International Journal of Radiation Biology, May 2015; 91(5): 459–461 © 2015 Informa UK, Ltd. ISSN 0955-3002 print / ISSN 1362-3095 online DOI: 10.3109/09553002.2015.1040202
OBITUARY
Dr. H. Rodney Withers (1932 – 2015) of the time Rod was there and died just before he completed his Ph.D. thesis. However, Rod benefitted from Dr. Gray’s vision of radiobiology as a fusion of physical, chemical, and biologic sciences and the fact that the Gray laboratory was a melting pot with scientists with different backgrounds coming from all over the world. It was an exciting time for radiobiology research in London with many emerging discoveries, such as that the cell division cycle could be divided into phases based around the period of DNA synthesis, the role of oxygen and hypoxia in cancer radiotherapy, pulse radiolysis, radiation sensitizers, quantitation of in vivo tumor survival curves, and high LET radiation effects. Interactions with physicists in particular must have shaped Rod’s thinking as he incorporated quantitation into practically every aspect of his radiobiological ideas. Hal Gray suggested that Rod work on “The Response of Normal Tissues to Radiation”. Till and McCulloch had just published the response of bone marrow stem cells to radiation and Harold Hewitt the first in vivo survival curve for tumors. For his thesis Rod developed a revolutionary assay for measuring, in situ, the survival of clonogenic cells of mouse skin after irradiation. In this assay, a doughnutshaped piece of mouse skin was first irradiated with a high dose to form a “moat” using ball bearings of various sizes to create a central shielded area that was then irradiated with graded test doses of radiation. The number of epithelial colonies regenerated from surviving clonogenic cells was counted per unit area. Rod’s thesis is a masterpiece of clear, logical thought with an emphasis on quantitation. Survival was measured over 7 logs and he was able to deduce that moist desquamation occurred if cell survival decreased to 106 per cm2. By splitting the dose and varying the time between the split doses, he established the radiation recovery characteristics of the skin stem cells and the kinetics of repair, reassortment, and repopulation in epithelial tissue; three of his (later to be famous) 4 R’s of radiobiology relevant to fractionated radiotherapy. He visited Mortimer (Mort) Elkind at the National Cancer Institute in Bethesda, Maryland, on his way back to Australia and, after a brief period, took up a Visiting Resident Scientist position in 1966. They became lifelong friends until Mort died of, ironically, a variant of Parkinson’s disease in 2000. Together, Mort and Rod developed the in situ mouse jejunal crypt stem cell assay, initially with “macrocolonies” counted visually and later “microcolonies” counted in histology sections, and confirmed that the DNA repair processes occur in vivo. By counting the number of surviving clones, recovery statistics could again be derived. These assays have been used to derive the most rigorous statistics on which much
Dr. Rodney Withers (“Rod”) died in Houston, TX, on 25 February 2015 at the age of 82 after a long struggle with a variant of Parkinson’s disease. He was a strong supporter of the Radiation Research Society (RRS) and was its 31st President (1982–1983). He gave the 25th Failla Award lecture in 1988, a presentation full of typically amusing thoughts and sharp observations. He entitled it “Contrarian Radiobiology’s Contribution to Radiotherapy”, espousing the idea that a contrarian view of current concepts in radiobiology was warranted before rather than after they undergo revision. Rod was an unassuming intellectual giant who shaped the discipline of radiobiology while retaining a warm, amusing, kind and helpful personality that is greatly missed. Rod was born in Stanthorpe, Australia and educated at the Church of England Grammar School, Brisbane, and the University of Queensland (M.B., B.S., 1956). He did his internship at the Royal Brisbane Hospital in 1957, and completed his residency in radiotherapy and pathology at the Queensland Radium Institute and the Royal Brisbane Hospital in 1963. He then travelled to London and entered graduate school as a University of Queensland Gaggin Fellow. His career as a clinician-scientist started when he worked at the Gray Laboratory at the Mt. Vernon Hospital in Middlesex from 1963–1965. The Gray Lab opened in 1957 under the direction of the physicist Louis Harold (“Hal”) Gray, who is often called the father of radiobiology. Rod became Dr. Gray’s first (and last) Ph.D. student. Unfortunately, Dr. Gray was ill for much 459
460
Obituary
of quantitative radiobiology is based and the concepts that they illustrate form the framework for clinical thought processes in radiotherapy. In 1996, Rod and Mort received the Enrico Fermi Award, a Presidential award that is one of the oldest and most prestigious science and technology honors bestowed by the U.S. Government. Except for a period as Professor and Director of the Institute of Oncology at the Prince of Wales Hospital/University of NSW from 1989 to 1991, Rod remained in the U.S.A. for the duration of his professional life. He was recruited by Herman Suit to the Department of Experimental Radiotherapy at the MD Anderson Cancer Center in 1968 and he became Chief of Section there in 1971. During this time, he worked with many members of the staff, but most notably Kathy Mason, to expand his studies to other normal tissues. As always, his focus was on quantitation and clinically relevant fractionation schedules. This led to a highly productive collaboration with the mathematician Howard Thames. They found that different normal tissues and tumors responded differently to changes in fraction size, which led to the establishment of the ratio α/β, from the LQ model, as a parameter to quantitate sensitivity to changes in fraction size. By plotting total dose, to achieve various isoeffects in different tissues, against size of the dose per fraction, they observed that acute reactions in normal tissues changed less than late reactions in response to increasing size of dose per fraction – in other words, late sequelae could be minimized relative to acute reactions by modifying dose fractionation. This observation had several consequences. The Nominal Standard Dose (NSD) equation had been introduced in the 1960s as the first widely used means of determining the effect on normal tissue tolerance of changing treatment schedules. It was based on the number of fractions and the overall treatment time. It was supplanted by the LQ model when it became clear that fraction size, not number, was the critical determinant of tissue responses and that fractionation dependence was tissue-specific. Another consequence was that if such differences existed between late responding normal tissues and tumors, an improvement in the therapeutic ratio should be obtainable by the use of doses per fraction less than the conventional 2 Gy, if given more than once per day (hyperfractionation). This prediction was subsequently tested in a number of phase III clinical trials, and hyperfractionation proved superior to conventional fractionation in the treatment of head and neck tumors. For “developing the concept of ‘hyperfractionation’ in radiation therapy”, Rod received the Charles F. Kettering Prize of the General Motors Cancer Foundation in 1998. At a very practical level, Rod was able to emphasize to clinical radiotherapists the “double trouble” that can result from hot spots in the treatment field where high physical doses are amplified by the inability of late responding tissues to cope with large fraction sizes. In 1980, Rod joined the Department of Radiation Oncology at UCLA, and became departmental Chair from 1995–2004 before becoming emeritus in 2008. His passion for quantitation continued as he engaged Jeremy Taylor and they worked together with Boguslaw Maciejewski from Gliwice, Poland, in modeling the hazards of accelerated
tumor clonogen repopulation during radiation therapy. Findings from these studies were that, after a lag phase, tumor repopulation could negate a third of the dose that is given in conventional treatment, justifying strategies aimed at accelerating treatment, defined as delivery of treatment more rapidly than with standard fractionation, but without resorting to increasing the size of dose per fraction. One such strategy was the concomitant boost technique championed by his close friend and colleague Lester Peters, which was subsequently shown to be superior to conventional treatment in the RTOG 9003 trial. At the practical level, these translational studies affected clinical thought processes in warning of the dangers of treatment breaks and protracted treatment time. Rod’s penchant for quantification in radiobiology also led him to examine the response of micrometastatic disease to chemotherapy in addition to radiation treatment. Building on earlier studies conducted with long-term collaborators Luka Milas and Bill McBride, he, Steve Lee, and Rafi Suwinsky at UCLA demonstrated how the tumor control probability curves for micrometastases differed from those for established tumors and how chemotherapy regimens in clinical use could be equated to radiation doses required for cure by radiation therapy. In many ways, Rod was the face of radiobiology in the clinic. He gave clinical radiation therapy rational guidelines for making treatment choices that were easily understood and highly accessible. The 4R’s of Radiotherapy summarized the key mechanisms governing tumor and tissue responses to fractionated schedules and give reasons to fractionate dose. They sum up his legacy for radiotherapy. Allowing Repair of sublethal/potentially lethal damage helps to spare late responding normal tissues. Reassortment of surviving cells within the division cycle allows resensitization of rapidly proliferating cells. Reoxygenation of hypoxic cells during fractionated treatment makes tumors more radiosensitive. Repopulation of surviving clonogenic cells during a course of treatment is a hazard to be minimized in the case of tumors and allowed for acute responding normal tissues. A fifth R (Radiosensitivity of clonogenic (*cancer stem”) cells) has since been added. There are few who have left a greater legacy to cancer treatment. The enormous respect that he garnered from his peers is recorded in the over 30 national and international award lectures that he presented over the span of his career and he received at least 12 Gold Medals. Apart from his service on many RRS committees and on the RRS Council, he served nationally and internationally on too many committees and in too many roles to mention. In 1998, he was awarded the Order of Australia by the Governor-General. Rod was a translational researcher who recognized the importance of stem cells and who addressed questions about biological systems that were relevant to clinical practice. Yet he was modest and self-effacing and helped numerous people with their personal problems, professionally as a clinician and with career guidance. He learnt from his time at the Gray lab to surround himself with people of diverse interests whom he encouraged to address
Obituary radiobiological problems. Everyone will remember him for his gentle charm and wonderful sense of humor. His blue eyes would twinkle most of the time but the twinkle would increase in intensity when he was about to tell a joke. He will be remembered warmly by his legion of loyal friends worldwide and most especially by his wife Janet, daughter Genevieve and granddaughters Sarah, and Emma. His monumental contributions to radiation research and to the translation of biological principles to clinical practice will continue to benefit cancer patients now and in the future.
461
W.H. McBride The University of Texas MD Anderson K.A. Mason The University of Texas MD Anderson L.J. Peters Peter MacCallum Cancer Centre H.D. Thames The University of Texas MD Anderson
Copyright of International Journal of Radiation Biology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
OBITUARY
Dr. H. Rodney Withers (1932 – 2015) of the time Rod was there and died just before he completed his Ph.D. thesis. However, Rod benefitted from Dr. Gray’s vision of radiobiology as a fusion of physical, chemical, and biologic sciences and the fact that the Gray laboratory was a melting pot with scientists with different backgrounds coming from all over the world. It was an exciting time for radiobiology research in London with many emerging discoveries, such as that the cell division cycle could be divided into phases based around the period of DNA synthesis, the role of oxygen and hypoxia in cancer radiotherapy, pulse radiolysis, radiation sensitizers, quantitation of in vivo tumor survival curves, and high LET radiation effects. Interactions with physicists in particular must have shaped Rod’s thinking as he incorporated quantitation into practically every aspect of his radiobiological ideas. Hal Gray suggested that Rod work on “The Response of Normal Tissues to Radiation”. Till and McCulloch had just published the response of bone marrow stem cells to radiation and Harold Hewitt the first in vivo survival curve for tumors. For his thesis Rod developed a revolutionary assay for measuring, in situ, the survival of clonogenic cells of mouse skin after irradiation. In this assay, a doughnutshaped piece of mouse skin was first irradiated with a high dose to form a “moat” using ball bearings of various sizes to create a central shielded area that was then irradiated with graded test doses of radiation. The number of epithelial colonies regenerated from surviving clonogenic cells was counted per unit area. Rod’s thesis is a masterpiece of clear, logical thought with an emphasis on quantitation. Survival was measured over 7 logs and he was able to deduce that moist desquamation occurred if cell survival decreased to 106 per cm2. By splitting the dose and varying the time between the split doses, he established the radiation recovery characteristics of the skin stem cells and the kinetics of repair, reassortment, and repopulation in epithelial tissue; three of his (later to be famous) 4 R’s of radiobiology relevant to fractionated radiotherapy. He visited Mortimer (Mort) Elkind at the National Cancer Institute in Bethesda, Maryland, on his way back to Australia and, after a brief period, took up a Visiting Resident Scientist position in 1966. They became lifelong friends until Mort died of, ironically, a variant of Parkinson’s disease in 2000. Together, Mort and Rod developed the in situ mouse jejunal crypt stem cell assay, initially with “macrocolonies” counted visually and later “microcolonies” counted in histology sections, and confirmed that the DNA repair processes occur in vivo. By counting the number of surviving clones, recovery statistics could again be derived. These assays have been used to derive the most rigorous statistics on which much
Dr. Rodney Withers (“Rod”) died in Houston, TX, on 25 February 2015 at the age of 82 after a long struggle with a variant of Parkinson’s disease. He was a strong supporter of the Radiation Research Society (RRS) and was its 31st President (1982–1983). He gave the 25th Failla Award lecture in 1988, a presentation full of typically amusing thoughts and sharp observations. He entitled it “Contrarian Radiobiology’s Contribution to Radiotherapy”, espousing the idea that a contrarian view of current concepts in radiobiology was warranted before rather than after they undergo revision. Rod was an unassuming intellectual giant who shaped the discipline of radiobiology while retaining a warm, amusing, kind and helpful personality that is greatly missed. Rod was born in Stanthorpe, Australia and educated at the Church of England Grammar School, Brisbane, and the University of Queensland (M.B., B.S., 1956). He did his internship at the Royal Brisbane Hospital in 1957, and completed his residency in radiotherapy and pathology at the Queensland Radium Institute and the Royal Brisbane Hospital in 1963. He then travelled to London and entered graduate school as a University of Queensland Gaggin Fellow. His career as a clinician-scientist started when he worked at the Gray Laboratory at the Mt. Vernon Hospital in Middlesex from 1963–1965. The Gray Lab opened in 1957 under the direction of the physicist Louis Harold (“Hal”) Gray, who is often called the father of radiobiology. Rod became Dr. Gray’s first (and last) Ph.D. student. Unfortunately, Dr. Gray was ill for much 459
460
Obituary
of quantitative radiobiology is based and the concepts that they illustrate form the framework for clinical thought processes in radiotherapy. In 1996, Rod and Mort received the Enrico Fermi Award, a Presidential award that is one of the oldest and most prestigious science and technology honors bestowed by the U.S. Government. Except for a period as Professor and Director of the Institute of Oncology at the Prince of Wales Hospital/University of NSW from 1989 to 1991, Rod remained in the U.S.A. for the duration of his professional life. He was recruited by Herman Suit to the Department of Experimental Radiotherapy at the MD Anderson Cancer Center in 1968 and he became Chief of Section there in 1971. During this time, he worked with many members of the staff, but most notably Kathy Mason, to expand his studies to other normal tissues. As always, his focus was on quantitation and clinically relevant fractionation schedules. This led to a highly productive collaboration with the mathematician Howard Thames. They found that different normal tissues and tumors responded differently to changes in fraction size, which led to the establishment of the ratio α/β, from the LQ model, as a parameter to quantitate sensitivity to changes in fraction size. By plotting total dose, to achieve various isoeffects in different tissues, against size of the dose per fraction, they observed that acute reactions in normal tissues changed less than late reactions in response to increasing size of dose per fraction – in other words, late sequelae could be minimized relative to acute reactions by modifying dose fractionation. This observation had several consequences. The Nominal Standard Dose (NSD) equation had been introduced in the 1960s as the first widely used means of determining the effect on normal tissue tolerance of changing treatment schedules. It was based on the number of fractions and the overall treatment time. It was supplanted by the LQ model when it became clear that fraction size, not number, was the critical determinant of tissue responses and that fractionation dependence was tissue-specific. Another consequence was that if such differences existed between late responding normal tissues and tumors, an improvement in the therapeutic ratio should be obtainable by the use of doses per fraction less than the conventional 2 Gy, if given more than once per day (hyperfractionation). This prediction was subsequently tested in a number of phase III clinical trials, and hyperfractionation proved superior to conventional fractionation in the treatment of head and neck tumors. For “developing the concept of ‘hyperfractionation’ in radiation therapy”, Rod received the Charles F. Kettering Prize of the General Motors Cancer Foundation in 1998. At a very practical level, Rod was able to emphasize to clinical radiotherapists the “double trouble” that can result from hot spots in the treatment field where high physical doses are amplified by the inability of late responding tissues to cope with large fraction sizes. In 1980, Rod joined the Department of Radiation Oncology at UCLA, and became departmental Chair from 1995–2004 before becoming emeritus in 2008. His passion for quantitation continued as he engaged Jeremy Taylor and they worked together with Boguslaw Maciejewski from Gliwice, Poland, in modeling the hazards of accelerated
tumor clonogen repopulation during radiation therapy. Findings from these studies were that, after a lag phase, tumor repopulation could negate a third of the dose that is given in conventional treatment, justifying strategies aimed at accelerating treatment, defined as delivery of treatment more rapidly than with standard fractionation, but without resorting to increasing the size of dose per fraction. One such strategy was the concomitant boost technique championed by his close friend and colleague Lester Peters, which was subsequently shown to be superior to conventional treatment in the RTOG 9003 trial. At the practical level, these translational studies affected clinical thought processes in warning of the dangers of treatment breaks and protracted treatment time. Rod’s penchant for quantification in radiobiology also led him to examine the response of micrometastatic disease to chemotherapy in addition to radiation treatment. Building on earlier studies conducted with long-term collaborators Luka Milas and Bill McBride, he, Steve Lee, and Rafi Suwinsky at UCLA demonstrated how the tumor control probability curves for micrometastases differed from those for established tumors and how chemotherapy regimens in clinical use could be equated to radiation doses required for cure by radiation therapy. In many ways, Rod was the face of radiobiology in the clinic. He gave clinical radiation therapy rational guidelines for making treatment choices that were easily understood and highly accessible. The 4R’s of Radiotherapy summarized the key mechanisms governing tumor and tissue responses to fractionated schedules and give reasons to fractionate dose. They sum up his legacy for radiotherapy. Allowing Repair of sublethal/potentially lethal damage helps to spare late responding normal tissues. Reassortment of surviving cells within the division cycle allows resensitization of rapidly proliferating cells. Reoxygenation of hypoxic cells during fractionated treatment makes tumors more radiosensitive. Repopulation of surviving clonogenic cells during a course of treatment is a hazard to be minimized in the case of tumors and allowed for acute responding normal tissues. A fifth R (Radiosensitivity of clonogenic (*cancer stem”) cells) has since been added. There are few who have left a greater legacy to cancer treatment. The enormous respect that he garnered from his peers is recorded in the over 30 national and international award lectures that he presented over the span of his career and he received at least 12 Gold Medals. Apart from his service on many RRS committees and on the RRS Council, he served nationally and internationally on too many committees and in too many roles to mention. In 1998, he was awarded the Order of Australia by the Governor-General. Rod was a translational researcher who recognized the importance of stem cells and who addressed questions about biological systems that were relevant to clinical practice. Yet he was modest and self-effacing and helped numerous people with their personal problems, professionally as a clinician and with career guidance. He learnt from his time at the Gray lab to surround himself with people of diverse interests whom he encouraged to address
Obituary radiobiological problems. Everyone will remember him for his gentle charm and wonderful sense of humor. His blue eyes would twinkle most of the time but the twinkle would increase in intensity when he was about to tell a joke. He will be remembered warmly by his legion of loyal friends worldwide and most especially by his wife Janet, daughter Genevieve and granddaughters Sarah, and Emma. His monumental contributions to radiation research and to the translation of biological principles to clinical practice will continue to benefit cancer patients now and in the future.
461
W.H. McBride The University of Texas MD Anderson K.A. Mason The University of Texas MD Anderson L.J. Peters Peter MacCallum Cancer Centre H.D. Thames The University of Texas MD Anderson
Copyright of International Journal of Radiation Biology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
