By Betty Coffman
John Pierce Wise, professor in the UofL Department of Pharmacology and Toxicology, has studied the connection between exposure to metals and cancer for nearly three decades. He and his team investigate the cellular and molecular mechanisms of cancer and how exposure to metals affects humans and wildlife.
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.
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