Making a Mark
Eszter Boros and her lab team are transforming the way physicians can treat and diagnose deadly cancers.
The glowing marker speeds through the patient’s bloodstream, ineffably drawn toward the tumorous tissue like a bright, miniature homing missile. Once it arrives at its appointed destination, the surgeon looks at a monitor and knows exactly where the cancer is and where to begin removing it.
Welcome to the future of medicine, brought to you by the UW–Madison Department of Chemistry.
The ongoing development of this cutting-edge tool is the result of work done in the radiopharmaceutical laboratory of Eszter Boros, the Hall-Fisher Associate Professor of Chemistry and an affiliate faculty member with the Department of Medical Physics in the School of Medicine and Public Health, and it’s just one example of the many ways researchers in the College of Letters & Science are advancing health, medicine and health policy. UW–Madison Chancellor Jennifer Mnookin’s RISE-THRIVE initiative drives state-of-the-art research like this, which is funded by federal entities such as the National Institutes of Health. Elsewhere in the Department of Chemistry, researchers are finding ways to block the proteins in our bodies from aggregating and leading to diseases like diabetes and Alzheimer’s. Meanwhile, researchers at the La Follette School of Public Affairs are exploring the ways that social genomics, a field focused on the complex relationship between social factors and the human genome, can have a dramatic effect on human health and lifespan. Over at the Sandra Rosenbaum School of Social Work, faculty members are busily mapping how the very environments in which we live can inflame our bodies and steer us toward dangerous disease states, especially as we age. They’re also searching for interventions to combat these issues.
It’s very optimistic and ambitious. But because we have the expertise on campus, I think we can be ambitious.
Bioluminescent chemical markers aren’t the only tools the Boros Lab is developing to help doctors treat different types of deadly cancers. Using what’s known as radiometal chemistry, they’re also studying ways to deliver targeted doses of radiation directly to cancer sites.
If you’ve ever heard of a standard positron emission tomography (PET) scan, you understand the essential concept. A PET scan depends on the presence of a radioactive isotope decaying and producing gamma rays that can be detected by a scanner to help with finding tumors or diagnosing diseases. Boros is an inorganic chemist, which means she works with metallic elements and ions rather than organic materials.
“A metal ion doesn’t just know where a cancer is on its own,” explains Boros. “These radioactive isotopes need to be incorporated into molecules that are cancer-seeking, and that requires chemical tools.”
Boros and her lab partner work with the Department of Medical Physics in the School of Medicine and Public Health to create those tools. Medical physics produces radioactive isotopes, and the Boros Lab then builds chemical cages around them, attaching the cage to a small molecule that can bind to a cancer cell. The chemical cage is injected into the patient’s bloodstream, carrying its radioactive payload directly to the cancer site. The emitted gamma rays make it possible for doctors to scan the patient and monitor what’s happening.
Unraveling which isotope and chemical combinations make for the best delivery systems occupies a large part of the Boros Lab’s time.
“That’s essentially what we do,” explains Boros, who came to UW–Madison two years ago after a six-year stint at Stony Brook University in New York.
“From scratch, we develop methods to incorporate these isotopes that have been in the field for 20 years,” Boros says. “We spend a lot of time trying to better understand their chemistry.”
Boros and her team of graduate students mine the bottom rows of the periodic table to find the radioactive elements most likely to be effective — elements that, unless you’re a chemist, you probably haven’t thought much about. Rare earth elements like scandium (Sc) and yttrium (Y), europium (Eu) and terbium (Tb). Transition and main-group metals like titanium, gallium, copper, manganese and cobalt are also effective, says Boros.
“If there’s an interesting chemistry problem to solve and turn into a new radiopharmaceutical, we’re interested in it,” she says.
The Boros Lab is closely watching the work of cancer biologists and biochemists who are identifying new cell surface receptors, potentially opening the doors for even more new ways to selectively deliver radioactive payloads.
“That’s really where the personalized medicine aspect of this comes in,” says Boros. “Identifying a biomarker that works for a specific patient for a specific cancer. Identifying just the right type of vehicle that delivers these radioactive payloads is going to be very powerful.”
Most of the team’s proof-of-concept work has been done with prostate cancer, a slower-developing cancer. Boros is anxious to test its efficacy in breast and ovarian cancer, which more often present in an advanced state, making therapies such as surgical resection and chemotherapy impossible.
“Having diagnostic imaging that shows the extent of disease, and then deploying radiotherapy, where we can then administer a second isotope that emits a particle that selectively kills cancer cells, is something that’s much more useful in a situation where there are too many cancer sites in the body,” explains Boros. “The radiopharmaceutical, because it’s cancer-seeking, can actually selectively deposit in the cancer cells.”
Much of the Boros Lab’s research has taken place with mouse models. But the lab is also interested in isotopes that start first in human subjects. One of the therapies they’re considering involves titanium oxide, a biocompatible chemical that shows up in the deodorants many of us use every day. Boros’ team has developed a molecular form of titanium that could be paired with a radioactive isotope to use for diagnostic imaging.
“The more tools we can demonstrate that are functional in humans, the more we can justify developing other chemistries and other isotopes that can be effective for these applications,” Boros says.
These radiopharmaceuticals involve very small amounts of material, which means researchers aren’t concerned with metal toxicity. They do pay close attention to levels of radioactivity to make sure healthy tissues aren’t being damaged. Since targeted radiotherapy predominantly hits cancer cells, patients generally don’t suffer from a lot of the side effects that typically accompany conventional chemotherapy.
Like most scientific advancements, development is often a slow and onerous process. Boros is hoping that the diagnostic titanium tracer could move into human trials in the next four years. The next step is finding a way to automate the procedures used to make the radiopharmaceuticals. That’s another area in which medical physics can help.
“It’s very optimistic and ambitious,” says Boros. “But because we have the expertise on campus, I think we can be ambitious.”
— Aaron R. Conklin
Nature and Nurture
Jason Fletcher and Lauren Schmitz study how our environments impact gene expression and how certain policies can predict health issues and biological aging.
With strict regulations on smoking and tobacco use, why are smoke breaks still normal? Why do some people age more rapidly than others? In depression cases, why do patients respond to treatment options in varied ways?
Biology offers only part of the answer to any of these questions. Environmental, genetic and social factors together influence public receptiveness to health campaigns, policy or even certain medications. The study of all these factors is called social genomics, and two researchers in the La Follette School of Public Affairs are leading experts on the topic.
“When we negate part of the story by focusing only on nature or only on nurture, it’s like tying one hand behind our back — we can’t solve the full problem,” says Jason Fletcher (MS’03, PhD’06), a Vilas Distinguished Achievement Professor of Public Affairs.
Fletcher’s research on social genomics seeks to bridge the gap between genomes and the environment to determine how public policy, childhood and genetic factors impact health and aging. He points to the smoking example and historic policies that established smoke-free zones, taxes on cigarettes and public anti-tobacco health campaigns as a prime example of how his research could better inform these efforts. While this approach was effective with some members of the population, others were left behind, like people with a family history of addiction in their genetics.
“Everybody in a specific area has those same top-down policies, yet they potentially are more effective on some people than others,” Fletcher says.
A more clinical use of Fletcher’s research looks at the application of social genomics in depression treatment. When physicians are weighing their options between therapy and antidepressant medications, Fletcher says they should also be looking at factors like family background, current environment and genetics. Knowing this will help predict how effective different treatments will be.
Lauren Schmitz, an associate professor of public affairs, also researches social genomics. Specifically, she looks at epigenetics, which is the study of how genes are turned on and off without changing the DNA sequence. While a person’s genetic code is fixed, their environment can alter how specific genes work, leaving a genetic marker called DNA methylation.
We used to have to wait for people to die to understand why some people are dying faster than others, and now we can see, kind of in real time, what’s going on in your body.
“If we look at people’s DNA methylation, it’s highly correlated with aging,” Schmitz says. “We can use people’s epigenome to measure their biological age.”
Schmitz looks at how epigenetics can be used to help evaluate health disparities among people of different socioeconomic backgrounds. For example, children whose mothers were malnourished may over-respond to calorie-dense food when they are born, causing metabolic disorders like diabetes or cardiovascular diseases.
Other prominent cases of epigenetics include regular exposure to lead pipes or pesticides. If a person is exposed to lead pipes throughout their life, this alters DNA methylation, leading to changes in brain development, cognition or behavior. Similarly, pesticides modify genetic expression patterns, which could disrupt endocrine and neurological functions. The exposure to these toxic substances is not evenly distributed among the general population, meaning some communities are more likely to be impacted.
Schmitz hopes that this data can help examine how certain policies, like parental leave, impact someone’s gene expression throughout their life, ultimately determining their biological clock.
“We used to have to wait for people to die to understand why some people are dying faster than others, and now we can see, kind of in real time, what’s going on in your body,” Schmitz says.
Currently, there are gaps between research in social genomics and real-world implementation, largely due to a lack of representative data for all communities.
“We need data that actually represents diverse populations, and we’re making progress there,” Fletcher explains. “Right now, we’re still years away from having truly equitable clinical applications of this research.”
— Margaret Shreiner
Stress, Out
Weidi Qin is looking out for older adults in her research that analyzes how neighborhood life factors into long-term health.
Medical experts have long known that inflammation is one of the primary factors that leads to chronic and debilitating conditions like heart disease and diabetes. They’re also aware that one of the primary things that leads to inflammation is stress. Stress looks different to everyone, but to older Americans, one of the biggest sources is the neighborhood environment in which they live.
Weidi Qin, a gerontologist and assistant professor with the Sandra Rosenbaum School of Social Work, studies the socio-structural determinants of cardiometabolic health in older adults. Her latest project looks at pathways linking older adults’ perceptions of their neighborhood disorder to health behaviors and the C-reactive protein, a general biomarker for inflammation.
Qin was born in China and raised by her grandparents, which cultivated her interest in and comfort around older adults. She examined data from the Health and Retirement Study, a national longitudinal survey of adults aged 51 and older in the U.S. that collects extensive data on socioeconomics and health.
“Do they see any graffiti?” asks Qin. “Because graffiti can sometimes be seen as a proxy of crime and perceived unsafe conditions in the neighborhood. Litter on the ground is another one, which indicates whether the streets are walkable and whether the environment is friendly for outdoor exercise.”
Older adults are a special population. They may have mobility and frailty issues, so it is important to consider their distinct needs in the neighborhood context.
Negative neighborhood perceptions can impact an older individual’s ability to get regular physical activity (leading to even more inflammation) and connect with neighborhood social networks. Interestingly, Qin’s findings suggest that physical activity accounts for the effects of neighborhood disorder on elevated inflammation among white participants, but not among Black participants.
“Older African American people may seek alternative coping mechanisms, such as reaching out to their family and friend networks for social support to help buffer the negative effects,” she says.
Qin’s eventual goal is to identify potential interventions for older adults living in neighborhoods that have disorders. One of her next projects will be to examine neighborhood and health among older African American Milwaukee residents.
“Older adults are a special population,” says Qin. “They may have mobility and frailty issues, so it is important to consider their distinct needs in the neighborhood context.”
— Aaron R. Conklin
