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Dr. Ruth Globus – Flying Through the Ages: Rodent Research for Human Health

Dr. Ruth Globus – Flying Through the Ages: Rodent Research for Human Health


[musical tones]
[electronic sounds of data] So welcome to the 2015
NASA Ames Summer Series. Space exploration allows us
to investigate the frontiers of space,
our future. It also allows us to make
science fiction a reality, and in the process,
we learn about ourselves, and our home planet, Earth. One of the ways that we study
and investigate space and make sure that we survive
that environment is to use model organisms. NASA Ames is
the lead research center for conducting, managing,
and building hardware to conduct rodent research
in space. Today’s seminar, entitled
“Flying Through the Ages: Rodent Research
for Human Health,” will be given
by Dr. Ruth Globus. Ruth earned a BA degree
in sociology in 1979 from the University
of California at Santa Cruz, followed by another
BA degree in 1981 in biology from the same university. After that, she worked
at the lab of Emily Holton here at NASA Ames,
where she got introduced and got the bug of being
at Ames Research Center. She worked for two years,
and then she realized that her future lies
in being a PI and doing space research and
ground research with rodents. So she went on to get a Ph.D.
degree in endocrinology from the University
of California at San Francisco, followed by a postdoc
in cell biology. She became
a principal investigator at NASA Ames in 1993 and then joined
the civil-servant staff in 1997. She has numerous awards
and publications, too many to go here
at this moment. Please join me in welcoming
Dr. Ruth Globus. [applause] Thank you very much, Jacob. Thank you, Ames, for giving me the opportunity
to share our work. I won’t say “my work.” I’ll say “our work,” and I think, as I proceed
through this talk, you’ll see why. We have been actively engaged in developing capability to conduct long-duration rodent
research on the Space Station. And it makes sense.
Why do we want to do that? What’s our big goal?
Where are we going? So, if we accept
as our big goal we want to have long-duration
human habitation in space, then let’s set as a goal to stay
healthy while we do that, both during and after we come
home to Earth. So ambitious goals call for ambitious questions, and here are some of
the questions that came to mind as I thought about it. What are the biological changes that are relevant
to human health? What changes occur,
and when do they occur? How far do the adverse changes
progress? Some changes may or may not have
an adverse effect. So, what, if anything, do we need to do
about those responses? Second big question that you’ll
see emerging during this talk is really “How do these changes
come about?” What are
the fundamental mechanisms at the molecular, cellular,
and physiological levels that lead to observed responses? We want to do this
both to better understand human biology and disease
on Earth, and also we hope that will
lead to a better ability to predict changes that occur and to identify interventions
that may be needed. In short, these type
of mechanistic studies that animal research and other analog research
makes possible is to take some of the guesswork
out of making decisions for our future in space. So general outline of what I want to talk to you
about today is, first, to provide
a background. What are some of the challenges
of the space environment? Why do we study rodents? I’ll touch briefly
on some of the past, some of what we’ve learned, and then I’m going to go
into some detail into what we’re doing now with the rodent research
project, the challenges we face
in accomplishing our objectives, what the capabilities are, and some of our new
and surprising findings that we’ve obtained. So, first, what are
the challenges that are posed by going into
a space environment? This should pose no surprise
to people in this audience and thinking about the problem. We’ve all evolved on Earth
in 1g, all species. This is continuous, except for very transient and
short periods of acceleration, so our cells,
our living systems, the intact organism has evolved
under that influence, and, in fact,
we already know quite well that we can adapt
to changes in that. We haven’t been
in that environment for much more than two years
at the most, so there are still
many unanswered questions. The second important aspect
of the space environment that most are aware of
is space radiation. Space radiation is unique, both in type
and in exposure rates, and so it poses
unique challenges potentially, both short-term and long-term, to the health of astronaut crew. But that’s not all. Those aren’t
the only challenges we face when we go into space. Here are some of the others. Now, these might look
somewhat familiar to you, because these are challenges that we certainly face
on Earth as well, and, in fact,
things like nutrition or demanding workload, we have a great deal
of understanding of. Others, somewhat less. For example,
in the ISS environment, there is a low but elevated
level of carbon dioxide that the crew breathes in, and that has
a biological effect. We know some–
something about that from studies
on long-duration submariners. But when you combine
all these challenges and these factors together, you end up with a realization
that the– that it is not possible
with reliability to predict
the long-term consequences of these environments, especially as we seek to live
in space. So what are those changes
that occur? Now, in microgravity,
we have widespread unloading, or muscular skeletal disuse. Also, because our circulatory
system has evolved in 1g, the entire system is tuned
to that, and when we go into space,
there’s a fluid shift, an equalization
and distribution of that fluid, and many different organ systems
in the body are affected and yield adaptations, some successful,
some somewhat less successful. And, in fact,
as I’ve already mentioned, we understand a lot. We’ve been going
to space for a while now. We know that there’s
muscle atrophy. We know that there’s
cardiovascular deconditioning and that there’s very rapid
vestibular responses. I’m heightening
bone decrements here, because this is my area
of research and something
I feel a lot of passion about, so we will talk in
a little more depth about that to illustrate some of the points
I’d like to make, but these points
equally pertain, differing in detail,
to some of the other systems that are affected
by space flight. And in bone decrements,
what do we know about fracture repair in space
in humans? Nothing.
It hasn’t happened yet. What do we know
about mechanisms? We know something,
but very little. We’ve also flown rodents,
and I’ll talk a little bit about some of that history
in a moment. We know things
from rodent research as well, and we’re making progress
in getting answers to some of these really
important questions from that research already. Pointing to my example here,
in terms of the bone decrements, already two space flight
experiments have looked at the ability of bone
to repair from a fracture and, in fact, have found
that deficits do occur. We also have more detailed
understanding of mechanisms than we’ve been able to obtain
from human flights. So, when I talk
about mechanisms, what do I mean here? In fact, there are
a hierarchy of mechanisms that we can think about when
we’re trying to solve a problem, and typically in biology, we can start
at the smaller level, from the molecular
understanding, which specific molecules are
responsible for a given outcome. The molecules organize
into cells, into communities of cells,
into tissues, into organs,
and into organ systems, and I’d like to pause here
for a moment to point out– As we all know, one organ system
or one tissue in our body communicates with many others. They don’t exist
in and of themselves to yield a healthy organism. They work together. So, in the end,
these together combine to result
in the observed behavior and biological function
of the organism– in this case, the mammal rodent. Now, you might ask me,
why rodents? Why do we study rodents? The simplest answer
is because of the benefits that can be accrued and have already been shown
to be accrued using those– using rats and mice primarily. 71 of the past Nobel Prizes
in medicine have been awarded to people who have used
animals in their research, and it’s made
possible discoveries that simply wouldn’t have been
possible otherwise, such as
the fracture-healing studies that have been conducted. We don’t embark lightly
on a plan to study rodents in long-duration habitation
in space and develop the hardware
and the plan and conduct the experiments. We do that
under the advice of experts, who review what’s needed, and the National Research
Council in 2011 produced a report
on really looking carefully at what’s needed in both
the life and physical sciences for space exploration and point out that the lack
of a facility for conducting long-term
rodent research on the station is a major impediment
for important– to achieve important goals for astronaut health, and it’s important to note
here also, that we observe carefully the federal regulations
and requirements to ensure the well-being
of the animals. So here’s another interesting
scientific reason why rodents, and we can think
about this together–aging. The typical life span
of a human, depending on many variables,
can be 70 to 90 years. Typical life span of a mouse
is two years. Now, despite this enormous
difference in life span, rodents acquire
age-related diseases that very closely resemble
those of humans. Osteoporosis, the loss of bone, cardiovascular deconditioning,
muscle wasting– these are
just several examples. So what that means is if you look
at various stages during aging, you have
a compressed timeline. Here you see in humans– age of 20- to 30-year-old
human, in years, corresponds to a 3-
to 6-month-old animal in mice and also approximately rats going on
to older and older ages. So what’s the consequence
of this for us, when we’re trying to solve
the problem of influence of long-duration
habitation in space on human health? Well, let’s grab a hypothesis. We’ll look at the hypothesis that’s really been long-standing
for many years, that’s been based
on the observation that age-related disease, such as bone loss
and muscle loss, is observed and is very similar
in the space-flight environment, as I just mentioned. The hypothesis is that living
in space accelerates aging. Let me emphasize–
this is a hypothesis. This is not a fact. What’s it gonna take for us
to test this hypothesis? The age of our astronauts
are 38– in the approximately
38- to 47-year range. This is a one-year-old animal. If you want to do
a life-span experiment– let’s just say,
design that experiment– that would require
roughly 40 years for humans– not very practical right now. That same experiment
could take about a year– much more doable. So now I’d like to describe
to you in a little more detail the biology of the changes
that occur in the microgravity environment. I just spoke to you about aging,
but very similar changes can occur
and have been shown to occur in various experiments
with aging, with radiation exposures, disuse on Earth,
and hormonal changes. In humans,
it takes months to decades to go from a bone
that looks like this to a bone that looks like this
in response to these factors. This is a micro-CT–
these are both micro-CT images, micro-computed tomography
images, that show the three-dimensional
structure of cancellous bone, which is the highly
metabolically active bone that’s inside the outside shell. This looks like this
in humans. It also looks like this
in rodents, but we can see this,
depending on the stimulus, even in a matter of days. Now, how do we get
to a structure that looks like this
to one that looks like this? It’s a product of cells. We don’t think about this
in the context of bone, but just like the other tissues,
cells contribute to the growth and maintenance
of tissue function, and I’m going to talk more
about that now, in the context of what we’ve
learned from space flight. We would like to understand
at the cellular level, as well as molecular level,
which cells are responsible– responsible for the changes
in bone structure that occur in the space environment. Two different lineages
or derivations of cells are found in the bone marrow
that give rise to– Excuse me– That give rise to the most
differentiated or mature cells. The osteoclasts,
which break down bone, and the osteoblasts,
which build or form bone. Together, these cells define whether bone looks like this
or this. These cells derive originally
from stem cells, two separate lineages, which divide
and mature sequentially to become the mature cells. Where in this process
do we see defects? And we’ve acquired information
from rodent experiments that the defect
is not found only in the mature cells
that are responsible for breaking down and forming
new bone, but also in the earlier
progenitors and precursors that supply a continuous source of cells throughout life. So now that I’ve introduced you to some of the concepts
that we’ll be talking about, let’s get into some details
about what we’ve learned from space-flight experiments
and the platforms, and I’ll only have time
to touch on those briefly, but there have been
three different space platforms that have been used to date. The Cosmos missions, which
have grown until recently into– continued into
the Bion missions, are unmanned missions
by the Russians, and really, in these missions,
performed groundbreaking work in the midst of the Cold War to determine what are the basic
physiological responses of rodents and mammals
to the space-flight environment. Many more experiments were
conducted in the shuttle era, and we’re coming
to the present in the ISS. So, to summarize some
of the most important features– take-home features–from this
shuttle era of experimentation, we really– one of the key aspects
of the shuttle program was it provided the opportunity
to do multiple experiments gathering new information and
taking the next logical step, which really formulates
the basis of making progress in research, and in that,
that frequent access that was made possible
in that program allowed us to both define
responses and test treatments. Now, what are some
of the gaps in knowledge that came as a consequence of this structure
of the shuttle program? One was the duration. We never learned what happens
after three weeks. That was the longest flight. In that period, we mostly–
not exclusively, but mostly studied growing rats,
not adult animals. We know–basic biology– that the processes that control
growth are very different than the processes
that control maintenance or aging. So what about adults? All but two
of the 27 rodent experiments that were conducted
using the shuttle platform entailed returning
the animals to Earth and recovering tissues
and studying them. Now this introduces
an additional variable of reentry, landing,
and a time delay, which in the shuttle era
was relatively brief, only a few hours, but we know even
that brief period can result in a change
in outcome, depending on what variable
is being analyzed. So these findings really point
to the science value for doing on-orbit
sample recovery. Now, moving beyond the shuttle
into long-duration missions, the first one was performed
on the ISS, using a mouse drawer system
developed by the Italians. They achieved 91 days
on station, launched in 2009,
via the shuttle. Male mice were flown, and samples were analyzed
after returned. Now this flight resulted in a limited number
of animals recovered. Nonetheless, there are some
interesting new findings that invite further study, and citations mentioned here– and as of today, we see more than five index
papers describing this study. More recently, we’ve had
an unmanned Bion-M1 mission, which is a Russian mission. U.S. investigators work closely
with them in tissue sharing. This is a 30-day mission
that flew older male animals. Again, this is a sample recovery
after landing, in this case, 13 hours,
a fairly long period of time. And new results are still
emerging from these studies. More than 13 papers
have been published to date. So learning
from these examples, what are our main objectives going into the rodent research
project here at Ames? What kind of gaps in knowledge
do we want to fill and what do we need to do
to fill those? First– Excuse me. We knew we wanted to provide
reliable, long-duration habitat for rodents on the ISS. We wanted a habitat
that could support the animals in groups or individually. Rodents are social animals.
They like to live together. It’s important to have
that capability. We also wanted the hardware
to have the potential for future modification so that
we can support, eventually, multiple generations in space. It also needed to have
relatively low maintenance, to minimize crew time,
which is at a premium… so we could conduct
daily health checks, to monitor animal welfare without taking up
extra crew time. We wanted to perform
multiple missions, capture some of what the shuttle was able to do for us
in that era. The current plan
for flying these is to conduct two flights
per year. And finally, we wanted
to make sure we had the science capability to apply
cutting-edge technologies to any samples that we recover
on orbit or after return, should those experiments
be conducted. What do I mean
by technical advances? Well, here are a couple
of examples. One is genetically modified
animals. These have already been applied
to previous platforms, but there’s a lot more work
that needs to be done. What do I mean
by genetically modified? Mice can be–the gene sequence
can be modified so that a particular gene
of interest is over-expressed or
under-expressed or knocked out, and that allows us to determine what the mechanism– how important
that particular gene and gene product is
for a given response. And a good example of that
for a flight experiment, is the Rodent Research-1
CASIS Novartis experiment. which I’ll talk about
in a moment. Second new technology
that we wanted to make sure our samples were good for, was to be able to apply really
cutting-edge technologies that have expanded so greatly
in the last 10 to 15 years, and those are loosely referred
to as omics. That is a characterization
of a large pool of molecules– they may be genes, RNA transcripts, metabolites– that allows us
to have greater insight into structure and function, and an example here from
a previous flight experiment where this technology
was applied to learn something new
and important is shown here. So talking about challenges. What were our challenges in
getting something to work here and getting it up and running? So we decided to adapt
legacy hardware, taking advantage of the fact
that we had 27 prior flights that successfully flew. We needed to interface
that hardware with new vehicles. We don’t have the shuttle
to take anymore, so we worked with SpaceX and developed the capability to use the unmanned
“Dragon” capsule to deliver the hardware. Finally, we needed
to take care of the animals, provide husbandry. That entails training of crew and monitoring
the animal welfare every day, which I already alluded to. This all seems pretty
straightforward, doesn’t it? I’m going to delve into that
for just a moment. This is the basic equipment
that you need to conduct a rodent experiment
on Earth. This is a standard mouse cage,
blown up here. The scientist can sit in the
chair and observe the animals. And one thing,
if you look at this, you can see, in fact,
that, you know, this is pretty straightforward,
with gravity, how this works. The animal’s in the cage, and,
you know, the water comes down, and the waste falls
into the bottom of the cage, and you provide–
this orange thing, in case you’re curious,
is enrichment. The animal plays and nests
in this type of material. This is what you need to conduct
an experiment on orbit. Not scaled to size. You need habitats that will
manage the waste and provide the food and water in a way that is
not gravity-dependent. You need to protect
the cabin environment, and so you need systems
in which you handle the animals and transfer the animals
in a controlled way. And you need a variety
of kits and things to do all that in a safe and productive way. So let’s talk about
the system that was developed to accomplish that. There are two hardwares
that the animals live in– the transport and the habitat. They look pretty similar
on the outside, so I’m showing you this
in a cutaway mode. The animals live inside here,
and this is a port that allows you
to access two chambers, both sides. There’s an air-flow system
through here that captures the waste. There’s also
an animal-access unit, which is a simple glove-box
type of arrangement that mates with either
the transporter or the habitat so that the crew can go in,
reach in, and recover the animals, placing
them in a mouse-transfer box, because you can’t take an animal
and walk acr– you know, walk across–
whoops, sorry– Walk across the room with it. It needs always to be contained, and it can be transferred
in the mouse transfer box. And then we have too many kits
to mention. This shows a view
from the inside, where the animals live. The Rodent Research-1– there were five animals
per compartment, two compartments
per hardware system. You’ll see grating
on all sides that allows the animals
to ambulate, air flow to be collected
in filters, Food–these are food bars that are supplied continuously
to the animal. There’s a water supply that is not gravity-dependent
for delivery, which you can’t see
from this picture. Lighting–we supply
a “lights on, lights off” cycle. The animals are most active
in the dark cycle, as you may already know. And video cameras
with infrared capability that allow us
to monitor and observe the behavior of the animals. So let’s develop our concept
of operations here. How are we going to get them
up there and get our samples? The animals are put
in a transporter and delivered to “Dragon”
or mounted in “Dragon” as a late load,
as a late payload. Undergoes launch, can be– In the case Rodent Research-1,
it was four days in transit before docking and the crew was scheduled and conducted
the transfer operation. The animal access unit was
attached, the animals recovered, and placed into habitats,
where they lived for as long as 33 days, making the longest stay
in microgravity 37 days. At the termination
of the experiment, the animals were then
transferred into the microgravity science
glove box, which had been prepared, and the animals
were humanely euthanized, and then tissues were retrieved and recovered
under specific conditions that made sample analysis
optimal. The samples were stowed
and returned to Earth. So that’s the plan,
but we don’t get to start yet, because we have to make sure
it all works before we go. So we conducted extensive
preflight testing to show that the animals thrive
in the hardware, the operations work,
and that samples recovered, as the crew would eventually do,
would be done so in a way that got
the expected science outcome. So now all systems go–
Rodent Research-1. There were two main aspects, main objectives
of Rodent Research-1. One was a validation. The goal of this was
to demonstrate the capability to support the health
of the animals in long-duration experiments. This was achieved by evaluating
all the key factors, including animal health,
behavior, and tissue results, which I’ll be talking about
in a moment. In addition, there were mice flown for the national lab,
which CASIS– the Center for the Advancement
of Science and Space– manages. And a Novartis scientist planned this experiment,
where MuRF-1 Knockout mice– These, again, are mice that have
a key gene knocked out and are resistant
to muscle wasting– As well as control mice
were flown. Here was our plan
for sample retrieval. For validation,
we were able to– CASIS kindly shared samples
with us so we could work together
to achieve our objectives. We recovered spleen, liver,
also preserved animals for measuring body weight
after return to Earth and also for conducting
postflight tissue retrieval. So let me take
a few minutes first now, as we start talking
about how the experiment went, to talk about behavioral
observations. Here are some qualitative
observations that were made. When animals first entered
the habitat, they very actively explored
the compartments, much like they do routinely
on Earth when you transfer them
from one cage to a novel cage. They’re also observed eating,
drinking, and grooming. They groom both themselves and
others while in the habitats. and these are all, again, considered normal behaviors
of healthy mice. They were interesting to watch. Mice propelled themselves
around the compartment in more than one way, mostly by pulling along the cage
with their forelimbs, although their hind limbs were
used to a more limited extent, also by floating from
one location to another and remarkably resembling how crew ambulate
around the cabin. As time went on,
the mice moved more and more quickly
around the compartment. They translated with ease
through the open spaces, but they also most often
anchored themselves, using their tails and paws. A detailed behavioral analysis
is now in progress. So I’m going to talk to you about our initial results
with the tissues. First, I want to take
a moment to explain the groups. There were, in fact,
four different groups to evaluate the responses from the validation aspect
of this flight. There was
the space-flight group, and there were three controls. So, as I pointed out to you, changes occur rapidly over time
with these animals, because their life span
is relatively short. So one independent variable
in this design of a long-duration experiment
is time. What are the changes
that take place over time just due to aging? And, so, for that, we have
what we call a basal group. These animals were euthanized, and tissues recovered
at the time of launch from the same group of animals that the flight animals
came from. They were compared–
you can compare those results to those of animals
that were maintained in standard cages
the way we normally do and where an investigator in a lab anywhere would do and answer the question, “What is the effect of time as an independent variable
on a given outcome?” What’s the other variable here? The other variable is cage. So the habitat– As you can imagine, nobody does experiments
in those habitats unless you’re planning
to go to space, and, in fact, changes in
the environment of the animals can have
very profound consequences for basic physiological
and cellular responses. And so… to facilitate
future investigators’ ability to evaluate whether the changes
in their control groups… Are due to the cage, we evaluate and compare
this vivarium group in standard cages
to the ground controls. And the ground controls
of the group of mice that are housed in
identical cages to the flight, they’re also kept
in an environmental chamber at Kennedy Space Center that has the environment
of carbon dioxide, temperature, and humidity matched to ambient conditions in the cabin
on the Space Station, because we want
the main variable making the comparison between space-flight
and ground-control animals to be space. And that is the final and key comparison. So this summarizes the results
we’ve obtained to date. We have body weight
and tissue weights from the validation mice. I’m not going to talk
about the variable of time and cage in detail, but, fortunately, there were not
huge differences, which yields
a simpler analysis. Now we can–In the case of
the space flight environment, we can simply compare the ground
controls to the flight group and ask “What were the direction
of changes?” Now, one thing I’ve done here
is I’ve put in green… The changes or lack of changes
that is new information. These are not changes
that we observed in shorter-duration
shuttle missions. They are different in direction
from some of those experiments, and so going through them
sequentially, we saw no difference
in body weights, between the ground control
and the flight, nor compared to any
of the other groups. There was an increase
in liver mass. There was no effect
on adrenal gland. Now, the adrenal gland
is responsible for producing a principal
stress hormone in the body. In humans, it’s cortisol. In mice, it’s corticosterone. And previous
short-duration experiments on occasion observed hypertrophy
or growth of the adrenal gland, which can occur in response
to a chronic stressor. So there was no effect
of the space environment on the gland size. The thymus and the spleen
are two glands that are involved
in the immune response. We saw an increase in mass– Shuttle missions in mice
have shown a decrease, in short duration– And a decrease in spleen mass. Now, what we did see
that was consistent with previous missions is a decline
in the soleus muscle mass, and the soleus muscle
is an antigravity or postural muscle in the leg that atrophies in response to disuse or microgravity, and that was
a very consistent finding. What about the quality
of our sample retrieved? So… We evaluated RNA quality recovered from the liver
and the spleen and looked
at the quantitative value of quality, and we found, from the flight animals
as well as the ground controls, that the quality was acceptable for even the most demanding
of analyses. RNA-Seq is a method
that allows it to sequence all of the RNA transcripts
in a sample and is demanding
for high RNA quality. In fact, we’ve achieved that. The analysis
hasn’t been complete, nor has the
liver-enzyme-activity analyses that are still in progress, but we achieved our goal of obtaining samples
of adequate quality, for applying these
very demanding techniques. Now, how can we expand
our science outcome from our original goals? One way we do that is through
biospecimen sharing. So, when we got the samples back from the Station, the project recovered
32 tissues from 40 validation mice, which yielded
more than 3,000 vials of tissues that are now being stored in
the Life Sciences Data Archive. These are destined
for distribution through
the Biospecimen Sharing Program of Space Biology, which includes our Russian
colleagues at IMBP, who’ve requested tissues. In addition,
some of the tissues will go to
the NASA Genelab Project, which I’ll talk about
in a moment. I just want to take one moment to describe
the Biospecimen Sharing because it’s been so successful
in the past. The images show a team
that traveled to Russia to recover samples
from the Bion-M1 mission, and you can see from the outcome
from previous flights– This is only a select group
of scientific manuscripts that came out of a single
shuttle experiment– How insight
into multiple systems can be derived
from this type of approach. So I’m very excited
about the future for the samples coming
out of Rodent Research-1. In addition,
we provided liver samples to the Genelab Project, who are processing these samples to analyze the RNA transcripts, DNA modifications,
and protein profile in the samples in some detail, and these samples and data sets will be made available
to the scientific community. So I’m going to take a moment
to summarize now where we are so far
with rodent research. The hardware and operations were
performed successfully on orbit. We got it all the way through
to sample return. The mice thrived through
37 days in microgravity. Some important analyses
are still in progress. It’s important to note
the common indicators of stress were not observed in
the animals, such as a loss of body weight, an increase
in adrenal gland weight. They were the same
in all the groups. Also, the preliminary findings
on wet tissue masses contrasted sharply to findings
from shuttle experiments, which were shorter in duration,
also had other variables, but duration may be one
of the key variables in defining those differences. And with biospecimen sharing,
much more to come. So I would suggest,
from these findings– and this is a hypothesis,
not a conclusion– that there are
at least two phases of physiological changes
that occur after entry into the space-flight
environment. Of course, we don’t know yet
how far they will progress. So I’m addressing the audience to think about and invite you
to pose your own hypotheses that might explain
such a thing. But one thing I’d like you
to keep in mind, as you think about this
in the future– This sort of diagrammatically
represents the problem that’s being posed with the magnitude
of the response on the Y axis and time and space
on the X axis. Each of the colors represents a different
organ-system response. So the green may represent the vestibular response
to microgravity, which occurs very rapidly. The red may be
cardiovascular adaptations, which improve over time, and the blue may be another
system that takes a longer time. So these various
time dependencies need to be taken into account as you think about whether
or not duration and space is a key variable
and might explain our results and help us design
new space-flight experiments. Maybe we’ll get some insight
from Rodent Research-2. That mission,
all the on-orbit activities have been completed
for Rodent Research-2. That’s a CASIS mission
that lasted 60 days. So perhaps we’ll get insight
into that. So I’d like to wrap up now with a couple
concluding comments. To live in space– Hopefully I’ve effectively
shared with you that there are multiple
challenges to the human body that are posed
by that environment and that many different
physiological systems can be affected. And I believe the resulting
complexity is such that the consequences
of these challenges and these responses are such that it’s virtually impossible
to predict with certainty what those consequences will be
for human health, for human reproduction,
over very long periods of time. We believe that insight into
those responses and mechanisms will improve our ability
to predict and potentially mitigate, make decisions
about what we need to do to protect humans in space– living in space, and also that
rodent research on the ISS will help us get there. I’ll finish up
with some acknowledgements. This shows
a very happy group of people, after staying up all night, talking the astronaut crew through some difficult
on-orbit operations in Rodent Research-1, but, of course,
they are a very small sample of the number of people who
actually had a hand in making– have a hand in making
rodent research work on Station. It would vie with the number
of people that showed up to break the “Guinness Book
of World Records” for dancing at the same place
at the same time in Mexico City, but still, there are
many important people who can’t be named here. And also I want to mention
the inspiration that comes from
the research lab that I work in, the Bone and Signaling Lab. And I’m going to finish up here and leave up
during the Q&A period– First, thank you very, very much
for listening so patiently. And also,
I’m going to leave this up in case you have interest in following up
with some of these links and some aspects
of what I’ve talked about today. [applause] So, thank you, Ruth. We have a few minutes
for questions. If you have a question,
please line up on the microphone in the center of the aisle. Please be brief,
and no follow-up questions. Thank you. Ruth, is this the first time that mice have been in space
for that 30-day duration? Is that the longest–
one of the longest periods? (Ruth)
So… And my follow-on question–
Sorry, I’ll ask– Is, you know, what– You know, basically,
I’m just really fascinated about what would happen with
adaptation of those animals over that long period of time, in terms of behavior,
interacting with feed systems, interacting with each other,
that kind of thing. Right, well, so… there were two other
flight experiments that– one, 30 days, the Bion mission
was a 30-day mission, and the “mouse drawer system”
experiment was a 90-day mission
that was flown once. You pose a good question
about interacting over time, and that is one
of the reasons why we are performing
a very careful and quantitative behavioral analysis of the video
collected from that mission. But I think we need
more longer-duration missions, so we can capture
a larger fraction of that total time in space. Hi. I was wondering
if there were any plans to do partial-gravity
assimilations in space or on the ground? Like one third? So JAXA,
the Japanese Space Agency, is going to be– is working on flying
a rodent experiment now where I do believe the plan is to completely
replace the gravity vector, but once the capability is developed
for centrifugation, then it’s possible to do
partial-gravity experiments, and there’s a lot of interest
in doing that, in thinking
about going to other planets. Would it be helpful
to have a centrifuge so you could tease out the effects of weightlessness
versus radiation? (Ruth)
Absolutely. It would be great. Ruth, there’s more data
on humans in space in terms of duration
than there are on mice. Have you done anything
to compare the mice results to data that you’ve gotten
from humans? That’s a really good question,
because, fundamentally, if we want to extrapolate
from the result– The assumption of these studies is that they will yield insight
into humans. So, as you can imagine, the answer to that question
is a work in progress. There are limits
to every model system, and in terms of going forward
with the new capability we have, that’s going to be
an important aspect to look at. So a work in progress. One follow-on question,
and that is, do you have data that suggests
where an end point would be? I mean, we know
the endocrine system is damaged, the muscles are problematic,
the skeleton has issues. At what point would we decide,
“Well, gee, we can’t do space. It’s gonna be too difficult. We’re never gonna be able
to colonize space.” Do you have a feeling after 40 years
of data collection? Well, I’m not sure
that I would answer that ques– That is a question that’s gonna take more than
rodent experiments to answer. It’s an excellent question
without a single end point, and I’m sorry I don’t have
a better answer for you, but I think the answer
to that question needs to take
into consideration both our ability to extrapolate
from the rodent experiments, also an understanding
of when the changes that we observe pass the bar from subclinical
into clinical significance, and that’s very important. The Human Research Program
at NASA spends a lot of time reviewing that, and they’ve compiled
evidence books related to all
of the major identified risks to human health, and part of that process– the goal of that process
is really to identify when do you see a change
that’s acceptable, and when do you pass into significant
versus very severe risk. And so I would say
there’s a whole program devoted to answering
that question. All right, please join me in thanking Dr. Ruth Globus
for an excellent seminar. [applause] [musical tones]
[electronic sounds of data]

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