In last week's issue of Critical Review of Toxicology, Edward Calabrese, Ph.D., lays out his understanding of the mechanisms at play in hormesis.* Hormesis is a dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition. Historically, dose-responses have been thought to occur in a linear fashion from low-dose to high. A non-linear response, such as the hormetic response, has potential application in most every scientific field. This paper offers the first wide-reaching documentation of mechanisms of hormetic dose/concentration responses. For the past 20 years, Calabrese has been at the center of much of the research on hormesis. He writes in the abstract:
Regardless of the model (i.e. in vitro or in vivo), inducing agent, endpoint, or receptor/cell signaling pathway mediated mechanism, the quantitative features of the hormetic dose/concentration responses are similar, suggesting that the magnitude of the response is a measure of biological plasticity, within a broad range of biological contexts. These findings represent an important advance in the understanding of the hormetic dose/concentration response, its generalizability and potential biomedical applications, including drugdiscovery/efficacy assessment and the risk assessment process.
I had the opportunity to hear Dr. Ed Calabrese's keynote lecture on hormesis at the 28th annual American Association of Naturopathic Physicians annual convention in Keystone, Colo. earlier this month. I sat alongside hundreds of naturopathic physicians from all over America, leaning in, to better grasp the meaning of his research and possible relevance to an extensive list of fields including biology, toxicology, the environment, pharmacology and medicine. His talk was riveting, funny and had broad sweeping implications and applications.
A professor of Toxicology at UMASS School of Public Health and Health Sciences, Calabrese has an impressive resume, including over 600 scholarly articles and more than 10 books. He was awarded the Marie Curie Prize in 2009 for his work on hormesis. In the past 20 years, Calabrese has conceived and carried out hundreds of experiments to test and re-confirm his findings. He continues to work with chemical toxins, radiation, drugs, hormones and other categories of molecules on cells, plants and animals. Regardless of the agent used or the organism exposed, the hormetic dose response is observed. A hands-on research scientist, his lecture was peppered with laboratory stories, compelling interactions with colleagues around the world and a delightful sprinkling of self-deprecation and humility.
I was inspired by Calabrese's commitment to the process of scientific inquiry and his tireless pursuit of truth. It is easy to think we have attained vast amounts of understanding about the natural world, but there is so much more to know. Researchers like Calabrese can inspire us to keep at it, to keep asking questions, to refine our understanding, to integrate feedback, and to look at problems from different angles -- in whatever fields we pursue. I am also inspired and encouraged by his personal story and his fortitude and resilience in the face of adversity. Hormesis has been a controversial and divisive topic. With novel ideas that go against much of the scientific mainstream, Calabrese has not always had a smooth ride. Regulators, scientists and those in the pharmaceutical and medical fields continue to debate the verity and relevance of hormesis. Calabrese receives overt criticism from within his chosen profession and the scientific community at large, yet he continues to secure funding and move forward. By asking precise questions and with decades of confirming laboratory results, he now has a body of work that illustrates and supports the idea of the hormetic dose response.
Dr. Calabrese's contextualized his work during his talk; his interest in dose-related response was first piqued as a biology undergraduate studying in a plant physiology class. While conducting an experiment using synthetic growth inhibitor on peppermint plants, it was observed that some plant growth was instead stimulated, the opposite of what was expected. His professor asked the 24 students in the class if anyone was interested in further investigating this unusual phenomenon and only Calabrese raised his hand. As it turned out, the group had made a dilutional error by a factor of 10, so in fact, with a very low dose of the growth inhibitor plants grew more than expected. At the higher doses of the growth inhibitor, indeed the plant growth was stunted, as predicted. His advisor urged Calabrese to do many more experiments to see if this observation was real and reproducible. And then his advisor wanted him to do experiments in a hydroponic setting, in case the soil was somehow contributing to the unusual effect. In experiment after experiment, the hormetic result was observed.
Other work in toxicology took up the first decades of Calabrese's career, but eventually he returned to the question of hormesis. I understand him to be a scientist in the true sense of the word: embracing inquiry-based research to help answer important questions. When a handful of studies was not enough, he did more. When colleagues claimed that "toxicology worships at the altar of mechanism," he went after mechanism, evidenced by this month's published paper. Keeping an open mind, being dispassionate about results, integrating feedback, remaining unbiased, all these help advance scientific discovery.
Calabrese's work, his passion, perseverance and high standards have garnered attention of colleagues, detractors, the chemical industry, the EPA and the experts in the worlds of pharmacology and medicine. Dr. Calabrese's ongoing work will impact environmental policy, understanding of biology, the pharmaceutical industry and medicine for years to come; hopefully other researchers and policy makers will take notice and help to further elucidate the relevance of the hormetic response.
*Calabrese, E.J. (2013). Hormetic Mechanisms. Critical Reviews in Toxicology 43(7):580-606.
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