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Project Title:  Blood-based Multi-scale Model for Cancer Risk from GCR in Genetically Diverse Populations Reduce
Images: icon  Fiscal Year: FY 2022 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 02/04/2016  
End Date: 10/01/2022  
Task Last Updated: 12/04/2021 
Download report in PDF pdf
Principal Investigator/Affiliation:   Costes, Sylvain  Ph.D. / NASA Ames Research Center 
Address:  Mail Stop 211-4 
 
Moffett Field , CA 94035-0001 
Email: sylvain.v.costes@nasa.gov 
Phone: 650-604-5343  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments: NOTE: Previously at Lawrence Berkeley National Laboratory until December 2016. 
Key Personnel Changes / Previous PI: NOTE (January 2018): The lab moved from Lawrence Berkeley National Lab (LBNL) to NASA Ames Research Center in 2017, where it was established as the Radiation Biophysics Lab in Space Biosciences Division. Dr. Costes will continue collaborating with LBNL and some funding will be left at LBNL to cover more plate processing in collaboration with Dr. Weil, Colorado State University (CSU) and for support from Dr. Snijders for the writing of the animal data. April 2017 report: - Elodie Guiet was a full time technician with a Bachelor in microbiology and biotechnology, working on this project from March 2016 until February 2017 -- she did not stay on the project when the lab moved to NASA Ames ; - Louise Viger was a Postdoc working partly on this project from June 2016 to January 2017 -- she was only here for a quick postdoc, focused primarily on modeling ; - Charlotte Degorre was a Postdoc who helped executing BNL run 16C -- visiting scientist for 1 month ; - Sebastien Penninckx was a PhD student who has been helping on data analysis -- visiting scientist for 3 months ; - Shayoni Ray is a new recruit at NASA Ames, postdoctoral fellow working on doing genomic analysis between animal DNA repair phenotypic data and their individual genes -- new postdoc full time at NASA Ames, started on April 10 2017 - Left in 2019 - Eloise Pariset was on the project until January 2020
Project Information: Grant/Contract No. Internal Project--ARC ; NNJ16HP24I 
Responsible Center: NASA ARC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: Internal Project--ARC ; NNJ16HP24I 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer-202:Evaluate the contribution of genetic background/diversity on carcinogenesis risk (IRP Rev M)
Flight Assignment/Project Notes: NOTE: End date changed to 10/1/2022 per PI/CoI information (Ed., 2/4/22)

NOTE: End date changed to 10/1/2021 per Space Radiation (Ed., 8/2/21)

NOTE: End date changed to 9/30/2021 per L.Lewis/ARC HRP (Ed., 12/9/20)

NOTE: Extended to 5/31/2021 per L. Lewis/ARC HRP (Ed., 9/24/20)

NOTE: Extended to 5/31/2020 per PI (Ed., 11/15/19)

NOTE: Extended to 9/30/2019 per F. Hernandez/ARC (Ed., 2/18/19)

Task Description: NOTE (January 2018): The lab moved from Lawrence Berkeley National Lab (LBNL) to NASA Ames Research Center in 2017, where it was established as the Radiation Biophysics Lab in Space Biosciences Division. Dr. Costes will continue collaborating with LBNL and some funding will be left at LBNL to cover more plate processing in collaboration with Dr. Weil, Colorado State University (CSU), and for support from Dr. Snijders for the writing of the animal data.

Crews on future exploration missions to Mars and other destinations in our solar system will be exposed to acute low doses (<100 mSv) and chronic low doses (<0.1 mSv/min) of high-LET (linear energy transfer) ionizing radiation from solar particle events (SPE) and galactic cosmic radiation (GCR). Predicting cancer risk associated with these radiation types is a mission-critical challenge for NASA radiation health scientists and mission planners. Epidemiological methods lack sensitivity and power to provide detailed risk estimates for cancer, mainly because the number of exposed individuals to date is relatively small, limited to several hundred individuals exposed to trapped radiation in low Earth orbit and fewer than two dozen Apollo astronauts exposed to GCR for several days at a time. Moreover, population-based studies do not take individual radiation sensitivity into account, are sensitive to the presence of other confounding environmental insults, and require long follow-up times.

In collaboration with the radiation Biodosimetry Laboratory and the modeling group at NASA Johnson Space Center and with the International Computer Science Institute (ICSI) at University of California (UC) Berkeley, our team will bring unique inter-disciplinary expertise to integrate the large array of cancer data generated over the past 25 years and archived by NASA under the various Human Research Program (HRP) funded projects. The main goal of this proposal is to identify factors influencing radiation-induced carcinogenesis and integrate them into a multi-scale model already started at the Berkeley Lab that encompasses DNA damage response and inter-cellular signaling to predict cancer risk for any types of HZE (high energy particles). Because experimental data are dispersed across many different cancer models, radiation qualities, and measurement types, this project will also generate a complete set of experimental data designed to fully inform and validate the model. In this project, the model will impose the types of measurements being made, with a strong emphasis on well-established blood biomarkers. In our approach we hypothesize that genetic factors strongly influence risk of cancer from space radiation and that biomarkers reflecting DNA damage and inflammatory processes in the blood are great tools to predict risk and monitor potential health effects post-flight. By using blood as a surrogate organ, the proposed work will allow extrapolation of cancer risk from mice to humans. A cohort of 6 different strains of mice (collaborative cross-mouse) with expected sensitivity to ionizing radiation will be monitored for biomarkers and cancer after exposure to 0.3 Gy of 1 GeV/amu Fe particle and compared to 1 Gy exposure of gamma ray control. Because we favor larger number of animals per radiation condition, we selected only one dose and the most carcinogenic particle to prove the principle of our approach while validating our model on a complete set of ex-vivo data and in-vivo longitudinal data. The collaborative cross-mouse model used in this work was a resource from the low dose program at DOE (Department of Energy) developed by the Lawrence Berkeley National Laboratory that has made it possible for our team to examine the impact of genetic diversity in an animal model in a systematic and reproducible manner. In parallel, we propose to fully characterize the DNA damage response and cell death from ionizing radiation administered ex-vivo to 30 genetically different strains of mice and to 1000 human blood donors, matching the age and gender distribution of the astronaut population. Taken together, an array of ex-vivo phenotypic features will be associated to genetic traits across mice and humans as a function of age and gender. At the end of this proposal, our team will provide NASA with a model to estimate individualized risk for an astronaut before a flight as well as estimating the risk during the flight. Information generated in this proposal will also be useful to generate guidelines and suggest the best biomarkers to monitor the healthy recovery of astronauts post-flight.

Research Impact/Earth Benefits: A current radiobiology challenge is the ability to predict cancer risk associated with exposure to acute (<100 mSv) and chronic (<0.1 mSv/min) low doses of high-LET ionizing radiation. Epidemiological methods lack the sensitivity and power to provide detailed risk estimates for cancer, mainly because the astronaut cohort exposed to galactic cosmic rays (GCR) is relatively small. Moreover, population-based studies do not take individual radiation sensitivity into account, are affected by the presence of other confounding environmental insults, and require long follow-up times. We have hypothesized that characterizing the dose and time dependence of 53BP1 radiation induced foci (RIF) after exposure to a systematic array of X-ray doses and time points is sufficient to describe someone’s ability to respond to any other LET. The main concept is that the non-physiological response to high doses of low-LET in cells can be used to predict the response to low doses of high-LET, and that the response to low and high doses of radiation is modulated by different pools of genes.

Such work provides a new approach combining novel biomarkers with sophisticated mathematical analysis to better characterize individual sensitivity to space radiation. Once validated across mice and eventually a large cohort of humans, this approach could be generalized to establish individualized health risk management for astronauts and for the population at large being exposed to ionizing radiation.

Task Progress & Bibliography Information FY2022 
Task Progress: The experimental work on the project has been significantly delayed by the ongoing Covid-19 pandemic. However, we were allowed to return to hands-on laboratory research in March 2021 and finished all particle irradiation experiments at Brookhaven National Laboratory (BNL) BNL21B run in June 2021.

We have irradiated the peripheral blood mononuclear cells (PBMCs) from all remaining subjects, including the repeats of previous BNL experiments that we were unable to analyze previously due to Covid restrictions. We have analyzed their DNA repair kinetics using immunostaining with fluorescently-tagged 53BP1 antibody followed by semi-automated high throughput microscopy, image processing, and quantification. Currently, we are collaborating with the lab of Dr. Christopher Mason at Weill Cornell Medicine to match the phenotypic outcomes of DNA repair with genotypes based on low coverage whole genome sequencing.

In summary, for this project we have collected DNA repair data from 750 subjects, whose PBMCs have been irradiated ex vivo with 3 types of particle radiation (350 MeV/n 28Si, 350 MeV/n 40Ar, 600 MeV/n 56Fe) as well as gamma rays, at 2 doses each (1.1 and 3 particle/100 micrometers2 fluence, which translates to 0.1 Gy and 0.3 Gy for 28Si, 0.18 Gy and 0.5 Gy for 40Ar, and 0.3 Gy and 0.82 Gy for 56Fe respectively; and 0.1 Gy and 1 Gy doses of gamma rays), and at 2 timepoints post irradiation: 4 and 24 hours; as well as at baseline that represents the time of collecting PBMCs. To our knowledge this is the largest such dataset of human ex vivo responses to simulated space radiation. We anticipate that our data, which we will publish open access on NASA GeneLab, will serve as a useful resource for multiple future investigations.

Furthermore, we have collected data on oxidative stress and cell death from a subset of ~400 subjects, analyzed additional responses to 5-ion simplified simulated GCRs (0.25 Gy and 0.5 Gy doses, 4 h and 24 h post irradiation) and 250 MeV/n 4He (0.15 Gy and 0.5 Gy doses, 4 h and 24 h post irradiation) as part of piggyback experiments at NASA Space Radiation Laboratory (NSRL), and collected supernatant for quantifying secreted factors from all our samples for follow-up studies that will be available for potential collaborations. Additional supernatant samples from 24 most variable subjects in response to 56Fe irradiation have also been collected for exosome quantification as part of a Human Research Program (HRP) Augmentation Award to our former postdoctoral scholar Eloise Pariset (awarded January 2021).

Finally, as part of a collaboration with the Mason lab, we have selected 96 subjects with maximal variability in DNA repair responses and collected their RNA for transcriptomic analysis after 56Fe and gamma irradiation (funded by the Mason lab) to validate whether genomic associations with radiosensitivity are reflected in changes in gene expression.

This year we have one review article on DNA damage markers in press (Penninckx et al., Quantification of radiation-induced DNA repair foci to evaluate and predict biological responses to ionizing radiation, NAR Cancer--ed. note: see Bibliography section) and one primary research article under revision (Cekanaviciute et al., Mouse Genomic Associations with Ex Vivo Sensitivity to Simulated Space Radiation). Our research was presented at the Human Research Program Investigators’ Workshop, the National Council on Radiation Protection (NCRP): Biomarkers & Countermeasures and Conclusions conference, the Radiation Research Society Annual Meeting, and the American Society for Gravitational and Space Research Annual Meeting (all Sylvain Costes, oral presentations) and will be presented at COSPAR 2022 (invited presentation, Sylvain Costes)).

Our main future directions for this project are reflected in two key collaborations that we have started this year, with the goals to use the data from this project to generate new results: a) applying AI/ML (artificial intelligence/machine learning) methods to analyze our data (with NASA GeneLab and Frontier Development Lab); and b) using network analysis to compare the effects of spaceflight stressors and terrestrial diseases and repurpose Food & Drug Administration (FDA)-approved therapeutics as countermeasures for space radiation (with the SPOKE project and Baranzini Lab at the University of California, San Francisco, on which we have published a pilot study: Nelson et al., Life 2021).

Bibliography Type: Description: (Last Updated: 02/04/2022) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Nelson CA, Acuna AU, Paul AM, Scott RT, Butte AJ, Cekanaviciute E, Baranzini SE, Costes SV. "Knowledge network embedding of transcriptomic data from spaceflown mice uncovers signs and symptoms associated with terrestrial diseases." Life (Basel). 2021 Jan 12;11(1):E42. https://doi.org/10.3390/life11010042 ; PMID: 33445483; PMCID: PMC7828077 , Jan-2021
Articles in Peer-reviewed Journals Penninckx S, Pariset E, Cekanaviciute E, Costes SV. "Quantification of radiation-induced DNA double strand break repair foci to evaluate and predict biological responses to ionizing radiation." NAR Cancer. 2021 Dec;3(4):zcab046. https://doi.org/10.1093/narcan/zcab046 , Dec-2021
Project Title:  Blood-based Multi-scale Model for Cancer Risk from GCR in Genetically Diverse Populations Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 02/04/2016  
End Date: 10/01/2021  
Task Last Updated: 12/01/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Costes, Sylvain  Ph.D. / NASA Ames Research Center 
Address:  Mail Stop 211-4 
 
Moffett Field , CA 94035-0001 
Email: sylvain.v.costes@nasa.gov 
Phone: 650-604-5343  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments: NOTE: Previously at Lawrence Berkeley National Laboratory until December 2016. 
Key Personnel Changes / Previous PI: NOTE (January 2018): The lab moved from Lawrence Berkeley National Lab (LBNL) to NASA Ames Research Center in 2017, where it was established as the Radiation Biophysics Lab in Space Biosciences Division. Dr. Costes will continue collaborating with LBNL and some funding will be left at LBNL to cover more plate processing in collaboration with Dr. Weil, Colorado State University (CSU) and for support from Dr. Snijders for the writing of the animal data. April 2017 report: - Elodie Guiet was a full time technician with a Bachelor in microbiology and biotechnology, working on this project from March 2016 until February 2017 -- she did not stay on the project when the lab moved to NASA Ames ; - Louise Viger was a Postdoc working partly on this project from June 2016 to January 2017 -- she was only here for a quick postdoc, focused primarily on modeling ; - Charlotte Degorre was a Postdoc who helped executing BNL run 16C -- visiting scientist for 1 month ; - Sebastien Penninckx was a PhD student who has been helping on data analysis -- visiting scientist for 3 months ; - Shayoni Ray is a new recruit at NASA Ames, postdoctoral fellow working on doing genomic analysis between animal DNA repair phenotypic data and their individual genes -- new postdoc full time at NASA Ames, started on April 10 2017.
Project Information: Grant/Contract No. Internal Project--ARC ; NNJ16HP24I 
Responsible Center: NASA ARC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: Internal Project--ARC ; NNJ16HP24I 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer-202:Evaluate the contribution of genetic background/diversity on carcinogenesis risk (IRP Rev M)
Flight Assignment/Project Notes: NOTE: End date changed to 10/1/2021 per Space Radiation (Ed., 8/2/21)

NOTE: End date changed to 9/30/2021 per L.Lewis/ARC HRP (Ed., 12/9/20)

NOTE: Extended to 5/31/2021 per L. Lewis/ARC HRP (Ed., 9/24/20)

NOTE: Extended to 5/31/2020 per PI (Ed., 11/15/19)

NOTE: Extended to 9/30/2019 per F. Hernandez/ARC (Ed., 2/18/19)

Task Description: NOTE (January 2018): The lab moved from Lawrence Berkeley National Lab (LBNL) to NASA Ames Research Center in 2017, where it was established as the Radiation Biophysics Lab in Space Biosciences Division. Dr. Costes will continue collaborating with LBNL and some funding will be left at LBNL to cover more plate processing in collaboration with Dr. Weil, Colorado State University (CSU), and for support from Dr. Snijders for the writing of the animal data.

Crews on future exploration missions to Mars and other destinations in our solar system will be exposed to acute low doses (<100 mSv) and chronic low doses (<0.1 mSv/min) of high-LET (linear energy transfer) ionizing radiation from solar particle events (SPE) and galactic cosmic radiation (GCR). Predicting cancer risk associated with these radiation types is a mission-critical challenge for NASA radiation health scientists and mission planners. Epidemiological methods lack sensitivity and power to provide detailed risk estimates for cancer, mainly because the number of exposed individuals to date is relatively small, limited to several hundred individuals exposed to trapped radiation in low Earth orbit and fewer than two dozen Apollo astronauts exposed to GCR for several days at a time. Moreover, population-based studies do not take individual radiation sensitivity into account, are sensitive to the presence of other confounding environmental insults, and require long follow-up times.

In collaboration with the radiation Biodosimetry Laboratory and the modeling group at NASA Johnson Space Center and with the International Computer Science Institute (ICSI) at University of California (UC) Berkeley, our team will bring unique inter-disciplinary expertise to integrate the large array of cancer data generated over the past 25 years and archived by NASA under the various Human Research Program (HRP) funded projects. The main goal of this proposal is to identify factors influencing radiation-induced carcinogenesis and integrate them into a multi-scale model already started at the Berkeley Lab that encompasses DNA damage response and inter-cellular signaling to predict cancer risk for any types of HZE (high energy particles). Because experimental data are dispersed across many different cancer models, radiation qualities, and measurement types, this project will also generate a complete set of experimental data designed to fully inform and validate the model. In this project, the model will impose the types of measurements being made, with a strong emphasis on well-established blood biomarkers. In our approach we hypothesize that genetic factors strongly influence risk of cancer from space radiation and that biomarkers reflecting DNA damage and inflammatory processes in the blood are great tools to predict risk and monitor potential health effects post-flight. By using blood as a surrogate organ, the proposed work will allow extrapolation of cancer risk from mice to humans. A cohort of 6 different strains of mice (collaborative cross-mouse) with expected sensitivity to ionizing radiation will be monitored for biomarkers and cancer after exposure to 0.3 Gy of 1 GeV/amu Fe particle and compared to 1 Gy exposure of gamma ray control. Because we favor larger number of animals per radiation condition, we selected only one dose and the most carcinogenic particle to prove the principle of our approach while validating our model on a complete set of ex-vivo data and in-vivo longitudinal data. The collaborative cross-mouse model used in this work was a resource from the low dose program at DOE (Department of Energy) developed by the Lawrence Berkeley National Laboratory that has made it possible for our team to examine the impact of genetic diversity in an animal model in a systematic and reproducible manner. In parallel, we propose to fully characterize the DNA damage response and cell death from ionizing radiation administered ex-vivo to 30 genetically different strains of mice and to 1000 human blood donors, matching the age and gender distribution of the astronaut population. Taken together, an array of ex-vivo phenotypic features will be associated to genetic traits across mice and humans as a function of age and gender. At the end of this proposal, our team will provide NASA with a model to estimate individualized risk for an astronaut before a flight as well as estimating the risk during the flight. Information generated in this proposal will also be useful to generate guidelines and suggest the best biomarkers to monitor the healthy recovery of astronauts post-flight.

Research Impact/Earth Benefits: A current radiobiology challenge is the ability to predict cancer risk associated with exposure to acute (<100 mSv) and chronic (<0.1 mSv/min) low doses of high-LET ionizing radiation. Epidemiological methods lack the sensitivity and power to provide detailed risk estimates for cancer, mainly because the astronaut cohort exposed to galactic cosmic rays (GCR) is relatively small. Moreover, population-based studies do not take individual radiation sensitivity into account, are affected by the presence of other confounding environmental insults, and require long follow-up times. We have hypothesized that characterizing the dose and time dependence of 53BP1 radiation induced foci (RIF) after exposure to a systematic array of X-ray doses and time points is sufficient to describe someone’s ability to respond to any other LET. The main concept is that the non-physiological response to high doses of low-LET in cells can be used to predict the response to low doses of high-LET, and that the response to low and high doses of radiation is modulated by different pools of genes.

Such work provides a new approach combining novel biomarkers with sophisticated mathematical analysis to better characterize individual sensitivity to space radiation. Once validated across mice and eventually a large cohort of humans, this approach could be generalized to establish individualized health risk management for astronauts and for the population at large being exposed to ionizing radiation.

Task Progress & Bibliography Information FY2021 
Task Progress: We are continuing sample processing and analysis to uncover the genomic associations with human ex vivo immune cell responses to simulated space radiation. All mouse sample analysis has been completed. All human DNA samples have been successfully sequenced using low-throughput whole-genome sequencing, and the sequencing results are in the process of being analyzed. Human immune cell analysis has been severely delayed by shelter-in-place, which contributed to sample degeneration, so this experiment will have to be partially repeated in the next Brookhaven National Laboratory (BNL) run to finish all sample collection and analysis.

We have published 6 peer-reviewed articles based on mouse and human data analysis, with more articles in preparation. We have presented our work in talks and posters in the NASA Human Research Program (HRP) Investigators’ Workshop (presentations: Sylvain Costes, Eloise Pariset) and the Radiation Research Society Annual Meeting (presentation: Sylvain Costes, posters: Eloise Pariset, Egle Cekanaviciute) and have been accepted to present it again at COSPAR (Committee on Space Research) 2021 (invited presentation: Sylvain Costes).

Furthermore, we have been awarded a NASA HRP Tissue Sharing grant (“Mapping peripheral immune signatures of mouse and human responses to space radiation for biomarker identification,” PI: Costes, Co-I/Science PI: Cekanaviciute, Co-I: Pariset) to follow up on this work. We will utilize the samples from this project together with samples collected by Dr. Susanna Rosi’s group on her HRP-funded project on mouse neuroimmune responses to combined exposures to ionizing radiation and simulated microgravity, in order to identify a shared signature of immune responses to spaceflight that could be utilized for biomarker and countermeasure development.

Bibliography Type: Description: (Last Updated: 02/04/2022) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Penninckx S, Pariset E, Acuna AU, Lucas S, Costes SV. "Considering cell proliferation to optimize detection of radiation-induced 53BP1-positive foci in 15 mouse strains ex vivo." Radiat Res. 2021 Jan 1;195(1):47-59. https://doi.org/10.1667/RADE-20-00165.1 ; PMID: 33181852 , Jan-2021
Articles in Peer-reviewed Journals Pariset E, Penninckx S, Kerbaul CD, Guiet E, Macha AL, Cekanaviciute E, Snijders AM, Mao JH, Paris F, Costes SV. "53BP1 repair kinetics for prediction of in vivo radiation susceptibility in 15 mouse strains." Radiat Res. 2020 Nov 10;194(5):485-99. https://doi.org/10.1667/RADE-20-00122.1 ; PMID: 32991727 , Nov-2020
Articles in Peer-reviewed Journals Pariset E, Malkani S, Cekanaviciute E, Costes SV. "Ionizing radiation-induced risks to the central nervous system and countermeasures in cellular and rodent models." Int J Radiat Biol. Published online: 20 Oct 2020. https://doi.org/10.1080/09553002.2020.1820598 ; PMID: 32946305 , Oct-2020
Articles in Peer-reviewed Journals Pariset E, Bertucci A, Petay M, Malkani S, Lopez Macha A, Paulino Lima IG, Gomez Gonzalez V, Tin AS, Tang J, Plante I, Cekanaviciute E, Vazquez M, Costes SV. "DNA damage baseline predicts resilience to space radiation and radiotherapy." Cell Rep. 2020 Dec 8;33(10:108434. https://doi.org/10.1016/j.celrep.2020.108434 ; PMID: 33242409 , Dec-2020
Articles in Peer-reviewed Journals Nikitaki Z, Pariset E, Sudar D, Costes SV, Georgakilas AG. "In situ detection of complex DNA damage using microscopy: A rough road ahead." Cancers (Basel). 2020 Nov 6;12(11):E3288. Review. https://doi.org/10.3390/cancers12113288 ; PMID: 33172046; PMCID: PMC7694657 , Nov-2020
Articles in Peer-reviewed Journals Afshinnekoo E, Scott RT, MacKay MJ, Pariset E, Cekanaviciute E, Barker R, Gilroy S, Hassane D, Smith SM, Zwart SR, Nelman-Gonzalez M, Crucian BE, Ponomarev SA, Orlov OI, Shiba D, Muratani M, Yamamoto M, Richards SE, Vaishampayan PA, Meydan C, Foox J, Myrrhe J, Istasse E, Singh N, Venkateswaran K, Keune JA, Ray HE, Basner M, Miller J, Vitaterna MH, Taylor DM, Wallace D, Rubins K, Bailey SM, Grabham P, Costes SV, Mason CE, Beheshti A. "Fundamental biological features of spaceflight: Advancing the field to enable deep-space exploration." Cell. 2020 Nov 25;183(5):1162-84. Review. https://doi.org/10.1016/j.cell.2020.10.050 ; PMID: 33242416 , Nov-2020
Project Title:  Blood-based Multi-scale Model for Cancer Risk from GCR in Genetically Diverse Populations Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 02/04/2016  
End Date: 05/31/2021  
Task Last Updated: 11/13/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Costes, Sylvain  Ph.D. / NASA Ames Research Center 
Address:  Mail Stop 211-4 
 
Moffett Field , CA 94035-0001 
Email: sylvain.v.costes@nasa.gov 
Phone: 650-604-5343  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments: NOTE: Previously at Lawrence Berkeley National Laboratory until December 2016. 
Key Personnel Changes / Previous PI: NOTE (January 2018): The lab moved from Lawrence Berkeley National Lab (LBNL) to NASA Ames Research Center in 2017, where it was established as the Radiation Biophysics Lab in Space Biosciences Division. Dr. Costes will continue collaborating with LBNL and some funding will be left at LBNL to cover more plate processing in collaboration with Dr. Weil, Colorado State University (CSU) and for support from Dr. Snijders for the writing of the animal data. April 2017 report: - Elodie Guiet was a full time technician with a Bachelor in microbiology and biotechnology, working on this project from March 2016 until February 2017 -- she did not stay on the project when the lab moved to NASA Ames ; - Louise Viger was a Postdoc working partly on this project from June 2016 to January 2017 -- she was only here for a quick postdoc, focused primarily on modeling ; - Charlotte Degorre was a Postdoc who helped executing BNL run 16C -- visiting scientist for 1 month ; - Sebastien Penninckx was a PhD student who has been helping on data analysis -- visiting scientist for 3 months ; - Shayoni Ray is a new recruit at NASA Ames, postdoctoral fellow working on doing genomic analysis between animal DNA repair phenotypic data and their individual genes -- new postdoc full time at NASA Ames, started on April 10 2017.
Project Information: Grant/Contract No. Internal Project--ARC ; NNJ16HP24I 
Responsible Center: NASA ARC 
Grant Monitor: Lewis, Laura  
Center Contact:  
laura.lewis@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: Internal Project--ARC ; NNJ16HP24I 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer-202:Evaluate the contribution of genetic background/diversity on carcinogenesis risk (IRP Rev M)
Flight Assignment/Project Notes: NOTE: Extended to 5/31/2021 per L. Lewis/ARC HRP (Ed., 9/24/20)

NOTE: Extended to 5/31/2020 per PI (Ed., 11/15/19)

NOTE: Extended to 9/30/2019 per F. Hernandez/ARC (Ed., 2/18/19)

Task Description: NOTE (January 2018): The lab moved from Lawrence Berkeley National Lab (LBNL) to NASA Ames Research Center in 2017, where it was established as the Radiation Biophysics Lab in Space Biosciences Division. Dr. Costes will continue collaborating with LBNL and some funding will be left at LBNL to cover more plate processing in collaboration with Dr. Weil, Colorado State University (CSU) and for support from Dr. Snijders for the writing of the animal data.

Crews on future exploration missions to Mars and other destinations in our solar system will be exposed to acute low doses (<100 mSv) and chronic low doses (<0.1 mSv/min) of high-LET (linear energy transfer) ionizing radiation from solar particle events (SPE) and galactic cosmic radiation (GCR). Predicting cancer risk associated with these radiation types is a mission-critical challenge for NASA radiation health scientists and mission planners. Epidemiological methods lack sensitivity and power to provide detailed risk estimates for cancer, mainly because the number of exposed individuals to date is relatively small, limited to several hundred individuals exposed to trapped radiation in low Earth orbit and fewer than two dozen Apollo astronauts exposed to GCR for several days at a time. Moreover, population-based studies do not take individual radiation sensitivity into account, are sensitive to the presence of other confounding environmental insults, and require long follow-up times.

In collaboration with the radiation Biodosimetry Laboratory and the modeling group at NASA Johnson Space Center and with the International Computer Science Institute (ICSI) at University of California (UC) Berkeley, our team will bring unique inter-disciplinary expertise to integrate the large array of cancer data generated over the past 25 years and archived by NASA under the various Human Research Program (HRP) funded projects. The main goal of this proposal is to identify factors influencing radiation-induced carcinogenesis and integrate them into a multi-scale model already started at the Berkeley Lab that encompasses DNA damage response and inter-cellular signaling to predict cancer risk for any types of HZE (high energy particles). Because experimental data are dispersed across many different cancer models, radiation qualities, and measurement types, this project will also generate a complete set of experimental data designed to fully inform and validate the model. In this project, the model will impose the types of measurements being made, with a strong emphasis on well-established blood biomarkers. In our approach we hypothesize that genetic factors strongly influence risk of cancer from space radiation and that biomarkers reflecting DNA damage and inflammatory processes in the blood are great tools to predict risk and monitor potential health effects post-flight. By using blood as a surrogate organ, the proposed work will allow extrapolation of cancer risk from mice to humans. A cohort of 6 different strains of mice (collaborative cross-mouse) with expected sensitivity to ionizing radiation will be monitored for biomarkers and cancer after exposure to 0.3 Gy of 1 GeV/amu Fe particle and compared to 1 Gy exposure of gamma ray control. Because we favor larger number of animals per radiation condition, we selected only one dose and the most carcinogenic particle to prove the principle of our approach while validating our model on a complete set of ex-vivo data and in-vivo longitudinal data. The collaborative cross-mouse model used in this work was a resource from the low dose program at DOE (Department of Energy) developed by the Lawrence Berkeley National Laboratory that has made it possible for our team to examine the impact of genetic diversity in an animal model in a systematic and reproducible manner. In parallel, we propose to fully characterize the DNA damage response and cell death from ionizing radiation administered ex-vivo to 30 genetically different strains of mice and to 1000 human blood donors, matching the age and gender distribution of the astronaut population. Taken together, an array of ex-vivo phenotypic features will be associated to genetic traits across mice and humans as a function of age and gender. At the end of this proposal, our team will provide NASA with a model to estimate individualized risk for an astronaut before a flight as well as estimating the risk during the flight. Information generated in this proposal will also be useful to generate guidelines and suggest the best biomarkers to monitor the healthy recovery of astronauts post-flight.

Research Impact/Earth Benefits: A current radiobiology challenge is the ability to predict cancer risk associated with exposure to acute (<100 mSv) and chronic (<0.1 mSv/min) low doses of high-LET ionizing radiation. Epidemiological methods lack the sensitivity and power to provide detailed risk estimates for cancer, mainly because the astronaut cohort exposed to galactic cosmic rays (GCR) is relatively small. Moreover, population-based studies do not take individual radiation sensitivity into account, are affected by the presence of other confounding environmental insults, and require long follow-up times. We have hypothesized that characterizing the dose and time dependence of 53BP1 radiation induced foci (RIF) after exposure to a systematic array of X-ray doses and time points is sufficient to describe someone’s ability to respond to any other LET. The main concept is that the non-physiological response to high doses of low-LET in cells can be used to predict the response to low doses of high-LET, and that the response to low and high doses of radiation is modulated by different pools of genes.

Such work provides a new approach combining novel biomarkers with sophisticated mathematical analysis to better characterize individual sensitivity to space radiation. Once validated across mice and eventually a large cohort of humans, this approach could be generalized to establish individualized health risk management for astronauts and for the population at large being exposed to ionizing radiation.

Task Progress & Bibliography Information FY2020 
Task Progress: During year 4, the Radiation Biophysics Lab at NASA Ames has completed the majority of experiments in the human research part of the proposal. We have also received a costed extension to expand the sample numbers to over 750 subjects instead of the original 500 for a more rigorous analysis of genomic associations with responses to ionizing radiation, and to finish the project by May 31, 2020. The human blood sample collection is complete: we have collected samples from 762 healthy subjects, 18-75 years old, 50/50 male/female, of Northern European origin. We have irradiated all primary immune cell samples from all subjects (compared to 192 irradiated at the time of the previous report) at Brookhaven National Laboratory (BNL) in the spring 19A run and fall 19C run. We have also isolated DNA from all subjects and prepared libraries for sequencing that is scheduled in December 2019. This year we have published one primary research manuscript on the comparison of radiation sensitivity between mouse lines6 and have submitted a review on radiation countermeasures in the central nervous system (Pariset, Malkani, Cekanaviciute and Costes, International Journal of Radiation Biology).

During year 3, the Radiation Biophysics Lab at NASA Ames has finished the mouse research component and significantly moved forward with the human research component of this proposal. Human blood sample collection to investigate genomic associations with radiation sensitivity began in February 2018, and by December 2018 we have collected, isolated, and stored peripheral blood mononuclear cells (PBMCs) from 602 healthy subjects, 18-75 years old, 50/50 male/female, of Northern European origin. We have irradiated primary immune cells from the first 192 subjects at Brookhaven National Laboratory (BNL) in the summer 18B run using 350 MeV/n 28Si, 350 MeV/n 38Ar, and 600 MeV/n 56Fe ions and gamma rays, immunostained them with DNA damage marker anti-53BP1, performed high-throughput imaging and quantification of DNA damage foci, and are in the process of analyzing the results. In addition, we have designed a flow cytometry-based analysis of oxidative stress and cell death and used it to quantify the cellular responses to particle and gamma radiation from the first 192 BNL samples. We have also started collecting the supernatants from irradiated cells for potential future analysis of secreted biomarkers of human radiation sensitivity.

Bibliography Type: Description: (Last Updated: 02/04/2022) 

Show Cumulative Bibliography Listing
 
Articles in Other Journals or Periodicals Pariset E, Malkani S, Cekanaviciute E, Costes SV. "Ionizing radiation-induced risks to the central nervous system and countermeasures in cellular and rodent models." International Journal of Radiation Biology (in press as of November 2019). , Nov-2019
Articles in Peer-reviewed Journals Cekanaviciute E, Rosi S, Costes SV. "Central nervous system responses to simulated galactic cosmic rays." Int J Mol Sci. 2018 Nov 20;19(11):E3669. https://doi.org/10.3390/ijms19113669 ; PubMed PMID: 30463349; PubMed Central PMCID: PMC6275046 , Nov-2018
Articles in Peer-reviewed Journals Ochola DO, Sharif R, Bedford JS, Keefe TJ, Kato TA, Fallgren CM, Demant P, Costes SV, Weil MM. "Persistence of gamma-H2AX foci in bronchial cells correlates with susceptibility to radiation associated lung cancer in mice." Radiat Res. 2019 Jan;191(1):67-75. Epub 2018 Nov 6. https://doi.org/10.1667/RR14979.1 ; PubMed PMID: 30398394 , Jan-2019
Articles in Peer-reviewed Journals Penninckx S, Cekanaviciute E, Degorre C, Guiet E, Viger L, Lucas S, Costes SV. "Dose, LET and strain dependence of radiation-induced 53BP1+ foci in 15 mouse strains ex vivo introducing novel DNA damage metrics." Radiat Res. 2019 Jul;192(1):1-12. Epub 2019 May 13. https://doi.org/10.1667/RR15338.1 ; PubMed PMID: 31081741 , Jul-2019
Project Title:  Blood-based Multi-scale Model for Cancer Risk from GCR in Genetically Diverse Populations Reduce
Images: icon  Fiscal Year: FY 2018 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 02/04/2016  
End Date: 09/30/2019  
Task Last Updated: 02/09/2018 
Download report in PDF pdf
Principal Investigator/Affiliation:   Costes, Sylvain  Ph.D. / NASA Ames Research Center 
Address:  Mail Stop 211-4 
 
Moffett Field , CA 94035-0001 
Email: sylvain.v.costes@nasa.gov 
Phone: 650-604-5343  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments: NOTE: Previously at Lawrence Berkeley National Laboratory until December 2016. 
Key Personnel Changes / Previous PI: NOTE (January 2018): The lab moved from Lawrence Berkeley National Lab (LBNL) to NASA Ames Research Center in 2017, where it was established as the Radiation Biophysics Lab in Space Biosciences Division. Dr. Costes will continue collaborating with LBNL and some funding will be left at LBNL to cover more plate processing in collaboration with Dr. Weil, Colorado State University (CSU) and for support from Dr. Snijders for the writing of the animal data. April 2017 report: - Elodie Guiet was a full time technician with a Bachelor in microbiology and biotechnology, working on this project from March 2016 until February 2017 -- she did not stay on the project when the lab moved to NASA Ames ; - Louise Viger was a Postdoc working partly on this project from June 2016 to January 2017 -- she was only here for a quick postdoc, focused primarily on modeling ; - Charlotte Degorre was a Postdoc who helped executing BNL run 16C -- visiting scientist for 1 month ; - Sebastien Penninckx was a PhD student who has been helping on data analysis -- visiting scientist for 3 months ; - Shayoni Ray is a new recruit at NASA Ames, postdoctoral fellow working on doing genomic analysis between animal DNA repair phenotypic data and their individual genes -- new postdoc full time at NASA Ames, started on April 10 2017.
Project Information: Grant/Contract No. Internal Project--ARC ; NNJ16HP24I 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: Internal Project--ARC ; NNJ16HP24I 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer-202:Evaluate the contribution of genetic background/diversity on carcinogenesis risk (IRP Rev M)
Flight Assignment/Project Notes: NOTE: Extended to 9/30/2019 per F. Hernandez/ARC (Ed., 2/18/19)

Task Description: NOTE (January 2018): The lab moved from Lawrence Berkeley National Lab (LBNL) to NASA Ames Research Center in 2017, where it was established as the Radiation Biophysics Lab in Space Biosciences Division. Dr. Costes will continue collaborating with LBNL and some funding will be left at LBNL to cover more plate processing in collaboration with Dr. Weil, Colorado State University (CSU) and for support from Dr. Snijders for the writing of the animal data.

Crews on future exploration missions to Mars and other destinations in our solar system will be exposed to acute low doses (<100 mSv) and chronic low doses (<0.1 mSv/min) of high-LET (linear energy transfer) ionizing radiation from solar particle events (SPE) and galactic cosmic radiation (GCR). Predicting cancer risk associated with these radiation types is a mission-critical challenge for NASA radiation health scientists and mission planners. Epidemiological methods lack sensitivity and power to provide detailed risk estimates for cancer, mainly because the number of exposed individuals to date is relatively small, limited to several hundred individuals exposed to trapped radiation in low Earth orbit and fewer than two dozen Apollo astronauts exposed to GCR for several days at a time. Moreover, population-based studies do not take individual radiation sensitivity into account, are sensitive to the presence of other confounding environmental insults, and require long follow-up times.

In collaboration with the radiation Biodosimetry Laboratory and the modeling group at NASA Johnson Space Center and with the International Computer Science Institute (ICSI) at University of California (UC) Berkeley, our team will bring unique inter-disciplinary expertise to integrate the large array of cancer data generated over the past 25 years and archived by NASA under the various Human Research Program (HRP) funded projects. The main goal of this proposal is to identify factors influencing radiation-induced carcinogenesis and integrate them into a multi-scale model already started at the Berkeley Lab that encompasses DNA damage response and inter-cellular signaling to predict cancer risk for any types of HZE (high energy particles). Because experimental data are dispersed across many different cancer models, radiation qualities, and measurement types, this project will also generate a complete set of experimental data designed to fully inform and validate the model. In this project, the model will impose the types of measurements being made, with a strong emphasis on well-established blood biomarkers. In our approach we hypothesize that genetic factors strongly influence risk of cancer from space radiation and that biomarkers reflecting DNA damage and inflammatory processes in the blood are great tools to predict risk and monitor potential health effects post-flight. By using blood as a surrogate organ, the proposed work will allow extrapolation of cancer risk from mice to humans. A cohort of 6 different strains of mice (collaborative cross-mouse) with expected sensitivity to ionizing radiation will be monitored for biomarkers and cancer after exposure to 0.3 Gy of 1 GeV/amu Fe particle and compared to 1 Gy exposure of gamma ray control. Because we favor larger number of animals per radiation condition, we selected only one dose and the most carcinogenic particle to prove the principle of our approach while validating our model on a complete set of ex-vivo data and in-vivo longitudinal data. The collaborative cross-mouse model is an SFA resource that will make it possible for our team to examine the impact of genetic diversity in an animal model in a systematic and reproducible manner. In parallel, we propose to fully characterize the DNA damage response and cell death from ionizing radiation administered ex-vivo to 30 genetically different strains of mice and to 1000 human blood donors, matching the age and gender distribution of the astronaut population. Taken together, an array of ex-vivo phenotypic features will be associated to genetic traits across mice and humans as a function of age and gender. At the end of this proposal, our team will provide NASA with a model to estimate individualized risk for an astronaut before a flight as well as estimating the risk during the flight. Information generated in this proposal will also be useful to generate guidelines and suggest the best biomarkers to monitor the healthy recovery of astronauts post-flight.

Research Impact/Earth Benefits: A current radiobiology challenge is the ability to predict cancer risk associated with exposure to acute (<100 mSv) and chronic (<0.1 mSv/min) low doses of high-LET ionizing radiation. Epidemiological methods lack the sensitivity and power to provide detailed risk estimates for cancer, mainly because the astronaut cohort exposed to galactic cosmic rays (GCR) is relatively small. Moreover, population-based studies do not take individual radiation sensitivity into account, are affected by the presence of other confounding environmental insults, and require long follow-up times. We have hypothesized that characterizing the dose and time dependence of 53BP1 radiation induced foci (RIF) after exposure to a systematic array of X-ray doses and time points is sufficient to describe someone’s ability to respond to any other LET. The main concept is that the non-physiological response to high doses of low-LET in cells can be used to predict the response to low doses of high-LET, and that the response to low and high doses of radiation is modulated by different pools of genes.

Such work provides a new approach combining novel biomarkers with sophisticated mathematical analysis to better characterize individual sensitivity to space radiation. Once validated across mice and eventually a large cohort of humans, this approach could be generalized to establish individualized health risk management for astronauts and for the population at large being exposed to ionizing radiation.

Task Progress & Bibliography Information FY2018 
Task Progress: In year 2, we have completed the first part of the study, which aims to identify the genomic risk factors of sensitivity to ionizing radiation in mice. The previously described experiments of exposing mouse skin fibroblasts to high-LET ionizing radiation and measuring the resulting DNA damage and repair allowed us to compare the mouse strains based on sensitivity to ionizing radiation-induced DNA damage. We then performed genome-wide association studies (GWAS) on these mouse strains in order to map the single nucleotide polymorphisms (SNPs) that are associated with ionizing radiation sensitivity.

We identified seven significant associations on chromosomes 2, 3, 7, 10, 11, and 19 corresponding to 350 Mev/n Ar, three significant associations on chromosomes 10 and 13, corresponding to 600 MeV/n Fe, and two significant loci at chromosome 2 and 6, corresponding to 350 MeV/n Si. For both the high LET radiations, Ar and Fe, a common locus on chromosome 10 was identified, with peak SNP as UNC18214722 (p value = 7.22 x 10-7) along with fourteen genes affiliated with chromatin modification, DNA replication, transcription, and double stranded break repair. For 350 Mev/n Ar, additionally, two other peak SNPs were identified on chromosome 10 (JAX00021248, p = 4.24 x 10-6) and on chromosome 11 (UNC20271233, p = 4.03 x 10-6) with five DNA damage response genes. For low LET Si, out of 21 genes in the LD, one repair-associated gene at peak SNP JAX00629117 on chromosome 6 (p = 1.2 x 10-6) was identified. Pathway analysis using DAVID identified DNA repair response as the most enriched pathway.

The second part of our study applies a similar approach to humans and aims to characterize the genomic risk factors associated with sensitivity to ionizing radiation in a large human cohort. We are in the process of collecting peripheral blood mononuclear cells (PBMCs) from a large cohort of at least 500 and up to 700 healthy human volunteers, combining samples from Institut Pasteur in France, Oklahoma Blood Institute, and NASA Ames. We have optimized all relevant protocols to isolate, freeze, thaw, and culture human PBMCs, and in order to measure DNA repair responses, we have developed an experimental setup for high-throughput immunocytochemistry for DNA repair markers 53-bp1 and gamma-H2AX on human PBMCs as well as automated image acquisition and analysis. We will also quantify primary human immune cell death and differentiation into pro- or anti-inflammatory phenotypes.

We will participate in the BNL (Brookhaven National Laboratory) summer and fall 2018 runs where we will expose these human PBMCs to high-LET radiation. Specifically, in summer 2018 we will expose PBMCs from 100 subjects (50 of the most susceptible and 50 of the least susceptible to low-LET radiation) to 2 fluences (1.1 and 3 particles/100um^2) of 14Si, 18Ar, and 26Fe ions and isolate them at 4 h, 24 h, and 48 h after irradiation to measure the time course of DNA repair and cellular responses. In fall 2018, we will repeat this experiment with PBMCs from 300 subjects, focusing specifically on responses to Fe irradiation. In this way, we have expanded our original experimental plan to include more subjects, which will allow us to achieve more conclusive results on modeling responses to high-LET radiation-induced DNA damage and repair.

Bibliography Type: Description: (Last Updated: 02/04/2022) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Cortese F, Klokov D, Osipov A, Stefaniak J, Moskalev A, Schastnaya J, Cantor C, Aliper A, Mamoshina P, Ushakov I, Sapetsky A, Vanheaelen Q, Alchinova I, Karganov M, Kovalchuk O, Wilkins RC, Shtemberg A, Moreels M, Baatout S, Izumchenko E, de Magalhães JP, Artemov AV, Costes SV, Beheshti A, Mao XW, Pecaut MJ, Kaminskiy D, Ozerov IV, Scheibye-Knudsen M, Zhavoronkov A. "Vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization." Oncotarget. 2018 Mar;9(18):14692-722. https://doi.org/10.18632/oncotarget.24461 ; PubMed PMID: 29581875; PubMed Central PMCID: PMC5865701 , Mar-2018
Articles in Peer-reviewed Journals Colmenares SU, Swenson JM, Langley SA, Kennedy C, Costes SV, Karpen GH. "Drosophila histone demethylase KDM4A has enzymatic and non-enzymatic roles in controlling heterochromatin integrity." Dev Cell. 2017 Jul 24;42(2):156-69.e5. https://doi.org/10.1016/j.devcel.2017.06.014 ; PubMed PMID: 28743002; PubMed Central PMCID: PMC5572651 , Jul-2017
Project Title:  Blood-based Multi-scale Model for Cancer Risk from GCR in Genetically Diverse Populations Reduce
Images: icon  Fiscal Year: FY 2017 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 02/04/2016  
End Date: 02/03/2019  
Task Last Updated: 04/19/2017 
Download report in PDF pdf
Principal Investigator/Affiliation:   Costes, Sylvain  Ph.D. / NASA Ames Research Center 
Address:  Mail Stop 211-4 
 
Moffett Field , CA 94035-0001 
Email: sylvain.v.costes@nasa.gov 
Phone: 650-604-5343  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments: NOTE: Previously at Lawrence Berkeley National Laboratory until December 2016. 
Co-Investigator(s)
Affiliation: 
Pluth, Janice  Ph.D. Lawrence Berkeley National Laboratory 
Snijders, Antoine  Ph.D. Lawrence Berkeley National Laboratory 
Key Personnel Changes / Previous PI: NOTE: The lab moved from Lawrence Berkeley National Lab (LBNL) to NASA Ames Research Center in 2017, where it was established as the Radiation Biophysics Lab in Space Biosciences Division. Dr. Costes will continue collaborating with LBNL and some funding will be left at LBNL to cover more plate processing in collaboration with Dr. Weil (CSU) and for support from CoI Dr. Snijders for the writing of the animal data. April 2017 report: - Elodie Guiet was a full time technician with a Bachelor in microbiology and biotechnology, working on this project from March 2016 until February 2017 -- she did not stay on the project when the lab moved to NASA Ames ; - Louise Viger was a Postdoc working partly on this project from June 2016 to January 2017 -- she was only here for a quick postdoc, focused primarily on modeling ; - Charlotte Degorre was a Postdoc who helped executing BNL run 16C -- visiting scientist for 1 month ; - Sebastien Penninckx was a PhD student who has been helping on data analysis -- visiting scientist for 3 months ; - Shayoni Ray is a new recruit at NASA Ames, postdoctoral fellow working on doing genomic analysis between animal DNA repair phenotypic data and their individual genes -- new postdoc full time at NASA Ames, started on April 10 2017.
Project Information: Grant/Contract No. NNJ16HP24I 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: NNJ16HP24I 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer-202:Evaluate the contribution of genetic background/diversity on carcinogenesis risk (IRP Rev M)
Task Description: Crews on future exploration missions to Mars and other destinations in our solar system will be exposed to acute low doses (<100 mSv) and chronic low doses (<0.1 mSv/min) of high-LET (linear energy transfer) ionizing radiation from solar particle events (SPE) and galactic cosmic radiation (GCR). Predicting cancer risk associated with these radiation types is a mission-critical challenge for NASA radiation health scientists and mission planners. Epidemiological methods lack sensitivity and power to provide detailed risk estimates for cancer, mainly because the number of exposed individuals to date is relatively small, limited to several hundred individuals exposed to trapped radiation in low Earth orbit and fewer than two dozen Apollo astronauts exposed to GCR for several days at a time. Moreover, population-based studies do not take individual radiation sensitivity into account, are sensitive to the presence of other confounding environmental insults, and require long follow-up times.

In collaboration with the radiation Biodosimetry Laboratory and the modeling group at NASA Johnson Space Center and with the International Computer Science Institute (ICSI) at University of California (UC) Berkeley, our team will bring unique inter-disciplinary expertise to integrate the large array of cancer data generated over the past 25 years and archived by NASA under the various Human Research Program (HRP) funded projects. The main goal of this proposal is to identify factors influencing radiation-induced carcinogenesis and integrate them into a multi-scale model already started at the Berkeley Lab that encompasses DNA damage response and inter-cellular signaling to predict cancer risk for any types of HZE (high energy particles). Because experimental data are dispersed across many different cancer models, radiation qualities, and measurement types, this project will also generate a complete set of experimental data designed to fully inform and validate the model. In this project, the model will impose the types of measurements being made, with a strong emphasis on well-established blood biomarkers. In our approach we hypothesize that genetic factors strongly influence risk of cancer from space radiation and that biomarkers reflecting DNA damage and inflammatory processes in the blood are great tools to predict risk and monitor potential health effects post-flight. By using blood as a surrogate organ, the proposed work will allow extrapolation of cancer risk from mice to humans. A cohort of 6 different strains of mice (collaborative cross-mouse) with expected sensitivity to ionizing radiation will be monitored for biomarkers and cancer after exposure to 0.3 Gy of 1 GeV/amu Fe particle and compared to 1 Gy exposure of gamma ray control. Because we favor larger number of animals per radiation condition, we selected only one dose and the most carcinogenic particle to prove the principle of our approach while validating our model on a complete set of ex-vivo data and in-vivo longitudinal data. The collaborative cross-mouse model is an SFA resource that will make it possible for our team to examine the impact of genetic diversity in an animal model in a systematic and reproducible manner. In parallel, we propose to fully characterize the DNA damage response and cell death from ionizing radiation administered ex-vivo to 30 genetically different strains of mice and to 1000 human blood donors, matching the age and gender distribution of the astronaut population. Taken together, an array of ex-vivo phenotypic features will be associated to genetic traits across mice and humans as a function of age and gender. At the end of this proposal, our team will provide NASA with a model to estimate individualized risk for an astronaut before a flight as well as estimating the risk during the flight. Information generated in this proposal will also be useful to generate guidelines and suggest the best biomarkers to monitor the healthy recovery of astronauts post-flight.

Research Impact/Earth Benefits: A current radiobiology challenge is the ability to predict cancer risk associated with exposure to acute (<100 mSv) and chronic (<0.1 mSv/min) low doses of high-LET ionizing radiation. Epidemiological methods lack the sensitivity and power to provide detailed risk estimates for cancer, mainly because the astronaut cohort exposed to galactic cosmic rays (GCR) is relatively small. Moreover, population-based studies do not take individual radiation sensitivity into account, are affected by the presence of other confounding environmental insults, and require long follow-up times. We have hypothesized that characterizing the dose and time dependence of 53BP1 radiation induced foci (RIF) after exposure to a systematic array of X-ray doses and time points is sufficient to describe someone’s ability to respond to any other LET. The main concept is that the non-physiological response to high doses of low-LET in cells can be used to predict the response to low doses of high-LET, and that the response to low and high doses of radiation is modulated by different pools of genes.

Such work provides a new approach combining novel biomarkers with sophisticated mathematical analysis to better characterize individual sensitivity to space radiation. Once validated across mice and eventually a large cohort of humans, this approach could be generalized to establish individualized health risk management for astronauts and for the population at large being exposed to ionizing radiation.

Task Progress & Bibliography Information FY2017 
Task Progress: Skin fibroblast cells were extracted and cultivated from 72 individual mice. This cohort was made on average of 3 males and 3 females from 15 different strains of mice with various genetic backgrounds, including the collaborative cross (CC) genetic model (10 strains) and five known reference mice. Cells were exposed to two fluences of three HZE particles at Brookhaven National Laboratory (Si 350MeV/n, Ar 350MeV/n and Fe 600 MeV/n) and to 0.1, 1, and 4 Gy from 160 kV X-ray at Lawrence Berkeley National Laboratory. Individual radiation sensitivity was investigated by DNA repair kinetics high throughput measurement evaluating RIF numbers at various time following the different doses and fluences for each radiation type. The high-LET particle dose response shows a linear dependence that is unchanged and very close to the number of track per cell for both 4 and 8 hours post-irradiation, even though each track are known to induce multiple DNA double strand breaks (DSB). By comparing the slope of the high-LET dose dependence to the expected number of tracks per cell for each dose, we propose a new approach where the number of remaining unrepaired tracks are evaluated against the time post-irradiation. The results obtained using this approach show that the percentage of unrepaired track over a 48 hours follow-up is strain dependent and is slower as the LET increases. We also observe a strong correlation between the high dose repair kinetic following exposure to 160 kV X-ray and the repair kinetic of tracks, with an increasing correlation with higher LET. At the in-vivo level for the 10 CC strains, we observe that drops in the number of T-cells and B-cells found in the blood of mice 24 hours after exposure to 0.1 Gy of 320 kV X-ray correlate well with slower DNA repair kinetic in skin cells.

Overall, our results suggest that repair kinetic found in skin is a surrogate marker for in vivo radiation sensitivity in other tissue, such as blood cells and such response is modulated by genetic. On the other hand, different genes seem to be involved for low dose of low-LET sensitivity versus high dose low-LET or high-LET sensitivity. This work also validates our hypothesis showing that DNA repair kinetic following high doses of X-ray is an accurate predictor for radiation sensitivity to high-LET when evaluated on cell culture.

Single-nucleotide polymorphism arrays are currently being used to identify potential pools of genes responsible for radiation sensitivity to low-LET and/or high-LET. To the best of our knowledge, this work is one of the most extensive studies done on such a large animal genetic diversity regarding both low dose radiation and high-LET.

NOTE: The lab moved from Lawrence Berkeley National Lab (LBNL) to NASA Ames Research Center in 2017, where it was established as the Radiation Biophysics Lab in Space Biosciences Division. Dr. Costes will continue collaborating with LBNL and some funding will be left at LBNL to cover more plate processing in collaboration with Dr. Weil (CSU) and for support from CoI Dr. Snijders for the writing of the animal data.

Bibliography Type: Description: (Last Updated: 02/04/2022) 

Show Cumulative Bibliography Listing
 
 None in FY 2017
Project Title:  Blood-based Multi-scale Model for Cancer Risk from GCR in Genetically Diverse Populations Reduce
Images: icon  Fiscal Year: FY 2016 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 02/04/2016  
End Date: 02/03/2019  
Task Last Updated: 03/04/2016 
Download report in PDF pdf
Principal Investigator/Affiliation:   Costes, Sylvain  Ph.D. / NASA Ames Research Center 
Address:  Mail Stop 211-4 
 
Moffett Field , CA 94035-0001 
Email: sylvain.v.costes@nasa.gov 
Phone: 650-604-5343  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments: NOTE: Previously at Lawrence Berkeley National Laboratory until December 2016. 
Project Information: Grant/Contract No. NNJ16HP24I 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: NNJ16HP24I 
Project Type: GROUND 
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TechPort: No 
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Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer-202:Evaluate the contribution of genetic background/diversity on carcinogenesis risk (IRP Rev M)
Task Description: Crews on future exploration missions to Mars and other destinations in our solar system will be exposed to acute low doses (< 100 mSv) and chronic low doses (<0.1 mSv/min) of high-LET ionizing radiation from solar particle events (SPE) and galactic cosmic radiation (GCR). Predicting cancer risk associated with these radiation types is a mission-critical challenge for NASA radiation health scientists and mission planners. Epidemiological methods lack sensitivity and power to provide detailed risk estimates for cancer, mainly because the number of exposed individuals to date is relatively small, limited to several hundred individuals exposed to trapped radiation in low Earth orbit and fewer than two dozen Apollo astronauts exposed to GCR for several days at a time. Moreover, population-based studies do not take individual radiation sensitivity into account, are sensitive to the presence of other confounding environmental insults, and require long follow-up times.

In collaboration with the radiation Biodosimetry Laboratory and the modeling group at NASA Johnson Space Center and with the International Computer Science Institute (ICSI) at UC Berkeley, our team will bring unique inter-disciplinary expertise to integrate the large array of cancer data generated over the past 25 years and archived by NASA under the various Human Research Program (HRP) funded projects. The main goal of this proposal is to identify factors influencing radiation-induced carcinogenesis and integrate them into a multi-scale model already started at the Berkeley Lab that encompasses DNA damage response and inter-cellular signaling to predict cancer risk for any types of HZE. Because experimental data are dispersed across many different cancer models, radiation qualities, and measurement types, this project will also generate a complete set of experimental data designed to fully inform and validate the model. In this project, the model will impose the types of measurements being made, with a strong emphasis on well-established blood biomarkers. In our approach we hypothesize that genetic factors strongly influence risk of cancer from space radiation and that biomarkers reflecting DNA damage and inflammatory processes in the blood are great tools to predict risk and monitor potential health effects post-flight. By using blood as a surrogate organ, the proposed work will allow extrapolation of cancer risk from mice to humans. A cohort of 6 different strains of mice (collaborative cross-mouse) with expected sensitivity to ionizing radiation will be monitored for biomarkers and cancer after exposure to 0.3 Gy of 1 GeV/amu Fe particle and compared to 1 Gy exposure of gamma ray control. Because we favor larger number of animals per radiation condition, we selected only one dose and the most carcinogenic particle to prove the principle of our approach while validating our model on a complete set of ex-vivo data and in-vivo longitudinal data. The collaborative cross-mouse model is an SFA resource that will make it possible for our team to examine the impact of genetic diversity in an animal model in a systematic and reproducible manner. In parallel, we propose to fully characterize the DNA damage response and cell death from ionizing radiation administered ex-vivo to 30 genetically different strains of mice and to 1000 human’s blood donors, matching the age and gender distribution of the astronaut population. Taken together, an array of ex-vivo phenotypic features will be associated to genetic traits across mice and humans as a function of age and gender. At the end of this proposal, our team will provide NASA with a model to estimate individualized risk for an astronaut before a flight as well as estimating the risk during the flight. Information generated in this proposal will also be useful to generate guidelines and suggest the best biomarkers to monitor the healthy recovery of astronauts post-flight.

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Task Progress & Bibliography Information FY2016 
Task Progress: New project for FY2016.

Bibliography Type: Description: (Last Updated: 02/04/2022) 

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 None in FY 2016