Caroline H. Johnson, Ph.D., an assistant professor in the Department of Environmental Health Sciences, joined the Yale School of Public Health in the summer of 2016. Her research uses mass spectrometry-based metabolomics to understand the role of metabolites (small molecules produced during metabolism) in human health. She is investigating the relationship between genetic and environmental influences in colon cancer as well as the effects of early-life exposures to certain toxins on health outcomes in later life. While still an emerging technology, metabolomics has the potential to elucidate the complex processes that influence the onset of many potentially deadly diseases. Johnson’s appointment allows the School of Public Health to harness this powerful and important tool as the school seeks solutions to the challenging public health problems of the 21st century.
You are investigating the relationship between genetic and environmental influences on colon cancer using metabolomics. This is a relatively new field. Can you explain what metabolomics is?
CJ: Metabolomics is the analysis of the pool of small molecules that are present in biological fluids, cells and tissues. The analytical techniques used in metabolomics (generally NMR spectroscopy or mass spectrometry) can reveal metabolites that are products of downstream genetic and enzymatic actions, as well as those that are environmentally derived. As the metabolome is inherently sensitive to subtle alterations in biological pathways, it can provide insight into biomarker discovery and the mechanisms that underlie various physiological conditions within disease states/progression and drug modes of action.
How and when was metabolomics developed as a field of research?
CJ: Metabolomics is deemed the small sibling of genomics and proteomics, but it is equally important. S.G. Oliver first coined the name metabolomics in 1998, but the concept of quantitative metabolic profiling came about in the 1970s. Since then, developments in mass spectrometry, NMR and bioinformatics have allowed metabolomics to become a powerful and essential research tool. It’s exciting to see so many labs and multidisciplinary teams adopting this technology.
How is metabolomics being used to advance our understanding of disease diagnosis and treatment?
CJ: It has been used in many disciplines to further the study of human disease and to help design targeted treatments. That’s because metabolites are at the heart of biological regulation and can provide novel mechanistic data. Most importantly, it is possible to determine both environmental and genetic influences on the disease or therapeutic response. I recently worked with a pharmaceutical company to understand how combination therapies work in comparison to single doses of the drugs. We showed it was a comprehensive effect on a multitude of metabolic pathways. This helped us to understand why patients have improved outcomes on these combination therapeutics.
How are you using metabolomics in your colon cancer research?
CJ: My interests are to determine the genetic and environmental factors that influence therapeutic response. Right-sided colon cancer patients have a higher mortality rate than left-sided patients, even when targeted therapeutics are used, but the reasons for this difference are not known. I am using metabolomics to understand how microbial metabolites that are produced in the right side of the colon effect cancer growth and therapeutic response.
What drew you to this field?
CJ: My interest in metabolism began in the late 1990s when I was as an undergraduate; the complexity of metabolic pathways fascinated me. While I was studying for my Ph.D. in analytical chemistry, I learned about the emerging field of metabolomics. To me, it was the perfect marriage of analytical chemistry and metabolism, and I decided this was the field I wanted to pursue.
What are biofilms and what role do they play in colon cancer development?
CJ: Biofilms are aggregations of microbial communities that are encased in a polymeric matrix. In colon cancer, biofilms invade the mucus layer and come into direct contact with host mucosal epithelial cells. The discovery of biofilms in colon cancer is very recent and is hypothesized to be pro-carcinogenic. Interestingly, in our study, biofilms were predominately located on right-sided colon tissues (proximal to the hepatic flexure). About 15% of individuals without colon cancer have thin biofilms, but they are not location specific, so it is only in colon cancer that they reside on the right side.
I believe that metabolomics will be fully incorporated into most areas of scientific research.
Caroline Johnson
The role of biofilms in colon cancer metabolism has been suggested but not evaluated. How are you using metabolomics to begin this evaluation process?
CJ: Using metabolomics, we observed that biofilm-associated colon cancers were correlated with increased polyamine and fatty-acid metabolism. This indicated that biofilms increase cell growth and inflammation, which was confirmed by immunohistochemistry. Upon removal of the biofilms, we saw that polyamine metabolites were reduced. Our hypothesis is that bacteria on the right side of the colon use host metabolites to build biofilms, and that biofilms propagate the cancers, causing a vicious cycle of cancer growth. It is also possible that polyamine transporters are upregulated, resulting in increased nitric oxide production, affecting both biofilm and cancer formation.
What, potentially, is the future of metabolomics, say, a decade from now?
CJ: I believe that metabolomics will be fully incorporated into most areas of scientific research. Its ability to show the origin, roles, and interactions of metabolites in any system makes it one of the only tools that can provide a holistic view of both environmental exposures and host genetics. This integration will be aided by the growth of bioinformatics, including in silico approaches for metabolite identification and multi-omic tools for metabolic pathway and network interpretation. User-friendly software, such as MetaboAnalyst and XCMSOnline, has made metabolomics more accessible to researchers wanting to move into this field. There is also the hope that metabolic biomarkers can reach the clinic for screening, just like those that are currently used for inborn errors of metabolism. However, this is an area that still needs major improvement to provide stringent controls and validation.
What other diseases are being researched with metabolomics?
CJ: Too many to mention! Metabolomics is suitable for the study of most aberrant systems, and it can also be used to further the understanding of normal biological processes, such as the effects of exercise and aging. In addition to colon cancer, my lab will be using mass spectrometry and metabolomics to understand the effects of environmental exposures on human health, particularly in adverse pregnancy outcomes.
You came to the Yale School of Public Health this summer. Where did you work before coming to the Yale School of Public Health?
CJ: I worked in Dr. Gary Siuzdak’s laboratory at The Scripps Research Institute in California. Dr. Siuzdak pioneered many of the analytical and bioinformatic tools that are commonly used by metabolomic researchers today, including XCMS software, and the METLIN metabolite database. While I was there I got involved with developing these tools and applying them to exposure and cancer research.
What are some of your interests outside of scientific research?
CJ: Exploring the local area; I particularly enjoy hiking in Sleeping Giant State Park and frequenting the superb restaurants in New Haven, including Mezcal and August.
To learn more about Dr. Johnson’s work with metabolomics, visit her faculty page at http://publichealth.yale.edu/people/caroline_johnson.profile.