How does biological protection help astronauts tolerate high levels of radiation

How Does Biological Protection Help
Astronauts Tolerate High Levels of
Radiation During
Deep Space Manned Missions
SMJ Mortazavi, Ph.D
Fox Chase Cancer Center
Philadelphia, PA 19111
Email: S.M.Javad.Mortazavi@fccc.edu
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Disclaimer: Opinions expressed in this presentation are my own professional
opinion, and do not represent those of Fox Chase Cancer Center.
© 2017 SMJ Mortazavi

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Prof SMJ Mortazavi
Prof A Niroomand-Rad
Prof J R Cameron
Dr Mohan Doss
(Technical Adviser)

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I should sincerely thank:
Prof. Ioana Voiculescu
Prof. Yiannis Andreopoulos

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Radiation Protection
Challenges in Space
Three General Guidelines:
• Time (Not Applicable in Space)
• Distance (Not Applicable in
Space)
• Shield (Not Easy in Space due to
Weight Limitations)

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Our Integrative Radiation
Protection Plan Includes:
Physical Shielding
Adaptive response
(Biological Protection)
Other Biological
Protection
Methods

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Our Integrative Protection
Plan:
Physical Shielding
Adaptive response
Biological Protection

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 Other researchers as well as our
team have conducted some
experiments on design and
fabrication of appropriate
radiation shields for spacecrafts.
 In spite of some advances in this
field, it will be discussed here
that improving the physical
shielding alone cannot solve the
problem of exposure to high
levels of radiation in a long term
space mission.
Our previous experience:

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Challenges of Physical Shielding in
Space:
• Weight Limitations
• Extravehicular Activities

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Physical shielding is extremely
inadequate during extravehicular
activity (EVA)!
Space Walking!

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“For space applications, however,
every kilogram of mass has a
significant impact upon the
mission cost and feasibility.”
http://large.stanford.edu/courses/20
15/ph241/clark1/

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“Examining the different methods
of space radiation shielding, it is
clear that no single good solution
currently exists to adequately
protect astronauts from the
radiation environment of space.”
http://large.stanford.edu/courses/20
15/ph241/clark1/

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Therefore, as physical
shielding alone cannot
solve current space
radiation problems, we
focused on:
• Adaptive Response
• Other Biological
Protection Methods

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Plan:
Physical Shielding
Adaptive response

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Adaptive response, that is
an increased
radioresistance in cells or
organisms exposed to a
high challenging dose after
pre-exposure to a low
adapting dose, can
considerably reduce the
radiation susceptibility of
humans (Olivieri et al.,
1984).
Mortazavi et al. 2003
Adaptive response

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 The Galactic Cosmic Radiation (GCR) ions originate from
outside our solar system and contain mostly highly energetic
protons and alpha particles, with a small component of high
charge and energy (HZE) nuclei moving at relativistic speeds
and energies.
 About 88% of all GCR particles are hydrogen (protons), 10%
are helium (alpha particles), and the remaining percentage
(~2%) consists of heavier ions.
 In addition to GCR, unpredictable and intermittent solar
particle events (SPEs) can produce large plasma clouds
containing highly energetic protons and some heavy ions that
may cause a rapid surge of radiation both outside and within
a spacecraft.
Space Environment

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 Radiation risk from high level cosmic
rays exposure and microgravity are
two important concerns that need to
be addressed prior to a long-term
space mission.
 It has been reported that microgravity
increases the radiation susceptibility
of living organisms by a synergistic
effect.
Radiation and Microgravity as
Two Main Barriers

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2003
Advances in
Space Research

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pp. 4299–4302 c
2003 by Universal Academy Press, Inc.

Mortazavi SMJ, Ph.D
Mortazavi et al., Advances in Space Research, Vol 31, No. 6, 1543-1552, 2003
21

Mortazavi SMJ, Ph.D
Two survey meters show dose rates
of 142 and 143 µSv/h on contact
with a bedroom wall
22
Our proposed theory was
based on the findings of the
1st report on the induction of
adaptive response in the
residents of High Background
Radiation Areas (HBRAs)
Theory

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We didn’t use this novel method but our papers received lots
of citations!

Mortazavi SMJ, Ph.D
190 citations recorded by Scopus
Adaptive response in the
residents of High
Background Radiation
Areas (HBRAs)
24
151 citations recorded by WoS (ISI)
334 citations recorded by G Scholar

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 We have previously shown that
chronic exposure of humans to
ionizing radiation can lead to
induction of adaptive response in
the majority of participants.
 However, some of the
participants did not show this
phenomenon and even their
lymphocytes became more
sensitive to subsequent high dose
exposures (Synergistic Effect).
Inter-individual variabilities!

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o Astronauts are chronically exposed to
different levels of galactic cosmic
radiation (GCR).
o If a solar particle event (SPE) occurs,
astronauts may receive doses as high
as 1 Gy in a short time.
o In this light selection of astronauts
with high magnitude of adaptive
response would be critical.
o In this case, astronauts will be
adapted by GCR and when SPE
occurs, they will show a significant
radioresistance.
GCR vs SPE!

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o “The likelihood that SPE will
produce doses that are above 1
Gy is small, while the occurrence
of doses that can induce
prodromal risks are quite
possible”.
o Wu et al.
Doses in SPE!

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 “The biological effects of space
radiation, including ARS, are a
significant concern.
 High doses of radiation can induce
profound radiation sickness and death.
 Lower doses of radiation induce
symptoms that are much milder
physiologically, but that pose
operational risks that are equally
serious.
 Both scenarios have the potential to
seriously affect crew health and/or
prevent the completion of mission
objectives”
o Wu et al.

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 “Complicating matters is the additional ~
20% probability of short-term solar particle
events (SPEs) during the roughly 400- day
round trip to and from Mars
 This could conceivably impart a relatively
high acute dose of predominantly protons and
light ions within 1 hour or less, significantly
increasing mission total dose equivalent
(TDE)”. Rodman et al., Leukemia, 2016
The Probability of a Solar Particle
Event in Mars Missions
http://www.nature.com/leu/journal/vaop/ncurrent/full/leu2016344a.html
20%

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Dicentrics
1
2
3
4
5
6

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A. Different individuals show different
levels of radioadaptation (and some
show no radioadaptation and even
show some kind of synergism; more
adverse biological effects).
B. Candidates for deep space missions
should be screened before the mission.
C. The level of the radioadaptation of
each individual can be measured by
some simple tests (needless to say
after exposing blood samples to a low
dose and then to a high dose radiation
and measuring parameters such as
chromosome aberrations, etc.).
Mortazavi et al., Adv Space Res, 2003
Summary of the hypothesis proposed by our team:

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D. The magnitude of radioadaptation of
the candidate can be compared now.
E. Candidates with a high magnitude of
radioadaptation will be good choices for a
deep space mission.
F. During space mission, the selected
astronauts will be adapted to radiation by
chronic galactic cosmic radiation (GCR).
 It’s worth noting that the
magnitude and duration of
solar particle event (SPE) are
currently unpredictable.
Summary of the hypothesis proposed by our team (cont.):

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G. If a solar particle event occurs it can
deliver potentially large doses of energetic
particles even behind modest spacecraft
shielding.
H. Adaptive response can help the selected
astronauts tolerate these relatively high
levels of radiation.
Summary of the hypothesis proposed by our team (cont.):

Two years after Mortazavi et al. 2003 report, other
scientists agreed that adaptive response is a
puzzling issue in space radiobiology
• 2005-Cancer specialist Dr. John
Dicello
• “Cells often react in unexpected ways to radiation, notes Dicello.
For example, there's a puzzling phenomenon known as adaptive
response. Sometimes, when tissue is exposed to damaging
radiation, it not only repairs itself, but also learns to repair itself
better next time. How that works is still being investigated”
• “The damage could be less than the two kinds added together -- or
it could be more! There could, perhaps, be an adaptive response in
which lightweight solar protons stimulate repair processes to help
reduce the effects of the heavy cosmic ray ions. Or something
totally unexpected could happen”.
• Mysterious Cancer http://science.nasa.gov/
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George et al. 2007:
“This study of adaptive response is very interesting and it is important
that the phenomenon be investigated further.
Four
years later,
in 2007:

• Durante and Manti 2008:
• “Another possibility is that an adaptive response to the space environment takes
place after the first exposure, which may confer the exposed individual an increased
radioresistance. Such a response would be similar to that hypothesized to explain
the apparent lack of adverse health effects in VHBRA and HBRA residents. As
pointed out by Mortazavi et al. (2003), radiobiological studies on these areas may
lead to the identification of the cellular and molecular mechanisms by which
susceptibility to genetic damage and cancer is decreased by chronic radiation
exposure, hence helping the astronaut selection process.”
Mortazavi SMJ, Ph.D
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After 8 years (in 2011) without citing the early idea:
Protons
Iron Ions

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After 8 years (in 2011) without citing the early idea:
o Low dose (10 cGy)
of protons followed
after either 5-15 min
(immediate) or 16-24
h (delayed) by 1 Gy
of iron ions
o Low dose (10 cGy) of
iron ions followed
after either 5-15 min
or 16-24 h by 1 Gy of
protons

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• “Moreover, a second spaceflight apparently does not proportionately increase the
yield of aberrations, suggesting a non-additive or even an infra-additive effect,
raising the possibility of a radio-adaptive response in crewmembers (i.e.,
“radiation hormesis”).”
• “Notwithstanding this finding, knowledge of the basic mechanisms specific to
low-dose radiation, to sequential doses of low-dose radiation and to adaptive
responses is still at a rudimentary stage.”
After 11 years (in 2014)
without citing the early
idea:
1st Mission
2nd Mission
Methodological
Error?
The Time
Interval Between
AD and CD?

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idea:
• Effects of mixed-field proton/iron ion irradiations on cellular
adaptive responses were examined by Elmore et al. using an in vitro
HeLa X human fibroblast hybrid cell transformation assay, but
interestingly was only shown to be radioprotective when 10 cGy 1
GeV/n iron ions was delivered prior to 1 Gy of 1 GeV protons, (that
is, the reverse order of our irradiations).
Protons
Iron Ions

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idea:
• More recently, Buonanno et al. reported significant radioprotection
for chromosomal damage (micronuclei) induction in primary
human fibroblasts exposed to 20 cGy of 50 MeV or 1 GeV protons
followed by 50 cGy of 1 GeV/n iron ions, with the radioprotective
effect persisting for 24 h.

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 Space particles have an inevitable impact
on organisms during space missions
 Radio-adaptive response (RAR) is a
critical radiation effect due to both low-
dose background and sudden high-dose
radiation exposure during solar storms.
Chenguang Deng et al. Effect of modeled microgravity on radiation-induced adaptive
response of root growth in Arabidopsis thaliana, Mutation Research/Fundamental and
Molecular Mechanisms of Mutagenesis 2017
After 14 years (in
2017):

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Plan:
Physical Shielding
Adaptive response

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1. Radiation mitigators vs
traditional radioprotectors!

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Conventional radioprotectors
cannot efficiently be used in
space due to 2 basic limitations:
• Their considerable toxicity
• They should be used before
exposure (when astronauts cannot
accurately calculate their doses)
Radioprotectors

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 In contrast with radioprotectors,
radiation mitigators can efficiently
be used after exposure (e.g. when an
intense solar particle event subsides
and astronauts can estimate their
doses).
 Radiation mitigators can be used
even 24 hours after exposure to high
levels of radiation.
Radiomitigators

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We introduced vitamin
C as an efficient
radiomitigator for deep
space manned missions!

S.M.J. Mortazavi, S. Sharif-Zadeh, H. Mozdarani,
M. Foadi, M. Haghani, E. Sabet. Future role of
vitamin C in radiation mitigation and its possible
applications in manned deep space missions:
Survival study and the measurement of cell
viability Physica Medica, Volume 30, Supplement
1, 2014, Page e97
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▪ Survival Rate in Control group
100%
▪ Animals received only LD50/30,
50%
▪ Received vitamin C
(+radiation):
• 1h, before radiation, 80%
• 1h, after radiation, 55%
Vit C (400 mg/kg) +
Gamma (LD50/30)
24 h after exposure
Only Gamma
(LD50/30)
30% Increase

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Increased survival
when exposed to:
• Protons?
• Energetic Ions?
DNA damage?
Cancer?
Vit C increased the
survival rate 24 h
after exposure to
gamma radiation

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Radioprotectors
Radiomitigators

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2. RF-Induced Increased
Survival

The first report on the RF-induced adaptive
response
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Mitomycin CRF
Micronuclei

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RF Gamma (LD 50)
Survival

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SMJ Mortazavi, et al. Increased
Radioresistance to Lethal Doses of
Gamma Rays in Mice and Rats
after Exposure to Microwave
Radiation Emitted by a GSM
Mobile Phone Simulator, Dose-
Response, 11 (2), 2012 DOI:
10.2203/dose-response.12-
010.Mortazavi
RF Gamma (LD 50)
Survival
Mice

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Our second experiment on another rodent with the same findings!
RF  
0  
100%
53.3%
SMJ Mortazavi, et al. Increased Radioresistance to Lethal
Doses of Gamma Rays in Mice and Rats after Exposure to
Microwave Radiation Emitted by a GSM Mobile Phone
Simulator, Dose-Response, 11 (2), 2012 DOI: 10.2203/dose-
response.12-010.Mortazavi
Rats

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3. Infection Prevention in Deep
Space Missions

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Infection Prevention in Deep Space Missions
 In two studies funded by NASA, it
was shown that key factors such as
microgravity and radiation could
change the behavior of bacterial
communities.
 In addition, immune system is highly
sensitive to stressors such as radiation
in space flight
Microgravity Radiation
Altered behavior of
Microorganisms

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Infection Prevention in Deep Space Missions
Thus, solar and
galactic radiation
along with
microgravity
increase the risk of
infection during
long-term stay of
human in space.
Galactic radiation
Infection Risk
Solar radiation
Microgravity
Intervention?

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 We showed that exposure to
radiofrequency radiation (RF)
increased the survival rate of
laboratory animals (56% in pre-
exposed animals vs 20% in non-
exposed animals) after i.p.
injection of E. coli bacteria.
Immune System and Radiation

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RF
E. coli injection
Survival

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RF Gamma (LD 50)
Survival

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4. Boosting the Immune System
in Immunosuppressed
Laboratory Animals

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 Over the past several years we
have conducted some experiments
on boosting the immune system
by pre-exposure to either ionizing,
or non-ionizing radiation. The
data currently are unpublished.
 The findings of these experiments
generally support the importance
of the biological protection in
long term manned space missions.
Our Unpublished Data:
RF
HU Rodents
T helper Cytokines

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Boosting the Immune System in
Immunosuppressed Laboratory Animals
 In our previous experiment we had used mice with normal
immune system but some scientists criticized our work for
not using immunosuppressed mice.
 Their rationale was this point that the immune system of
astronauts in a long-term space mission can be affected by
different stresses such as microgravity and higher levels of
radiation.
 Therefore, we designed a new study to investigate the effect
of RF-EMFs-induced adaptive responses on immune system
modulation in a mouse model of hindlimb unloading (HU).

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“Mortazavi et al. [42] described exactly the same above experimental
protocol, ….. RF + E. coli may have important clinical implications
in treating bacterial infections and, for decreasing the risk of
infection in immunosuppressed irradiated individuals: the authors
have not mentioned the use of immune-suppressed animals for the
experiments in both publications.”

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Immunosuppressed Laboratory Animals
 We used hindlimb unloading rodent model that
is widely accepted by the scientific community
as the model of choice for simulating
spaceflight.
 Serum levels of T helper cytokines were
determined in HU mice, RF-EMF treated mice
and HU mice pre-exposed to RF-EMF
compared to those of untreated controls.
 Th-related cytokines measured were Th1 (IFN-
γ, TNF-α, IL-2), Th2 (IL-4, IL-5, IL-6, IL-10
and IL-13), Th17 (IL-17A, IL-17F, IL-21),
Th9 (IL-9) and Th22 (IL-22).

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Immunosuppressed Laboratory Animals (cont.)
 Mice were exposed to 2450 MHz RF-EMF
with a SAR level of 0.478W.kg-1for 12 h per
day on 3 successive days and serum cytokine
levels were determined by multiplex
cytometric bead-based assay.
 Our findings may help space research
scientists maintain the immune system
balance in long-term manned space missions
in the future.

Adaptive
Response in
Space
Research
• Different methods that
can be used for
reducing the risk of
radiation during deep
space missions.
Mortazavi SMJ, Ph.D
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