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Fifty Years of Research - Randy L. Jirtle

12 November 2020: In the past 50 years, I have gone from the physical to the biological sciences, and from studying tumor vascularity and blood flow to determine the human imprintome. It has been an exciting journey!

I grew up in the beautiful town of Algoma, Wisconsin on the shore of Lake Michigan. In 1970, I graduated from the University of Wisconsin (UW) in Madison, WI with a B.S. in Nuclear Engineering (Randy Jirtle). During my junior year, however, I learned about the field of radiation biology from Kelly H. Clifton. He started the radiobiology division in the medical center at UW, and gave a series of lectures on the biological effects of ionizing radiation in a reactor design course that I was taking. Those lectures changed my life! I transitioned from nuclear engineering into biology, and Dr. Clifton became my advisor for graduate studies in Radiobiology.

I studied the effects of ionizing radiation on the vascularization and blood flow in tumors, and published my first research paper in 1971 (Jirtle and Clifton, 1971). As a UW postdoctoral fellow in the Department of Physiology, I developed the first technique to measure tumor blood flow in conscious animals (Jirtle et al, 1978).

After I joined the faculty at Duke University in 1977, I continued these tumor blood flow studies. Bill Kaelin was the first student to join my lab as a third-year medical student. He showed that the calcium antagonists verapamil and flunarizine significantly increased tumor blood flow, indicating their potential usefulness in improving cancer treatment with both chemotherapeutic agents and ionizing radiation. These were the last tumor vascularity studies performed in my lab; however, Dr. Kaelin continued his investigations in this field of research after he graduated from medical school. In 2019, he received the Nobel Prize in Physiology or Medicine for his discoveries of how cells sense and adapt to oxygen availability.

I became interested in determining the molecular mechanisms involved in the regulation of normal cell growth and the genesis of liver cancer. To facilitate such studies, I developed the first quantitative in vivo transplantation system for isolated hepatocytes (Jirtle et al, 1980). I used this system to investigate the phenomenon of liver regeneration and carcinogenesis (Jirtle and Michalopoulos, 1982), and the survival of hepatocytes exposed to ionizing radiation (Jirtle et al, 1981).

These investigations led to our lab's discovery that the IGF2R (Insulin-like Growth Factor 2 Receptor) is a human liver tumor suppressor gene (De Souza et al, 1995), and that mutation of this gene occurs early in the carcinogenic process (Yamada et al, 1997). Interestingly, this was the first imprinted tumor suppressor to be characterized since Denise Barlow had demonstrated that the Igf2r is expressed only from the maternal copy (Barlow et al, 1991).

Our lab further enhanced these carcinogenic studies by showing that the phenomenon of genomic imprinting evolved approximately 150 million years ago with the advent of placentation and viviparity in a common ancestor to Therian mammals (Killian et al, 2000, Killian et al, 2001A, Killian et al, 2001B, Nolan et al, 2001). These phylogenetic studies with the IGF2R gene also provided the first genetic sequence data that unambiguously supported the accuracy of the Theria hypothesis of mammalian evolution (Killian et al, 2001C).

Realizing that the imprinted IGF2R gene functions as a tumor suppressor, I then determined if epigenetic regulatory elements could be modified early in development by exposure to environmental factors, thereby altering disease susceptibility in adulthood. Using the agouti viable yellow (Avy) mouse, our lab was the first to demonstrate that maternal dietary supplementation during pregnancy with nutritional supplements (e.g., methyl donors and genistein) (Waterland and Jirtle, 2003), and exposure to toxicological (e.g., bisphenol A) (Dolinoy et al, 2007) and physical (e.g., ionizing radiation) (Bernal et al, 2013) changes coat color and adult disease incidence in Avy offspring by altering DNA methylation at the Agouti locus. These pioneering studies ushered in the era of Environmental Epigenomics - a research field that continues to grow exponentially (Jirtle, 2009).

Only 24 imprint control regions (ICRs) are currently known, but it is postulated that approximately 500 imprinted genes exist in the human genome. Thus, it is critical to determine the complete repertoire of human imprinted genes and their regulatory elements - the human imprintome (Jirtle, 2009, Skaar et al, 2012). Additionally, an imprintome custom DNA methylation chip needs to be developed in order to determine the role of genomic imprinting in the etiology of human diseases and neurological disorders in a systematic way.

Over the past fifty years, I have had the pleasure and honor to work with many highly intelligent and motivated university colleagues, students, and technical staff. Without their contributions, the discoveries made in my lab would not have been possible. I thank all of them for making this fifty-year research journey not only productive, but truly fun!