AAI In Memoriam

Christine A. Biron

AAI extends condolences to the family, friends, and colleagues of Christine A. Biron, Ph.D., DFAAI (AAI ’84), a devoted and active AAI member of 37 years who died unexpectedly on October 16.

Dr. Biron was the Esther Elizabeth Brintzenhoff Professor of Medical Science at Brown University, where she had also served as director of the Pathobiology Graduate Program and later as chair of the Department of Molecular Microbiology and Immunology.

Biron was elected in 2021 as a Distinguished Fellow of AAI, one of the highest honors bestowed by AAI. This honor recognizes active, long-term members for distinguished careers and outstanding scientific contributions as well as their service to AAI and the immunology community.

Biron was a past member and chair of the AAI Awards Committee and also served on the Finance, Nominating, and Program Committees. In 2015, she was selected as an AAI Distinguished Lecturer. She also participated at AAI annual meetings as a major symposium chair and speaker as well as serving as an abstract programming chair. Additionally, she was a past section editor and associate editor for The Journal of Immunology and served as a faculty member for the AAI Advanced Course in Immunology.

The following remembrance was authored by Biron colleagues Jordan S. Orange, M.D., Ph.D. (AAI ’04), professor and chair, Columbia University Medical Center; Marion T. Kasaian, Ph.D. (AAI ’90), scientist, Pfizer Research; and Helen C. Su, M.D., Ph.D., senior investigator, NIAID, NIH. AAI gratefully acknowledges their submission.

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On October 16th, we lost a trailblazer in immunology, a strong advocate for women in science and career development, a committed and caring colleague and teacher, and a dear friend, Dr. Christine Anne Biron. There is much to be said about her career and life, but some key themes must be stated right away. Christine was a scientist because she was curious, loved discovery-based research, and took joy in her work. She believed in pursuing the truth with robustness and rigor and taking on questions that mattered even when they seemed impossible to solve. She never retreated from an approach or experiment because it was too difficult or too intensive and often wondered whether those might be the best questions to pursue. Some of the experiments she performed herself were inspiring and have greatly influenced the field. Also, Christine was generous with her time and efforts on behalf of others. She was eager to give feedback on and help improve an idea, giving her very best energies and thoughts and almost always asking key and even transformative questions about hypotheses.

Christine was born and raised in Bellingham, MA, the oldest of five siblings. Her father was the town moderator and her mother a strong matriarch, and they instilled in her the values of industry, integrity, and responsibility. After receiving her undergraduate degree in biochemistry at the University of Massachusetts (UMass) Amherst, she obtained her Ph.D. in microbiology and immunology at the University of North Carolina (UNC) Chapel Hill. In her Ph.D. work with Joseph Pagano, she examined cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses against Epstein Barr virus (EBV), exploring the role of interferon in their activation and blastogenesis. She challenged the idea that NK cells were end stage, incapable of further expansion. In a postdoctoral fellowship with Raymond Welsh in the laboratory of Michael Oldstone at Scripps, and continuing at the UMass Medical School in Worcester, MA, Christine took on the challenging initiative to purify cells after experimental viral infection of mice according to size using centrifugal elutriation. In some extremely difficult experiments published in 1982 and thereafter, she was able to demonstrate that the large blasting cells observed early after viral infection were the ones possessing the NK cell activities.

In launching her own independent research program at UMass, Christine went on to show that blast NK cells were induced in response to interferons elicited during viral infection. These pioneering studies confirmed the proliferative capacity of NK cells, while elucidating cytokine regulation of NK cell antiviral and immunopathogenic responses. These interactions were further delineated in a 1999 Annual Review of Immunology treatise entitled “NK cells in antiviral defense: function and regulation by innate cytokines”, which has been cited well over 1,500 times.

While mostly focused upon murine experimental immunology, Christine ventured into human immunology through the extensive characterization of an NK cell deficient adolescent patient, who experienced successive waves of severe infections with herpes-group viruses. This landmark study, for which Christine performed most of the NK cell characterization and profiling herself, was published in the New England Journal of Medicine in 1989 and has been cited approximately 1,000 times. In an era in which innate mechanisms were considered secondary to the adaptive responses, this report clearly demonstrated the profound importance of NK cells in herpesviral defense in humans. This theme of phenotypic and functional characterization associated with immune deficiency has carried forward to this day and has been validated through the existence of many similar phenotypes and associated Mendelian genotypes.

In 1987, Christine moved to Brown University as assistant professor of medical science. She would remain dedicated to building the immunology program at Brown and to investigating cytokine control of anti-viral responses for the rest of her career. One aspect that set Christine apart was her willingness to confront the complexities and intricacies of in vivo models. There is a role for reductive research and simplification, but she understood that what happens inside an animal is nuanced, with antiviral responses regulated in both time and space, greatly influencing the ultimate outcome. From the initial observation that lymphocytic choriomeningitis virus (LCMV) is cleared by CD8⁺ CTL, while murine cytomegalovirus (MCMV) is also controlled by NK cells, Christine identified waves of innate and adaptive cellular responses orchestrated by cytokines. In MCMV infection, dendritic cells (DCs) release an early wave of interleukin-12 (IL-12), activating NK cells to produce interferon (IFN)-γ. In an elegant example of cross-regulation, subsequent plasmacytoid DC (pDC)-induced IFN-α/β feeds back to limit this IL-12 secretion and, along with IL-2, potentiates NK cell expansion. In LCMV infection, however, an early wave of IFN-α/β activates NK expansion, but prevents IL-12 induction, limiting IFN-γ production. Subsequent T cell activation and generation of transforming growth factor (TGF)-β reduces NK proliferation, driving the shift from innate to adaptive immunity. Spatial trafficking of NK cells from bone marrow to secondary compartments underlies these dynamics, localizing the NK cells to receive cellular activation signals and to propagate the response.

The signaling downstream of cytokine regulation, and how this facilitates response to and protection from immunopathology, subsequently emerged as a major focus for Christine. Building on the observation that IL-12/ signal transducer and activator of transcription (STAT)4 is critical for NK cell IFN-γ expression, whereas IFN-α/β/STAT1 drives NK cytotoxicity but negatively regulates IFN-γ, Christine investigated the dynamics of STAT expression in infection. Her 2002 landmark publication in Science demonstrated that STATs were fundamental in both inducing and regulating the antiviral interferon response. These groundbreaking observations gave rise to many related works and avenues, encapsulated nicely in a 2006 perspective published in Science entitled “Type I interferons and the virus-host relationship: a lesson in détente”. Her body of work is truly central to immunology’s understanding of the coordination of antiviral and innate cytokine regulation and response.

A unifying characteristic of Christine’s papers is their rigor and humility. She never overstated her findings and felt that robust works would speak for themselves and stand the test of time. She taught her trainees that the ideal was to be able to make the same point in six different ways and that one could never be careful enough. One colleague, speaking for many, stated that her work was to be noticed and always believed. Naturally, to achieve this ideal required long hours and tenacity, habits which she modeled and imparted to others along with an enthusiasm for experimental discovery.

Christine’s infectious love of science inspired students, trainees, and colleagues throughout her career, including 12 postdoctoral fellows, three M.D./Ph.D. students, and six graduate students. She was known at Brown for her lively advanced seminar courses, which also drew undergraduates, many of whom were inspired to pursue scientific careers. For much of her teaching career, she dedicated herself to ensuring that the medical students would thoroughly understand immunology in preparation for their future careers as physicians. Christine had an intense focus on those who worked in her laboratory. She cared about people and invested the energy to get to know them, finding ways to bring science to them in a meaningful way and inspire them to (as she would say) “get hooked by science.” That is what happened to so many of us, thanks to her special talents, kindness, brilliance, and attention. Mentoring others was incredibly important to Christine, and she maintained lifelong connections with several of her former trainees. She was especially supportive and encouraging of junior colleagues, including women faculty who were faced with barriers in their career advancement.

Christine’s inquisitive nature and scientific curiosity were apparent even as a graduate student at UNC, when she was teased for being the one who was always first to ask questions at meetings, courses, or lectures. Throughout her career, she continued to be generous with her time and offered perspectives and suggestions that influenced the thinking and direction of her colleagues. She served on various editorial boards, was a member and Distinguished Fellow of AAI, was a member of the American Society for Virology, and was an elected fellow of both the American Association for the Advancement of Science and the American Academy of Microbiology. Additionally, she had the distinction of serving on the Board of Scientific Counselors for both the National Institute of Allergy and Infectious Diseases and the National Cancer Institute.

Outside of her work, Christine was the quintessential New Englander who enjoyed spending time with her close-knit family, often at her cottage on Cape Cod, where she would also invite friends and close colleagues. She was an amateur photographer and had a beautiful soprano voice. Her distinctive laughter was emblematic of her enthusiastic personality. She was also an intensely private and courageous person of faith who accomplished much despite having an increasingly debilitating autoimmune disease. To honor her, in 2020 an annual endowed lectureship was established in her name at Brown University. We are grateful to have known her; she will be sorely missed.

The inaugural Dr. Christine Biron Molecular Microbiology and Immunology Lectureship at Brown University was held on October 28, 2021. Donations in Christine’s memory may be made at https://brown.edu/go/Biron.

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See also the obituary published by the family in the Providence Journal.