epidemiology who coincidently holds a master's degree in plant genetics and a PhD in microbiology, harness arginine (a natural amino acid that is required to make proteins) to improve oral health?

The human mouth is home to hundreds of species of bacteria.

"Much as in a garden," Rickard notes, "some species can be unsightly and cause disease, while others can co-exist harmoniously and actually benefit the garden as a whole." Rickard and his laboratory team recently discovered that high concentrations of arginine, which is commonly found in certain foods, could stop the formation of dental plaque - which can cause caries and periodontal disease. He and his team now believe that arginine could eventually replace current plaque-controlling antimicrobial substances, and they're collaborating with colleagues at the U-M School of Dentistry and Newcastle (England) University's School of Dental Sciences to better understand how arginine works.

The research is important, Rickard says, because many existing treatments to fight caries and periodontal disease involve chemical antimicrobial agents that can stain teeth and affect the sense of taste. There is considerable debate about overuse of these agents, and scientists have sought ways to reduce their use. Dental plaque also contributes to billions of dollars of dental treatments and office visits every year in the U.S.

Focus on Midlife

As Carrie Karvonen-Gutierrez began research on a study of women in midlife, she was surprised to learn about the burden that arthritis and musculoskeletal disease had on women ages 50 to 65, who had become afflicted with these conditions. The women were looking forward to an active retirement, but the pain, stiffness and swelling associated with their illness were hampering their ability to function.

Karvonen-Gutierrez, an assistant research professor at SPH, says that while temporal trends in disability are actually remaining stable among individuals 65 to 84, and even improving among those 85 and over, "the data is worrisome" when it comes to women in midlife, with overall physical functioning worsening and disability rates increasing.

With Sioban Harlow, professor of epidemiology, Karvonen-Gutierrez is working to understand the critical physiologic changes that occur in women during the midlife period just before they start late adulthood. Harlow directs the U-M Center for Midlife Science, which focuses on health-related changes in the reproductive and musculoskeletal systems, and on risk factors for cardiovascular diseases and diabetes, as women transition through their forties, fifties and sixties. The researchers hope to develop effective interventions that will help women stay on a healthier course as they age.

Research typically focuses on health after age 60 or 65, when it's often too late for interventions to be helpful. A case in point, according to Karvonen-Gutierrez, is osteoarthritis, where many prevention studies don't enroll participants until they're 65.

Dietary modifications, drug trials, and exercise interventions have proven disappointing, she says, "because by that point those who are likely to get the disease already have it, so interventions aren't helpful."

Midlife "is a life phase that is very understudied," Harlow notes. Until recently, a commonly held belief was that, except for menopause, the midlife was not a period of change and that women in midlife were relatively healthy and high-functioning.

"What we've learned is that midlife is actually a period of considerable transition, both in terms of reproductive life but also in many other aspects of health," Harlow says.

It's important to look at the subclinical precursors of disease and disability during this life stage to better understand the trajectories of change in bone density, body size metabolism, cardiovascular health, and muscle strength. Such information can help scientists predict who is going to be at high risk as they age, Harlow explains, "and how we might facilitate healthy aging."

This type of research is particularly important at a time when life expectancy is increasing and a large proportion of the population is entering old age. As midlife research unfolds, it could form the basis for discussions on appropriate dietary activity and medical interventions, and could have implications for policy defining retirement benefit ages - insights that all can come from paying better attention to midlife health.

- Julie Halpert

Listen to the Cancer

Despite the fact that most breast cancers in high-income countries are diagnosed early - thus heightening the odds of successful treatment - some 30 percent of women who receive early diagnoses still die from the disease. Sofia Merajver wants to reduce that number, and she thinks she knows how.

A professor of epidemiology and internal medicine, scientific director of the U-M Breast Oncology Program, and director of the U-M Breast and Ovarian Cancer Risk and Evaluation Program, Merajver is working to understand the biology of specific genomic clones in those cancers that, despite early detection and treatment, later return to cause metastasis and often death. She's hoping to find out which clones - or genetically identical cancer cells - are most significant in terms of metastatic potential, so that researchers can then develop personalized therapies to destroy those clones.

In collaboration with multiple teams led by faculty from the U-M College of Engineering, Merajver and her research group are using a new technology - small, inexpensive, plastic devices, or "niches," built by U-M engineers - to analyze and separate minute numbers of live cells from cancers. By observing the behavior of these cells - or, in Merajver's words, by "listening" to the cancer cells - she and her colleagues can determine the characteristics, or phenotype, of those cells and better understand their potential to metastasize at distant organ sites.

Says Merajver, "I want the cancer cells to tell me their story - not the other way around. I don't want to tell them what I think their story is."

Each device, or niche, is the size of an adult's thumbnail and, depending on its application, made of either rough glass or plastic. A fluid inside the device keeps cells alive and allows researchers to separate more aggressive cancer cells from less aggressive ones.
Unlike animal models, which scientists have long used to study cancers, the devices are relatively cheap and easy to reproduce and permit the quantitative measurement of cellular properties that are not accessible in animal models. And because cells can be analyzed so much more quickly in the device than in animal models, scientists can experiment quickly. Eventually, says Merajver, researchers will be able to test hundreds of different drugs and get results within a matter of days or even hours. This means that while a cancer patient is undergoing diagnosis and/or other local treatments, her cells can be tested, and personalized therapies designed to attack the deadliest clones.

Merajver envisions a future in which scientists have a suite of such devices, each optimized to evaluate a particular kind of cancer or to answer a crucial biological question. Patients will be treated with targeted therapies according to the specific genomic clones found in their cancer cells. "Our overarching aim," she says with excitement, "is to turn cancer into a manageable chronic disease."

Embrace the Unexpected

Thirty years ago, at the start of her career as a toxicologist, Rita Loch-Caruso wanted to study cell biology, with an eye toward addressing birth defects. But the molecular tools and techniques she needed did not yet exist, so she turned to researching the effects of environmental chemicals on uterine contractions during childbirth. One day, as she and a graduate student were testing the effects of polychlorinated biphenyl, or PCB, on uterine muscle, they decided to see what would happen if they separated the uterine lining from the muscle. The result was stunning: the muscle tissue proved far less responsive without the lining.

It was a classic "eureka" moment, says Loch-Caruso, now a professor of environmental health sciences at SPH. "I thought, 'Maybe I'm studying the wrong thing.'"

She switched her research agenda and is today a global expert on the effects of environmental toxicants on the placenta and other gestational tissues necessary for a healthy pregnancy and delivery. These highly sensitive membranes, says Loch-Caruso, play a critical role in a woman's risk for preterm birth - in part by serving as a protective mechanism against potentially devastating microbial infections.

Loch-Caruso hopes her work can lead to policy changes aimed at lowering women's risk for preterm birth - one of the leading causes of infant death, impaired cognition, blindness, and lung afflictions. She'd also like to see her research contribute to the development of better interventions to prevent microbial infections associated with preterm birth.

Her story, Loch-Caruso says, is a prime example "of the fortune that can be found when things don't work the way you anticipated."

Build on a Great Idea

By his own admission, SPH toxicologist Rudy Richardson "kind of fell out of my chair" when early last year he stumbled on a Japanese research study showing that chlorine dioxide, a chemical compound commonly used in water treatment and bleaching, oxidizes a specific amino acid in the hemagglutinin protein of the human influenza virus H1N1. "It was one of those ah, ha! moments," Richardson says eagerly.

That's because the findings were unexpected. Scientists have long known that disinfectants like chlorine dioxide can inactivate viruses, "but we thought it was indiscriminate," he says. "And we knew little about how it happened." The Japanese study - which Richardson found by chance while searching for material to help one of his students with her work - showed that chlorine dioxide is actually highly selective in this case. It inactivates hemagglutinin, which is found on the surface of influenza viruses, "probably by disrupting the protein's binding to recognition sites on human cells." The findings alter "our fundamental understanding of protein oxidation," Richardson explains, and could have far-reaching implications for both infectious- disease prevention and oxidative stress, a process scientists have yet to understand at the molecular level. Oxidative stress is implicated in many diseases associated with aging, among them Alzheimer's and Parkinson's.

Richardson is now using computational approaches to model protein oxidation in an effort to discover how and why this "selectivity happens with chlorine dioxide. If we can figure that out, we may be able to design other ways of inactivating viruses." He thinks his research could lead to new anti-influenza drugs, which could in turn lead to the development of other antivirals, including drugs to combat norovirus and the common cold.

"Virology is not my thing," he admits, "but I find myself more excited about this than any other area of my research." He credits the Japanese study with having "unlocked the door. It's an example of how, by looking at the same thing other scientists have observed, but in a different way, you can come up with something completely new." Richardson is collaborating with Christian Lastoskie, an associate professor in the U-M Department of Civil and Environmental Engineering, and U-M engineering doctoral student Margaret Reuter.