Dr. Loren Wold is a Professor in the Department of Physiology and Cell Biology at The Ohio State University College of Medicine. He is also the Assistant Dean for Biological Health Research in the OSU College of Nursing. Dr. Wold’s lab studies the effects of Alzheimer’s disease on cardiac function, the effects of e-cigarette usage on the cardiovascular system, and the cardiac effects of dust from the collapsed World Trade Center on first responders in a preclinical model. We were able to sit down with him to learn more about his research and get his thoughts on the current state and future of inhalation toxicology research.
My Ph.D. was in cardiovascular physiology, from the University of North Dakota in 2003, and then I did a postdoc at the University of Southern California/Good Samaritan Hospital. At that time, I was looking at the basic mechanisms of cardiomyocyte biology and different disease states.
Towards the middle of my postdoc we were looking at the effects of particulate matter on the heart, in particular ultrafine particulates. We used a crude ex vivo preparation to perfuse the rat hearts. That’s really where my interest in inhalation toxicology started.
Leaving my postdoc, I stepped back from the inhalation world and was working more on diabetic cardiomyopathy. Once I obtained my first independent position at Columbus Children’s Research Institute (now the Abigail Wexner Research Institute at Nationwide Children’s Hospital), here at Ohio State University in 2007, I got back into the inhalation and toxicology world, looking at more of the effects of fine particulates on the heart and lungs in an in vivo exposure system.
My main interest right now is looking at environmental triggers of cardiovascular disease. We’re actively looking at particulate matter and fine particulate exposures and using various animal models. Currently, we’re looking at Alzheimer’s disease and how that is potentially affected by particulate exposure. We are also looking at e-cigarette vapour exposure in adult mice, adolescents, and Alzheimer’s models. We are also interested in intergenerational effects and the effects of in utero, pre-natal or preconception exposure to particulates and e-cigarette vapour.
Yes, so we’re looking at the epigenetics of the gametes in the pre-conception models. We’re looking to see if exposure can carry along effects to the offspring in the F2 and F3 generations, etc. Were mostly looking at the epigenetics of the gametes but also some cardiovascular epigenetics; even though that’s not my expertise, we are collaborating with the smart people who know how to do that.
I think what’s interesting, and it really was reinforced recently with the pandemic that we’re going through, is that there’s so many things that are connected to environmental exposures. We now know that living in a heavily polluted environment or exposing your body to high concentrations of toxicants can have a long-lasting effect and in multiple organ systems. We’re sort of focused on the heart but what I find intriguing is it’s not only isolated to that person who’s either smoking, or using a vape product, or living in a heavily polluted area, but that can change their genetic makeup to cause them to have offspring and future generations that could show effects from the exposure of the parents.
Linking now to the pandemic that we’re going through, we know that there is a pretty strong link to environmental exposures. There is a beautiful paper in the New England Journal of Medicine looking at air pollution and the greater incidence of acquiring and having worse outcomes of Covid-19, so we’re seeing that these environmental exposures can exacerbate other pre-existing medical conditions.
Obviously, the general landscape being environmental exposures, is not a large field, it’s predominantly toxicologists looking at very basic mechanisms of isolated exposure paradigms. We’re interested in heterogeneous particulate exposure but some groups will look at exposures of one heavy metal, for example, in isolation, so I think that the landscape is pretty vast because there’s a whole range of people looking at various things. We sort of come to the middle where we’re interested in the real-world exposure paradigm. As an example, with the E-cigarette vapor exposure we know there’s lots of things in the E-cig vape but we’re mostly interested in the organ system effects following real world exposure.
This was really reinforced recently after receiving a large American Heart Association grant, we have a clinical study that colleagues are running looking at adolescent vapers. They’re actually able to identify all of the characteristics of the vape – basically the person vapes and they’re able to tell concentration, time, dose, wattage… everything from each individual puff and we’re then taking that and translating that to a mouse exposure. Using computational modeling we’re able to do animal exposures that are truly translational, looking at basic mechanisms and designing therapies based on the true usage in the human population.
We’re trying to set it up so that we are asking the right questions and using the right model to identify the mechanisms of exposure and the effects on the heart. I think frequently the exposures are all over the map, no one’s using the same concentrations and there is no standardization, so in order to answer these questions we have to be able to come back to the middle and be asking the right questions and using the right model.
I think translatability and reproducibility are huge and the key strength of the equipment. We looked for a while for a commercially available, scalable product. Before that everything was homemade and we were having to construct the particulate exposure system, basically using parts purchased at Lowe’s, so now having a commercially available system that can standardize and control the exposures in a real-world, non-stressful environment for the animals…we’re not restraining, we’re not intubating, we’re allowing animals to basically be relaxed and breathe vape or concentrated particulates. I especially like the commercial aspect of being able to scale up easily and quickly, but also to have that sort of QC approved equipment because it was very difficult to describe in a paper how you were doing the exposures using the homemade system.
Right now we’re strictly using mice. We have several different transgenic lines, we’re using adult as well as adolescents and we’re using pregnant dams. So, at this time we’re exposing over 200 animals per day (when we’re allowed to be in the lab!).
I wouldn’t say challenges per se, but obviously making sure that our preclinical exposure paradigms are truly driven by real-world exposures is the biggest “challenge” we face on a daily basis.
I think the biggest satisfaction I’ve had is the mentoring of students. The way I run my lab is that every student has their own project, and not having a hierarchy, so the postdoc is treated the same as an undergrad. When they get that first paper, with their name on it, that is still is the most exciting part of my career. I’ve been very lucky getting funding, of course I continue to worry about this all of the time, but not having as much worry there I can focus now on helping junior faculty with their grants.
As far as the research, what I really enjoy is working in an area that has major public health implications. My sister is a fourth-grade teacher and she catches kids with vape products, so really getting that knowledge out regarding our studies is important to me.
I think the biggest advice, and this has been passed down to me from my mentors, is that you’re the expert in your area. The key is being able to sell why what you’re doing is important and impactful.
If you think what you’re doing is exciting and state of the art, stick with it, because I’ve had grants that were killed and I turned them around and submit to a different study section and they would score well. It’s knowing and having that sort of understanding that what you’re doing is exciting and impactful; staying the course. I went for multiple years where every grant was getting killed and I was just persistent and probably wore down the reviewers enough where they said “let’s just fund him so he doesn’t come back”.
Always following the data is the other thing, some of the most exciting things of my career have come from negative data. I think a lot of people are very nervous about that. They have pressure to publish pressure, to get grants, but the data will never distract you from the path that you need to be on, so follow the data where it takes you and you can never go wrong.
I think the last part that’s been drilled into me since being a kid: always do the right thing. It’s very easy to say “well that’s an outlier and let’s get rid of that piece of data”, but always focus on the data and do the right thing.
If I only had a crystal ball! I think moving forward the focus is going to be the vaping grant, to look at the translatability of what we’re seeing with the clinical trial and also looking at therapeutics. Pushing for policy change is a big movement, I think we’re never going to be able to totally get rid of tobacco and e-cigarette products, I think they’re always going to be there, so it’s a matter of just getting the information out about the harms of these products. I would love to say I want to work myself out of a job.
