Wise recently received a $6.7 million grant from the National Institute of Environmental Health Sciences through the Revolutionizing Innovative, Visionary Environmental health Research (RIVER) program to conduct research over the next eight years to better understand how metals disrupt chromosomes and cause lung cancer, with the ultimate goal of finding ways to prevent and reverse this process. UofL News talked to Wise about what drives him to chase this important discovery, which has long stumped scientists.

UofL News: What inspired you to do biomedical research?

John Wise Sr.: I was interested in science from when I was 5. People would ask me what I want to be when I grow up and I would say I wanted to be a naturalist, which is a strange thing for a 5-year-old to say. I was a very outdoorsy kind of kid. Then I was interested in genetic engineering, which is also strange for a kid to say. I don’t have an explanation for where that one came from.

Growing up, my mother said I had two choices for my life, I could be a doctor or I could be a lawyer. That was just understood.

When I was doing my degree in biology at George Mason University in Virginia, I faced that decision that a lot of biology undergraduates face: whether to go to medical school or graduate school.

You can boil them down to two jobs: you can either be a mechanic and fix things, or you can be a detective and solve puzzles. If you like fixing things, medical school is where you go. If you like solving mysteries, graduate school is where you go. I like to solve puzzles, so I went to graduate school and got my PhD in pharmacology with a research focus on toxicology and how metals cause cancer. After a decade in Virginia, I was a faculty member at Yale for four years. Then I spent 12 years at the University of Southern Maine before coming to UofL in 2015.

UofL News: Was your mother satisfied with the graduate school decision?

Wise: No, but she wasn’t negative, either. She was very happy I got my PhD. My brother is an attorney, so she went 1-for-2.

UofL News: How would you describe your research – the big picture?

Wise: One of our driving interests is in lung cancer. It is the number one killer for cancers. It kills nearly as many people as the next three cancers combined. But lung cancer suffers from a stigma and that is smoking. Most of the world thinks that if you smoke you are going to get lung cancer and you should just quit smoking.

But when you dig into it, you learn that 1 in 5 women and 1 in 12 men who have lung cancer never smoked, so something other than tobacco is a big issue, especially for women. And when you look at what in the environment is causing lung cancer, the most prevalent group of chemicals that are known to cause lung cancer are metals.

Traditionally, people think of cancer resulting from minute changes in the sequence of DNA, but metals don’t do that well. What metals do well is change the chromosomes, which means big change in the structure of the DNA.

Humans all have 46 chromosomes. Metal exposure will change the number of chromosomes and will change the structure of the chromosomes, so a piece of chromosome 1 might end up on chromosome 2. These changes are hallmarks of lung cancer, but it’s poorly understood how chemicals cause this chromosome instability and that is at the heart of what we do.

We got interested in the great whales because they have low rates of cancer. Why?

We reasoned that maybe whales have better repair mechanisms, so we have started to ask that question with chromium. We found that in humans, chromium will break DNA and inhibit the ability to fix it, leading to the chromosome instability.

In whale cells, chromium breaks the DNA but it cannot inhibit the repair so you don’t see those changes in the chromosomes.

What is it in a whale cell that prevents the loss of repair? That’s what we are trying to figure out. If we can figure out how the whales are resistant, we can try to adapt that to human systems.

UofL News: Your team’s field work involves obtaining cell samples from whales in the ocean using a crossbow from a sailboat. What prompted this work and how did you begin using this method?

Wise: When I was at Yale, we were doing cancer and cell culture, so I called the Mystic Aquarium, which was an hour or two away from New Haven, because they had Beluga whales. Belugas have high rates of cancer in the wild, so I asked if I could get some tissues from the whales. I figured if I could get to the whales that don’t get cancer, I should get cells from whales that do get cancer for a comparison point.

The research director at Mystic said, ‘Are you only willing to do these two whales? Why don’t we do all of them?’ I thought, ‘How many marine mammals can there be?’ so I said, ‘Sure, let’s do all of them!’

So far, we have cultured cells from 35 out of about 130 marine mammal species in the world. We have 900 individual animals in culture. In fact, the University of Louisville has the world’s largest collection of marine mammal cell lines in our freezers.

The Deepwater Horizon oil spill in the Gulf of Mexico in 2010 led to us going to sea to sample the whales directly.

A group we collaborate with, Ocean Alliance, had developed a technique to biopsy whales with a crossbow. This allows us to get a pen cap-sized sample of the whale’s skin and blubber without interrupting their activity. Now we go out each year and gather as many species as we can find.

UofL News: Why is your new grant through the RIVER program a special opportunity?

Wise: The reason this is such an exceptional grant is one, you have eight years of a lot of money. On top of that, the program requires that half of your time be spent on this research question, so you have an amount of your own time that is committed to work on the ideas. And because the grant is funding a scientist’s vision, not a specific project, you have the freedom to change ideas and move into different directions.

It is a highly prestigious honor to receive this award.

UofL News: What other research are you working on?

Wise: The whales get a lot of attention, but we also sample sea turtles and alligators. It’s the same approach, but additional species that live a long time and get exposed. They are also sentinels for climate change. Because they are cold-blooded animals, they are going to be affected first.

We are also looking at how space travel and chromium interact. We did some experiments with NASA where we flew samples on the “vomit comet” [parabolic flights creating brief periods of weightlessness] and we found that altering gravity greatly increases the negative impacts of chromium. We hope to get onto the space station and see if chromium is going to cause a problem there. More and more people are going into space, so it is a concern.

UofL News: Do you have a favorite place to contemplate the problems you are trying to solve?

Wise: My favorite place to contemplate is at sea on a boat with the whales. There are moments in the research when we aren’t actively sampling for one reason or another. During that time – the best time is sunset, the whales are breeching and breathing – I always make a point to stop the boat, turn everything off and have everybody just listen and think about things with that background. It just reminds people of the importance of the work we do and just how complex the world is.

You can get overfocused on work. Always remember where you are because you won’t be doing this forever. Let it be special.

Wise, professor in the UofL Department of Pharmacology and Toxicology, now has received $6.7 million over eight years from the National Institute of Environmental Health Sciences through the Revolutionizing Innovative, Visionary Environmental health Research (RIVER) program to investigate how chromosome instability resulting from exposure to metals leads to lung cancer.

Lung cancer is the leading cause of cancer death in the U.S., and Kentucky has the highest rates of lung cancer incidence and mortality of any state. Despite the widely held perception that lung cancer is simply attributed to smoking, 1 in 5 women and 1 in 12 men who develop lung cancer never smoked. In addition to high rates of cancer, lung cancer has a five-year survival rate of 21%, one of the lowest of any cancer site.

“Lung cancer has a substantial impact on human health, particularly here in Kentucky, and it is time the misconception that smoking is the only cause of lung cancer is dispelled,” said UofL interim president Lori Stewart Gonzalez. “We are grateful for the institute’s confidence in Dr. Wise and our university to lead this work in addressing such a significant health concern. I am excited to see this amazing research continue and expand at UofL thanks to this grant.”

Metals are some of the top environmental causes of human lung cancer, but scientists do not fully understand how the metals cause cancer. Wise’s research has shown that one such metal, hexavalent chromium, causes chromosome instability, in which the chromosomes are increased, deleted or rearranged in inappropriate ways. This chromosome instability can lead to the development of cancer.

Wise has studied metals-induced chromosome instability in humans and animals. Through his field work in sampling skin and blubber from whales, Wise has discovered that while the animals are exposed to hexavalent chromium in the ocean, it results in much less chromosome instability and cancer.

“What’s thought to underlie that is a double-strand break in the DNA helix. In human and whale cells, chromium induces the same number of breaks, so you would expect the same amount of effect on the chromosomes, but you don’t see that,” Wise said. “One of the things we’ve found is that chromium also inhibits the repair of these breaks in humans – you get the breaks and you can’t fix them. In whale cells you get the breaks, but you can fix them. What about whales is protective or corrective? That’s what we’re digging into.”

Wise has assembled a team of researchers from around the world to investigate this process further with the hope that this knowledge ultimately will lead to ways of preventing and reversing metals-induced lung cancer in people.

The research will include laboratory studies and then translate those findings to wildlife and human populations of workers exposed to metals. In addition to Wise, project researchers include KeJian Liu of the University of New Mexico, who will lead lab studies and Tongzhang Zeng of Brown University, who will lead work with human populations. Doctoral students in Wise’s lab and UofL faculty members Sandra Wise, Michael Merchant and Matt Cave also will participate, along with additional researchers in the U.S., Germany, China and Japan.

“UofL is one of the top institutions in the country in research and discovery for how human health is influenced by our environment, and preeminent researchers like Dr. Wise are the reason,” said Kevin Gardner, UofL executive vice president of research and innovation. “This grant is recognition of the incredible contributions Dr. Wise has made to the field and provides ongoing support for continued discovery for years to come.”

RIVER grants are awarded to select investigators who have shown a broad vision and potential for impactful research. They allow the investigator increased flexibility and the freedom to set specific research goals toward a given objective, adjusting the research based on new findings, without seeking new funding. Cave received a RIVER grant in 2017 to conduct research into the effects of environmental exposures on fatty liver disease.

This research is built on 20 years of previous support from the NIEHS as well as seed funding from the Kentucky Lung Cancer Research program and the Jewish Heritage Fund for Excellence.

As part of an honors class, a group of undergraduate students studied — through interviews, research and first-hand experience — how towns like New Albany, Clarksville and Jeffersonville, Indiana, benefit from and can better promote kayaking, concerts and other riverside activities.

They worked with the U.S. National Park Service – Rivers, Trails and Conservation Assistance program to conduct river town reviews. The program’s team effort approach to looking with “fresh eyes on enhancing tourism and outdoor recreation” helped these communities explore how they can further realize the benefits of the Ohio River and the development of the 270-mile Ohio River Recreation Trail from Portsmouth, Ohio, to West Point, Kentucky.

“I think the main takeaway is that there is so much potential for the Ohio River and the communities that surround it,” said Forest Clevenger, a political science major who worked on the project. “By focusing on recreation, it not only reinvigorates the economies of these communities, but it makes it so that conservation (of rivers) is an economic asset and something that is supported.”

The results of the students’ research, including observations, models, maps and photos from their trips to the Ohio River Greenway, currently are on display at the main branch of the Louisville Free Public Library. The exhibit, “River of Life: Cities and Towns Along the Mighty Ohio,” is expected to run through the summer.

“The students’ work in this exhibit uses photos and explorations to understand past initiatives that encouraged river recreation,” said David Wicks, who taught the class and also is director of River City Paddle Sports. “They put a lot of work into this and it really shows. Their work could help shed new light on the role of rivers – how they shape and grow our towns.”

The exhibit also spawned an offshoot project called “Ripple Effects: Exploring Water in Louisville.” That project began with a photo contest that asked kids in grades K-12 to capture their feelings about water on film. The goal is to learn more about youth attitudes toward water — what it means to them, its role in their everyday lives and how they engage with it.

Mary Brydon-Miller, professor in the UofL College of ����ֱ�� and Human Development, will prepare a summary of the main themes that come out of the entries to present as part of an upcoming National Oceanic and Atmospheric Administration forum on extreme rainfall and community resilience.

“The important thing is the engagement of youth across the Louisville metro area in thinking about the importance of water in our community,” she said. “And asking kids to tell that story in a creative way will tell us a lot about how they see water’s role in their lives.”

Winners of the photo contest will be announced at Louisville Waterfront Park on June 21 and featured in another exhibit at LFPL this fall as part of the Louisville Photo Biennial.

More information on the exhibit, including sponsor listing, is available on , as well as more information on .

“In environmental health, the study of liver disease is relatively new, particularly in the field of endocrine disrupting chemicals,” said Cave, associate professor of medicine in gastroenterology at the University of Louisville School of Medicine. “These chemicals, such as bisphenol-A (BPA), found in plastic drink bottles, may cause endocrine and metabolic diseases like diabetes and obesity, or make them worse.” 

With the NIEHS award, Cave plans to explore how any number of endocrine disrupting chemicals contribute to fatty liver disease. The flexible nature of the award allows him to redirect the research over the course of the funding, and adapt the work in light of new leads.

Cave is one of eight environmental health scientists receiving the new Revolutionizing Innovative, Visionary Environmental health Research (RIVER) Outstanding Investigator Award from the NIEHS. Awardees were selected based on their record of innovative and impactful research. Cave’s 8-year funding is the maximum awarded for this program. The new RIVER awards differ from the NIH’s traditional approach of funding projects designed to study specific aims, which can steadily produce new knowledge but may limit scientists when their results suggest new directions. Through RIVER, Cave will be able to explore novel directions of research in environmental liver disease.

“The RIVER program is designed to fund people, not projects. It gives outstanding environmental health scientists stable funding, time, and importantly, flexibility to pursue creative scientific ideas, rather than constantly writing grants to support their research programs,” said David Balshaw, PhD, chief of the NIEHS Exposure, Response and Technology Branch who leads the NIEHS team overseeing this initiative.

“This funding mechanism gives us the flexibility to study this evolving field and the freedom to pursue the hot leads as they develop,” Cave said. “I am very flattered to receive this award. It demonstrates the confidence the NIEHS has in my work.”

While the specific projects will evolve over time, Cave’s initial work will focus on exposures to polychlorinated biphenyls (PCBs) and vinyl chloride. PCBs are chemical compounds previously used in electrical equipment and other products. Although banned from production in 1979, PCBs do not readily break down and can remain in the environment. Vinyl chloride is used in the production of polyvinyl chloride (PVC), from which plastic pipes and other construction materials are formed. Both compounds are known to cause liver damage. Cave plans a multi-tiered research approach, beginning with cell cultures and animal models and then in humans.

As a framework for his research, Cave will establish the Environmental Liver Disease Revolutionizing Innovative, Visionary Environmental Health Research Program (ELD-RIVER), a unique integrative and collaborative research program including collaborations with academia, government agencies, industry, and scientific/medical societies. Cave and award co-investigator Juliane Beier Arteel, Ph.D., are collaborating with UofL’s NIAAA Alcohol Research Center, Diabetes and Obesity Center, and researchers in cardiology, biochemistry, pharmacology and toxicology, as well as the Environmental Protection Agency.

More information about Cave’s grant is below: