It is with both sadness and a deep sense of gratitude that we reflect on the life and career of a titan of the radiation sciences community, Professor John Bertram Little, who passed away peacefully on May 24, 2020. Dr. Little's pioneering research has shaped many fundamental aspects of our understanding of the biological effects of radiation. Born October 5, 1929 in Boston, Massachusetts, John (Jack) Little spent most of his life in nearby Brookline. He was a forward-thinking and innovative scientist, a clear and captivating teacher and an outstanding mentor. His ground-breaking discoveries on the mechanistic aspects of cell cycle control, DNA repair, mutagenesis, genomic instability, and other non-targeted effects of exposure that each influence the radiation response of higher organisms led to critical advances that helped elucidate the causes, development and treatment of cancer. Dr. Little was the Director of the John B. Little Center for Radiation Sciences and Environmental Health and of the Kresge Center for Environmental Health at the Harvard School of Public Health (now the Harvard-T.H. Chan School of Public Health), where he served as Chairman of the Department of Physiology and the Department of Cancer Cell Biology. He was the James Stevens Simmons Professor of Radiobiology until his retirement in 2006. As a distinguished Emeritus Professor, Dr. Little remained a highly productive researcher, a generous colleague and thoughtful advisor to many until the final weeks of his extraordinary life.

Dr. Little earned his AB in Physics from Harvard University in 1951 and an MD from Boston University in 1955. He interned on the Osler Service at the Johns Hopkins Hospital and served as a U.S. Army Captain in the Medical Corps in Texas, and in Bussac, France. He completed his training in Radiology at the Massachusetts General Hospital and was board certified in Radiology. Dr. Little served as a consultant in Radiology at the Massachusetts General Hospital starting in 1965. He became an instructor in radiobiology at Harvard in 1963, where he spent the entirety of his remarkable career. In his Laboratory of Radiobiology, he created a unique and enriching environment where trainees worked together and shared the joys of discovery. “The door of his office was always open, and students and fellows could walk right in” (‘A Little Bit of History’ by Ms. Selina Little, Boston, MA).

Dr. Little had a keen interest in most things mechanical and was also known for his collection of old radios, televisions, medical instruments, and cars. His office, at the corner of the second floor of Building I at HSPH, contained a wealth of curious equipment interspersed with stacks of notes and journal articles that were fastidiously organized to facilitate the preparation of manuscripts and grant applications. The careful maintenance and nurturing of old X-ray machines was also a specialty of Dr. Little's laboratory. When, after four decades, the second floor was to be remodeled, his personal correspondence was moved to the Countway Library, and the collection of antique medical equipment and inventions made by Dr. Little was donated to the Historical Instruments Collection in Cambridge. Outside the laboratory, he had abiding interests in classical music and the fine arts, the history of New England, gastronomy and oenology that he shared enthusiastically with his trainees and colleagues whenever possible.

Throughout his long and distinguished research career, Dr. Little always advocated strongly that the study of radiation response should be grounded in the underlying mechanisms of cellular and molecular biology. This approach inspired generations of students, fellows, and post-docs in his laboratory, who were always encouraged to investigate new directions in the field. Dr. Little's remarkable patience and support, combined with his exceptional ability to clearly articulate novel connections and concepts, led to a large number of foundational discoveries. Though the scope of his work was tremendously broad, his overall career interests remained consistent: mechanisms of radiosensitivity and radiation carcinogenesis, and low-dose radiation effects. Shortly after establishing his laboratory, Dr. Little focused on the role of polonium-210 in cigarette-induced lung cancer, and then followed with studies of polonium-induced lung cancer in animal models (1, 2 ). As he moved his focus to in vitro systems, Dr. Little was a leader in studying radiation response in stationary phase cell cultures as a model for human tissues (3 ). Using such systems, he identified cellular repair processes, such as Potentially Lethal Damage Repair, as major determinants of mammalian cell radiation response that impact radiotherapeutic outcomes (4 ). Dr. Little's pioneering findings firmly established the existence of the radiation-induced G1 cell cycle checkpoint (5 ) and apoptosis (6 ), which each 345 inspired decades of subsequent research on molecular changes associated with cellular response to radiation exposure in normal and cancer cells. His early reports characterized cellular repair deficiencies in heritable human radiosensitive disorders (7, 8 ). He became a leader in the study of radiation-induced malignant transformation in vitro (9 ), which led to an initial glimpse of radiation-induced genomic instability (10 ). Dr. Little later became a major contributor in the field of radiation-induced genomic instability (1113 ) as the field blossomed, building on contributions in studying radiation-induced mutational and cytogenetic change (14, 15 ). His contributions in genomic instability were followed by landmark studies that identified the radiation-induced bystander effect (16, 17 ) in mammalian systems. These breakthrough studies opened a floodgate of work on this topic over the past three decades. Dr. Little was thereby a leader in establishing a new paradigm for mechanisms leading to radiation-induced lethality and genetic damage. Instead of occurring only in irradiated cells, these outcomes could also occur in bystander cells that are unirradiated but neighboring to irradiated cells, or through persistent instability in the distant progeny of irradiated cells (18 ).

Dr. Little's expertise was in frequent demand by numerous organizations that provide scholarly input to the development of federal and international guidance on radiation protection of the public, as well as those with occupational or medical exposure to radiation. He was a Member of the National Council on Radiation Protection and Measurements (NCRP) from 1991–2009, when he became a Distinguished Emeritus Member. During his service to the NCRP, he was a Member of Scientific Committee 1 and a Consultant to Scientific Committee 83. He was also a member of the 1996 Annual Meeting Program Committee. Dr. Little was awarded the highest honor of the NCRP when he was selected as the Lauriston S. Taylor Lecturer in 2005. Dr. Little's Taylor Lecture, delivered at the NCRP Annual Meeting, was entitled “Nontargeted Effects of Radiation: Implications for Low Dose Exposures.” Notably, Dr. Little served as Chairman of the Board on Radiation Effects Research, Commission of Life Sciences, National Research Council, National Academies from 1992–1998, and Chairman of the Board of Scientific Councilors of the National Institute of Environmental Health Sciences, and many other committees and editorial boards.

Dr. Little was deeply committed to international organizations devoted to scholarship and guidance on radiation health effects. He served as Chairman of the Science Council of the Radiation Effects Research Foundation in Hiroshima from 1992–1998. He was also a Member of the International Commission on Radiological Protection Committee 1. He was constantly in demand as an invited lecturer at institutions of higher learning worldwide. The composition of Dr. Little's laboratory directly reflected his commitment to the need for international cooperation in scientific discovery and in the dissemination of learning in the radiation sciences. Many languages could be heard in the various labs and offices of Dr. Little's Laboratory of Radiobiology. Dr. Little supported the academic programs of departments around the world with great vigor and generosity. “He was appreciated not only for his remarkable knowledge but also for his incredible kindness” (Professor Jean-Paul Jay-Gerin, Université de Sherbrooke, Canada).

Dr. Little had a special home in the Radiation Research Society, where he served as President from 1986–1987. He was the recipient of the Radiation Research Society's highest scholastic honor, the Failla Memorial Lecture Award, in 1994. A legacy fund was established in 2019 in Dr. Little's honor, which was first used to support a “JBL Plenary Lecture” delivered by Professor Joann Sweasy at the 65th Annual Meeting of the RRS held in San Diego, CA. Dr. Little was also a fixture at meetings of the International Association for Radiation Research, where he was the recipient of the Henry S. Kaplan Distinguished Scientist Award in Dublin, Ireland, in 1999. Dr. Little was also a member of the American Association for Cancer Research, the American Physiological Society, the American Society for Photobiology and the Health Physics Society. He authored or co-authored more than 525 scientific papers and holds a patent for “Cell Lines and Methods for Assaying Human Interchromosomal Recombination.”

The NIH awarded Dr. Little an Outstanding Investigator Award from 1988–2000 in recognition of his visionary science. However, perhaps his most important accomplishment was his inspired leadership of an NIH Radiation Biology training grant starting in 1975. In an unparalleled period spanning many decades, Dr. Little mentored more than 250 individuals from all over the world, including undergraduate students, doctoral candidates, postdoctoral fellows and clinician-scientists. He was always willing to listen to their intriguing ideas and shared with them his passion for discovery. Hundreds of students from HSPH, the Harvard “main” campus, Harvard Medical School and MIT enrolled in his staple Radiation Biology course, which led some students to change career paths and move into the field. Memorable highlights of Dr. Little's course included a time-lapse movie of irradiated cells accompanied by Dr. Little's enthusiastic narration. In another lecture, Dr. Little presented an active illustration of the Poisson distribution of “hits” that involved throwing chalk from a good distance at a grid carefully drawn on the blackboard. Dr. Little's trainees nominated him for the first Scholar-in-Training Excellence in Mentoring Award from the Radiation Research Society, which he was awarded in 2005. Many of his trainees are now leaders in the fields of cancer biology, radiation biophysics, radiation oncology, occupational health, public health and science education. Sixteen of Dr. Little's trainees have become department chairs at their various institutions, and two became university deans.

As impressive as the roster of trainees certainly is, it does not quite capture the legacy of mentorship and community that Dr. Little created. He was exceptionally humble and accessible, a man of few words who spoke with great clarity and incisiveness. Always analytical, meticulous, and precise in discussing new findings, and at the same time supportive and encouraging. Many trainees remember Dr. Little's collection of freshly sharpened pencils, and how he loved to illustrate a point by drawing freehand graphs, or by leaving perfectly legible margin notes in draft documents. He created a community environment, where people who never overlapped in the lab nevertheless frequently became friendly, drawn together by their shared affinity for Dr. Little. Dr. Little's wife, Françoise, who had a distinguished career of her own as a general surgeon, helped immeasurably in fostering the community, notably through hosting many visitors at their home, and the annual midsummer “Christmas” party (complete with Christmas decorations) for all lab members as well as many alumni and friends. In 1998, the first Annual Symposium of the John B. Little Center for Radiation Sciences and Environmental Health was organized, funded by a generous gift from his former trainee Dr. Gerald Chan. Later, Dr. Chan provided the transformative gift to what is now the Harvard T.H. Chan School of Public Health, which in no small part was due to the impact of Dr. Little's mentorship. Over the years, the “JBL Symposium”, held in the Harvard Medical Area, has become an impressive scholarly event, drawing a cadre of outstanding speakers from many institutions and large audiences. In addition to providing a venue for scholarship, the JBL Symposia also serve as a focal point for reunions of former members of Dr. Little's extended laboratory family who bring their students and share ideas that sometimes lead to future collaborations. He was generous with his time for each of his trainees, championed them, and nurtured their pursuit of innovative science long after they had become independent investigators.

Dr. Little's scientific contributions have led to a “big bang” that has greatly expanded the horizons of radiation research. His oeuvre has led to paradigm shifts in our understanding of the cellular responses to radiation along with detailed mechanistic findings that inform the therapeutic uses of radiation in medicine. His legacy will endure for generations to come. The Radiation Research Society and the community-at-large extend condolences to his wife, Françoise, his children, John and Frédéric, daughters-in-law Pamela and Claudia, his five grandchildren, his sister Selina and brother Warren.

REFERENCES

REFERENCES
1
Little
JB,
Radford
EP,
Jr
McCombs
HL,
Hunt
VR.
Distribution of polonium-210 in pulmonary tissues of cigarette smokers.
N Engl J Med
1965
;
273
:
1343
1351
2
Little
JB,
Kennedy
AR,
McGandy,
RB.
Lung cancer induced in hamsters by low doses of alpha radiation from polonium-210.
Science
1975
;
188
:
737
738
3
Hahn
GM,
Little
JB.
Plateau-phase cultures of mammalian cells: an in vitro model for human cancer.
Curr. Top. Radiat. Res.
1972
;
Quart. 8: No. 1,
39
83
(
Jul 1972
).
4
Little
JB.
Repair of sub-lethal and potentially lethal radiation damage in plateau phase cultures of human cells.
Nature
1969
;
224
:
804
06
.
5
Little
JB.
Delayed initiation of DNA synthesis in irradiated human diploid cells.
Nature
1968
;
218
:
1064
65
.
6
Williams
JR,
Little
JB,
Shipley,
WU.
Association of mammalian cell death with a specific endonucleolytic degradation of DNA.
Nature
1974
;
252
:
754
55
.
7
Weichselbaum
RR,
Nove
J,
Little
JB.
X-ray sensitivity of fifty-three human diploid fibroblast cell strains from patients with characterized genetic disorders.
Cancer Res
1980
;
40
:
920
25
.
8
Weichselbaum
RR,
Nove
J,
Little
JB.
Deficient recovery from potentially lethal radiation damage in ataxia telangiectasia and xeroderma pigmentosum.
Nature
1978
;
271
:
261
62
.
9
Terzaghi,
M,
Little
JB.
X-radiation-induced transformation in a C3H mouse embryo derived cell line.
Cancer Res
1976
;
36
:
1367
374
.
10
Kennedy
AR,
Fox
M,
Murphy
G,
Little
JB.
Relationship between x-ray exposure and malignant transformation in C3H 10T1/2 cells.
Proc Natl Acad Sci U S A
1980
;
77
:
7262
7266
.
11
Gorgojo
L,
Little
JB.
Expression of lethal mutations in progeny of irradiated mammalian cells.
Int J Radiat Biol
1989
;
55
:
619
30
.
12
Little
JB,
Nagasawa
H,
Pfenning
T.
Vetrovs
H.
Radiation-induced genomic instability: delayed mutagenic and cytogenetic effects of X rays and alpha particles.
Radiat Res
1997
;
148
:
299
307
.
13
Little
JB.
Radiation-induced genomic instability.
Int J Radiat Biol
1998
;
74
:
663
71
.
14
Liber
HL,
Yandell
DW,
Little
JB.
A comparison of mutation induction at the tk and hprt loci in human lymphoblastoid cells; quantitative differences are due to an additional class of mutations at the autosomal tk locus.
Mutat Res
1987
;
216
:
9
17
.
15
Fornace
AJ,
Jr,
Nagasawa
J,
Little
JB.
Relationship of DNA repair to chromosome aberrations, sister-chromatid exchanges and survival during liquid-holding recovery in X-irradiated mammalian cells.
Mutat Res
1980
;
70
:
323
36
.
16
Nagasawa
H,
Little
JB.
Induction of sister chromatid exchanges by extremely low doses of a-particles.
Cancer Res
1992
;
52
:
6394
96
.
17
Azzam
EI,
De Toledo
SM,
Little
JB.
Direct evidence for the participation of gap junction-mediated intercellular communication in the transmission of damage signals from a-particle irradiated to nonirradiated cells.
Proc Natl Acad Sci U S A
2001
;
98
:
473
78
.
18
Little
JB.
Genomic instability and bystander effects: a historical perspective.
Oncogene
2003
;
22
:
6978
87
.