https://orcid.org/0000-0003-4299-2290
The Radiation Biology community lost a stalwart citizen when John Moulder died last year. But John’s impact remains with us and will last even longer in his published work. This special issue emphasizes that legacy because it features some of John’s colleagues and also builds on the groundbreaking foundations of his career. We, the editors of this issue, greatly appreciate the contributions published herein and know that the reader will too.
Commentary
John’s longtime office manager Yvonne Morauski worked with him from 1981 until John’s retirement. She writes that
We remained friends and stayed in touch after he moved and started his new life in Minneapolis, where he volunteered at the community theater, taught Somali refugees to ride bikes, and dog sledded. John was a man of integrity, a mentor par excellence, and a teacher who was a joy to work with. He was athletic, kind, sensitive, strong, and respectful, and he could be quite silly at times. But he never compromised his research. John didn’t dwell on his successes but used them to solve the next big problem. He gave all that he could right up to the end. It was an honor and a pleasure to have worked with John.
Reviews
The Radiation and Nuclear Countermeasures team (DiCarlo, et al) outlines John’s legacy from a unique perspective, centering on the impact of the National Institutes of Health (NIH) funding that he obtained for his research laboratory. The manuscript focused on his myriad of contributions to the field of radiation biology, as well as the many collaborators and students who were fortunate to have worked with and been mentored by him over his long and distinguished scientific career. The article also showed the diversity of John’s expertise, highlighting not only his NIH successes in studying mitigation of normal tissue injuries in both radiation oncology and emergency medical preparedness, but also calling attention to his seminal studies of non-ionizing radiation exposure and his dedication to training and education of the next generation of radiation scientists.
Kenchegowda et al review severity scoring systems for radiation-induced gastrointestinal (GI) injury including the use of the biomarker of blood citrulline levels based on the use of various animal radiation exposure scenarios (i.e. total body-, total abdominal-radiation, etc.), radiation therapy, and radiation accidents. A worksheet tool was developed to provide a triage diagnostic approach to assist first-responders to assess individuals suspected of showing GI-acute radiation syndrome (ARS) to guide the development of early-phase medical management of radiological casualties.
Kerns et al review radiation-induced bladder injury including recent data from their bedside-to-bench approach that combined investigators in radiation biology, epidemiology, and population genetics. The collaborative team of Sarah Kerns, Brian Marples and Jacqueline Williams emphasized how their work was reflective of John Moulder’s successful approach, being interdisciplinary and an adroit mix of bench and bedside investigation. This paper demonstrated that radiation-induced normal tissue injury was reduced by the use of angiotensin converting enzyme (ACE) inhibitors, and now adds the bladder to the list of tissues that can be mitigated by ACE inhibitors after radiotherapy, with supporting evidence from preclinical and clinical studies in prostate cancer patients treated with standard of care radiotherapy.
Kiang and Blakely report and review the growing number of studies of combined radiation injury and how these affect development and efficacy of radiation countermeasures. This requires attention for the pre-clinical development of radiation countermeasures since there are no FDA-approved drugs available for treating combined radiation injury. Injury biomarkers are apt to be influenced by both radiation and the added injury of burns or trauma, which may result in an over-estimated radiation dose due to the synergistic effect between radiation and added injury of burn or trauma and affect the decision made during the course of triage. Blood radiation biomarkers that predict radiation doses in combined injury are presented.
Vijayalaxmi and Foster contribute a valuable synthesis of studies that address the genotoxic potential of radiofrequency electromagnetic fields (RF-EMF). John’s interest in this non-ionizing part of the electromagnetic spectrum led him to establish a very successful and popular on-line frequently asked questions (FAQ) website on this topic, in which he carefully distilled the evidence for and against such injury. In their present paper, they point out that the higher quality studies of the effects of RF-EMF were less likely to find significant damaging effects than were lower quality studies. Further, they emphasize John’s rigorous scientific approach to this topic.
MacVittie reviews the current status and progress of radiation injury models and the challenges of the FDA Animal Rule (AR) with regard to development and approval of medical countermeasures (MCM). He emphasizes the relevance of the small animal model(s) in support of the non-human primate (NHP) model to establish a critical path for MCM development in adherence to criteria of the FDA AR. The variables relative to the radiation nuclear scenario are significant and include the quality, dose, dose rate and exposure geometry inherent to the nature of the radiation from prompt and fallout exposures. It is likely that pivotal efficacy studies of any MCM against the lethal ARS and DEARE, organ-specific injury, should be performed using NHP.
Prasanna et al. review the literature on the roles of miRNA and therapy-induced senescence (TIS) in the pathogenesis of radiation-induced pulmonary fibrosis (RIPF). They link both to John’s work that showed the benefits of antagonists of the renin-angiotensin system to mitigate radiation-pneumonitis and RIPF. Understanding the TIS as a mechanism of RIPF regulated through miRNA may help develop and translate next-generation miRNA therapeutics and repurpose approved pharmaceutical agents.
Wu et al review the investigation and development of countermeasures for delayed effects of acute radiation exposure (DEARE), a theme that John Moulder pioneered. They emphasize that while there are approved countermeasures for acute radiation syndrome (ARS), none are approved for DEARE in any organ. Their development will be useful for mitigating late effects after clinical radiotherapy.
Original articles
Beach et al report their establishment of a rat model for ARS and DEARE. Hitherto, the bulk of data for ARS and DEARE in a rat model have been in John’s WAG/RijCmcr rat strain. Using more than one strain is vital for verifying mitigator efficacy. This report confirms a threshold of 8 Gy single fraction irradiation for the development of DEARE in Wistar rats, particularly for lung and kidney. It has the additional merit of consistency in the timing of irradiation. Thus, commercially available Wistar rats are suitable for studies of mechanisms and mediators of DEARE.
Bergom and colleagues report their studies of radiation-induced cardiotoxicity, in which they emphasize the male vs female differences in SS Dahl rats, with females showing greater reductions in cardiac function, which in part was attributed to concurrent lung injury. This work can clearly provide a basis upon which to explore mediators of injury and also help develop suitable mitigators. Cardiac toxicity was not a specific focus of John’s work, but he was interested in normal tissue injuries, especially delayed injuries of any kind.
Cheema et al use the well-established Moulder WAG/RijCmcr model to establish the metabolomic profile in its 13 Gy leg-out (partial body irradiation) version and to show that mitigation with recombinant activated protein C can alleviate metabolic dysregulation caused by ionizing radiation exposure. These studies can form the foundation for ones at lower radiation doses that would be applicable to survivable human exposures.
Fish et al use their well-established WAG/RijCmcr model to show that a novel and orally administered compound mitigates both lung and kidney DEARE. IPW-5371 appears to antagonize the profibrotic effects of TGF-beta signaling, which provides additional support for TGF-beta as a mechanism for DEARE. In addition, IPW-5371 is an effective mitigator when given starting 15 days after irradiation, which is a substantial advantage for its possible future use as a MCM in humans.
Gasperetti et al from the Himburg lab report the use of the WAG/RijCmcr rat model to show both the mitigation of ARS by peg-GCSF and that this reveals that rat survivors of lethal H-ARS are indeed at greater risk for progressive renal failure. The threshold TBI dose for significant late DEARE in this model appeared to be 8 Gy, which is consistent with data in non-human primates. The WAG/RijCmcr is thus a suitable model for testing medical countermeasures against kidney-related DEARE.
Personal statements
Dr. Christopher Schultz, Chairman of Radiation Oncology MCW,
It was my good fortune to know and work with John Moulder for nearly 30 years. I first met John in 1983 when I was a second-year medical student at the Medical College of Wisconsin (MCW). John delivered a series of lectures on Radiobiology that were fascinating and ultimately inspiring. What I remember about John’s lectures was his command of the material and clear delivery that changed forever my awareness of radiobiology and its relevance to medicine and public health in general. As a trainee at Columbia Presbyterian that included time in Eric Hall and Charles Geard’s lab, I gained greater insight regarding John’s many contributions to the understanding of electromagnetic field exposure and the mitigation of radiation induced normal tissue injury. Little did I know that our paths would cross again or that I would spend time in his lab and subsequently be his colleague and eventual Department Chief. Over our nearly three decades together at MCW, I gained an even deeper understanding and appreciation of John’s keen intellect, wit, and his generous collaborative spirit. Most importantly I developed a great respect for John’s remarkable contributions across all missions of MCW and more broadly, the field of Radiobiology and Radiation Oncology that remain relevant today.
Dr. Colleen Lawton,
I knew and worked with John Moulder starting as a junior faculty member of MCW in the late 1980s. At that time, we were noticing some late renal toxicity in our bone marrow transplant survivors and wondered if and how radiation might have played a role in this problem? John and I had many conversations about this issue, which prompted both our initiating and reporting on renal shielding for these patients. The renal shielding proved successful, but John pushed me to try to better understand the mechanism of the radiation renal injury and possible ways to mitigate it. His insights prompted me to apply and subsequently receive an American Cancer Society (ACS) Career Development Award. John’s lab did the laboratory work for this award, and I did the clinical piece. All of this resulted in almost eliminating this problem for our post-transplant patients. I continued to work with John over the ensuing decades both clinically and as the program director for our radiation oncology medical residency program. His leadership in teaching radiobiology to our residents was exemplary. Many programs struggle to get their radiation biologist engaged in this work but not us. John took the lead and did an excellent job. John’s practical way of explaining complicated radiation biology concepts was pivotal in our residents education for over a three decades. His reach in both the lab side of radiation oncology and the clinic was unmatched. What an honor to know and learn from such an inspiring leader.
Dr. Stephen Brown,
The news of John’s sudden passing came with shock and a heavy heart. John lived life to the fullest; his days were filled with vigor and good cheer. He will be remembered in the field for his rigorous scientific contributions to radiation biology. His seminal works on the pharmacological mitigation of normal tissue damage following a radiation exposure including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers which strongly influence the field today. His comprehensive studies on the hypoxic fraction of solid tumors remain standards of the field decades later. His knowledge of the lack of bioeffects of radiofrequency radiation elevated his stature to that of a legal expert. He will be remembered outside of his contributions to science as an avid biker, for his love of fine food and wine but mostly as a generous mentor and dear friend.
Dr. John Baker,
John was responsible for my entry into the field of radiation biology. John was developing strategies to decrease early mortalities after whole body exposure to radiation as part of his first U19 award. This prompted us to look to the horizon and ask, if long term survival was possible, what would be the delayed effect of radiation on the heart? With our ideas in a conceptual stage of development, John encouraged me to apply for a pilot award as part his U19 grant. With his guidance, we successfully obtained funding and utilized his model of whole-body exposure to radiation in the rat to characterize late injury to the heart. Whole body irradiation with 10 Gy, a dose relevant to a radiological terrorist threat, in conjunction with bone marrow transplantation to extend survival, worsened the lipid profile, injured coronary microvasculature, altered endothelial physiology, and disrupted myocardial mechanics. These late occurring changes were not manifest following local thorax irradiation. This interesting finding led to subsequent collaborations that showed targeted irradiation of the kidneys caused disease in the non-targeted heart, with the effect mediated by the immune system. We then showed the potential for intestinal microbiota to provide a non-invasive diagnostic tool to rapidly identify prior exposure to ionizing radiation. Inspired by this line of research, our laboratory made a mechanistic connection between intestinal microbiota and the severity of injury from an induced myocardial infarction in rats. This basic science discovery led to a successful clinical trial showing a specific probiotic improves vascular endothelial function and reduces inflammatory biomarkers in men with stable coronary artery disease. Grants have been forthcoming from the NIH and NASA, and our laboratory continues to investigate the fascinating impact of radiation on living systems. None of these achievements would have been possible without John. l miss John’s enthusiasm, insight, support, and energy. His memory and his work live on.
Dr. Marek Lenarczyk,
In 2006 Prof. John Moulder offered me the chance to work with him after supporting me as a fellow under U.S. Government funded Center for Medical Countermeasures Against Radiological Terrorism at Medical College of Wisconsin (MCW). John was a very friendly mentor, giving excellent guidance. I greatly appreciate that he was a senior colleague in professional and private life as well. I am very grateful for John and those years, I used to work with him. John influenced and convinced me to stay at MCW and continue my work in the radiation research field. Following John’s advice, I started to investigate cardiac injury that occurs in a rat model after TBI and then successfully mitigated those effects by simvastatin. This research was supported by the pilot project, the one out of many John generously awarded to others.
Meetha Medhora comments that John’s pioneering efforts to mitigate radiation injuries address the looming threat of nuclear war, a major challenge of our time. His efforts are clear and amplified in the contributions to this special issue. These are a tribute to John’s knowledge, mentorship, and vision of the future of radiation research. No longer are the late effects of radiation exposure inevitable and irreversible. The work that was initiated or supported by him has inspired and created many new facets of normal tissue radiation biology
Brian Fish adds in closing that John pioneered the mitigation of the delayed effects of radiation exposure. He changed the world.
Additional information
Funding
Notes on contributors
Eric P. Cohen
Eric P. Cohen is a Nephrologist and Radiation Biologist who has had the good fortune to work with John and Brian starting in 1990. He is currently developing a method for non-invasive quantification of radiation-induced fibrosis.
Brian L. Fish
Brian L. Fish is a Radiation Biologist recruited by John to supervise his lab in 1981. He worked for John until he retired. Introduced to Eric Cohen in 1990 and Meetha Medhora in 2004, together with John, he developed the WAG/RijCmcr rat model for the testing of medical counter measures for radiation injuries. This work continues till today.
Meetha Medhora
Meetha Medhora is a Molecular Biologist who is trained in pulmonary physiology by Elizabeth Jacobs and in radiation biology by John Moulder and Brian Fish at MCW. Her recent research focuses on mitigation and biomarkers of radiation injury to the lungs and heart.