Primary Sclerosing Cholangitis (PSC)

Welcome to the online home of the Chris M. Carlos and Catherine Nicole Jockisch Carlos Endowment for Primary Sclerosing Cholangitis (PSC). Thanks to support provided by this endowment, dedicated Mayo Clinic investigators and their teams are making strides to better understand and treat PSC patients, with the ultimate goal of developing a cure for this disease.

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Mon, Jan 14, 2019 8:05am

PSC Investigator Profile: Dr. Gary Miller

By Konstantinos N. Lazaridis, M.D., @klazaridis

2019-01-11 metabolomics

Mayo Clinic is at the forefront of research designed to uncover the environment’s role in PSC, thanks to a unique collaboration with Gary Miller, PhD, a toxicologist and Professor of Environmental Health Sciences and Vice Dean, Research Strategy and Innovation, at Columbia University.

Dr. Miller’s interest in figuring out how environmental chemicals affect neurodegeneration in Parkinson’s disease spurred him, and former colleagues at Emory University, to devise novel methods for measuring the exposome, a concept introduced in 2005. He’s since served as the founding director of the first exposome-based research center in the U.S., and penned the first book on the topic (The Exposome: A Primer). Since 2017, Dr. Miller has worked with Mayo Clinic’s Dr. Konstantinos Lazaridis to become the worldwide leader in understanding the environmental culprits contributing to PSC pathogenesis and outcomes.

For Mayo Clinic Connect, Dr. Miller explains what the exposome is and reveals the promise an improved understanding of it offers patients with PSC.

The exposome is a measure of all the external forces acting upon us

In biology, we think about the forces acting upon organisms and the nature vs. nurture paradigm. The nature part is primarily represented by genetics and understanding our genetic programming. We think about nurture as a combination of all the external forces acting upon us – dietary effects, the air we breathe, the water we drink, emotional or work-related stresses we have, radiation, sunlight – and the environment in this very large way is what the exposome is.

The role of genetics and environment in PSC

There’s so little information about how environmental factors affect PSC. The study that was recently funded by the National Institute of Diabetes and Digestive and Kidney Diseases is really going to give the first picture of how our complex environment plays a key part in PSC. Based on the genetic data that I’ve seen, the environmental part has to play a significant role. Is it dietary? Is it exposure to chemicals at work? I don’t know what it is yet, but we’re doing this study to learn.

Developing a comprehensive and unbiased way of measuring environmental exposures or non-genetic factors in disease

We have a very comprehensive way of doing genetic studies, but we’ve historically had a very biased way of looking at the environment. We tend to study chemicals that are in the news. We’re worried most about bisphenol A (BPA) plasticizers when there are many other things in our lives that have a much bigger influence. When you think about all the concern around plasticizers, I can tell you that cigarette smoke is causing more health problems than all of those plasticizers combined. If you only think about one compound at a time, we tend to make very cursory analyses and don’t get the whole picture.

The exposome is really about doing studies in an unbiased way. We don’t concern what the external forces are, we just want to see which ones are most associated with a disease outcome. When you use this unbiased approach, you also have the ability to find things that may promote a healthy outcome. The exposome is much more about looking at multiple exposures at the same time, looking at how nutrients and toxicants are adding in together so you have to look at them at the same time. That’s something that’s been very difficult to do and had remained totally conceptual until we developed the HERULES Exposome Research Center at Emory University. At that time, about five years ago, we weren’t ready to do exposome studies. We were building the infrastructure, building up the technology, putting a lot of effort into the informatics, really developing the tools that we would need to do the studies. 

Understanding the exposome offers promise for PSC patients

When Dr. Lazaridis contacted me, we were just at the point where we thought we had an approach to measure the exposome. We hadn’t published it yet, but we thought it was the way to go. The PSC project was the first test case that really had this highly integrated, comprehensive analysis of chemicals and responses in the body, it was and remains very exciting.

What I think is most promising for the PSC patients is that we can take a blood sample and see what a patient’s overall exposome looks like. It’s not necessarily only about what caused PSC in a patient, it’s about what we can do to improve the care and therapy of a patient with PSC. If a scientist or clinician has a drug or some intervention that might help treat PSC, it could take years to see a change in outcomes like liver failure. But with the exposomics techniques that we’re using, we can detect perturbations in patients’ biology. We’re trying to measure all these chemicals in the body, and it’s not just exogenous chemicals coming from outside; we also want to measure the endogenous chemistry, so we’re measuring external chemicals and the body’s response to them at the metabolic level. We can see the problem, so for example, if an intervention such as a change in diet restores or improves the normal function, we could measure that in weeks to months. The idea is that we can assess and measure the restoration of what’s happening in the body – a shift to a healthier state – before waiting for a long-term outcome.

If we were to find that altering someone’s diet improves his/her blood profile for substances that we think are bad for PSC, people could make changes right away. You get to make decisions about what you bring into your body; for example, you can change your diet, and a clinician can recommend you change your diet without FDA approval. Now I’m not saying we know there is something like that, but we can look for something that can provide a very quick intervention.

Or if we found 100 chemicals that were elevated in PSC patients’ blood, we could test whether any of those chemicals affect liver function using cell culture, animal models, or other systems. Rather than guessing, we would use that data to say we know these chemicals get elevated in patients, do they have bad outcomes. Also, it may be that chemical X is only bad if you have gene Y and this is a goal of our grant that the National Institute of Diabetes and Digestive and Kidney Diseases awarded to our team.

Mayo Clinic investigative team: going to great lengths for PSC patients

We need to bring comprehensive evaluation of the environment into medicine, and I think the exposome is the way to do it. It’s not about looking at one or two chemicals, it’s about looking at the exposome level and saying it’s not just chemicals from air pollution, it’s also the chemicals in the water, the pharmaceuticals we take, all of these different things. We need to find a way to allow clinicians to incorporate the environment into how they care for patients, and it’s not really there now, there’s not a way to do it.

I was very much struck by the group at Mayo reaching out to us; it was very illustrative of the innovation they bring to treatment. They’re looking for information wherever they can find it. They’re very open to new ideas, they’re so driven to learn more about conditions, and their willingness to look at a fairly untested concept is a testament to that dedication.

The future of exposome research

At Mayo Clinic, they do extraordinary work treating patients. As a scientist in a school of public health, my interest is how we can use this information to improve the public health. Monitoring people over time to show how their lifestyle changes are improving their internal chemistry is, I think, a much better, holistic way to monitor someone’s health or improve management of a disease. We’re looking at applying the exposome broadly to studies of cancer, cardiovascular disease, Alzheimer’s disease, and kidney conditions. From a public health standpoint, we’re trying to affect the lives of millions of people and modifying the environment to me is one of the most powerful ways of doing that.

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