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>> The idea of studying twins
was actually Scott Kelly's idea.
When he spoke to NASA, he said,
"You know, I have an identical twin brother.
"Might that be helpful in terms of biomedical research?"
It turns out he's got a really good point
because Scott and Mark Kelly,
they both have the same DNA sequence,
in other words, the letters of the alphabet,
but because they're two different people
who've had two different life experiences,
including these differences in flying in space,
then there are other marks on the DNA
called epigenetic information
that could be different between the two twins
and not just that, but the activity of genes
could be different between the two,
so it's a very interesting way
to approach differences that might occur to Scott
that aren't related directly to his DNA sequence.
>> It was really important for us to have a set of twins
that were both experienced in space flight,
so for us, Mark had previously flown on short missions
and he'd been retired for a while
and then we had Scott,
who was gonna go on this really long mission
and what's great about having twins
is that their DNA is identical,
so any changes that we might see in Scott
that weren't seen in Mark are not gonna be
due to differences in genetic sequence
and so since we know that genetic sequence
and DNA can play such a huge role
in distinguishing people from each other,
it's nice to be able to have that control in Mark,
so that what we see is gonna be independent
of that DNA sequence.
>> Epigenetics is information
in addition to your DNA sequence
that tells genes not what they are,
which is what the DNA sequence does,
but what they should do.
So where the DNA sequence are the letters and words
of our genome, epigenetics is kind of the grammar
and it's related to which genes are working,
which ones are silent, and that has to do with
fundamentally, why the different tissues of the body
are different from each other.
The eyeball, the heart, the spleen;
they're all different tissues.
They have the same genetic sequence,
but they have different instructions
that are telling them what to do.
That sort of information telling genes
what they should be doing and not,
it's not just related to the different parts of the body
it's also related to your exposure to the environment,
so at some level, epigenetic information
then includes the effects of environmental exposure.
So that could be, for example, space travel
could be obviously one of the things
that would be considered here.
The way that that information is stored in the DNA
involves chemical changes in the DNA,
such as a chemical change called DNA methylation,
which is an extra carbon with three hydrogens, or CH3,
that's stuck on to one of the four building blocks
of DNA called cytosine, and that is a mark for genes.
Generally, the genes are turned off.
>> The focus of our study was to investigate
how the epigenetics differed between Mark and Scott
and also just within Scott from his time
before he went on his mission,
during his mission, and then how it looked after.
And what epigenetics is is a way that's kind of
not changing the DNA sequence itself,
but it's chemical modifications
that occur to specific bases in the DNA sequence
that can control or regulate how genes are turned off or on.
So if you have a lot of what we measure,
which is DNA methylation,
which is a small chemical tag on cytosine residues,
when you have a lot of methylation around a gene promoter,
for instance, that gene is typically turned off.
However, when there's no methylation
present around that gene,
it tends to be more highly expressed, or turns on,
and so what we're really looking for
are these chemical modifications
all along the DNA, throughout the entire genome,
and how they differ both within Scott
during his mission over time,
as well as between Scott and Mark,
so that we can distinguish what changes
may be associated with his time in space.
One of the main challenges of this study
was actually getting the samples
from the Space Station back to the lab.
For epigenetic studies, for what we needed,
it's very important for us to get
freshly isolated cell types out of the blood
because we know that DNA methylation epigenetics
in particular can very wildly,
amongst tissues and amongst cell types in the body,
it's just like how your heart cells
have very different epigenetic profiles
than your brain cells.
They have very different functions
and epigenetics is involved in controlling that
and so when we needed our samples,
we needed to get specific cell types out of the blood.
Well, to do that, we have to have freshly isolated blood,
so what Scott actually had to do on the Space Station
was when they were getting a delivery
of supplies from Earth, he had to draw blood that day
and put it on the spaceship
that was gonna return that blood home.
We actually had samples within 38 hours
of the blood being drawn on the Space Station
to back in the lab here on Earth.
Within 38 hours, which is quite a feat in itself.
So they would go from the Space Station
onto the rocket that landed in Russia,
on a plane to Houston, on a truck to the lab,
and then someone would be waiting at the lab
at whatever time of the day that might be
to isolate those cell types,
at which point they could then be frozen and distributed
to the labs that were gonna analyze the data.
>> Over the course of the year,
we found out there were changes.
If you look at all the genes across the genome,
overall there was a change in Scott's
level of DNA methylation and Mark's, both of them.
Scott's overall level of DNA methylation
went down a little bit, Mark's went up a little bit.
The variability in DNA methylation in Scott
became greater over the course of the year
and then went down after he returned to space.
Overall, these levels converged
to the same the levels that they had before the year
and also very similar to each other during that time.
You can't say that this is related to spaceflight,
however, because both Scott and Mark
were in their own environments.
With an n of one is what we call it,
you can't say that the differences we see
are related to spaceflight itself.
It could just be differences in general
between the environments,
or it could be related to just random chance
over that amount of time.
>> Our main finding in the epigenetics study
was that we saw variation in DNA methylation
and epigenetics in both Mark and Scott
and what was perhaps surprising to us
is that we saw just as much variability
in Mark, if not more;
in fact, more than we saw in Scott
and while we only have two subjects in this particular case
and so we can't say that the changes we saw in Scott
were directly attributable to spaceflight,
what we can say is that we didn't see
levels of variation that were way off the charts,
or out of normal for what we would expect
for someone just living their life, such as Mark.
What was also really interesting is that that variation
in Mark was actually more, I'm not gonna say extreme,
but it was a greater amount of variation
than we saw in Scott
and that could be attributable to many different things,
including the environment on the Space Station;
you're in an isolated space for an entire year,
whereas Mark could travel the world if he wanted;
also the diets are gonna be very different.
Mark can eat whatever he wants,
whereas whatever gets delivered to the Space Station,
that's what Scott has to eat.
So there are many different things
that could contribute to the differences that we did see.
Another finding that we had was the changes that we saw
in Scott over his time in space,
at specific regions of the genome
were different than those that we saw in Mark,
so while they both changed at many different places,
the specific locations and the genes
where those changes occurred
were different between the twins in many cases
and while alone, our data having only two subjects
isn't enough to say that these particular genes
were significantly differently methylated,
or there's big changes in epigenetics here.
What it points to is genes that we could look at
in future studies that may, when we have more data,
reach that level of statistical significance
and what was encouraging was that it was consistent
with data collected by other twins investigators,
suggesting that these genes and pathways
may be impacted by the space environment
that Scott experienced.
>> In general with science, you can't draw a conclusion
from a single observation, and actually,
I use the term n of one;
that is the very words that Scott Kelly used
when he himself was talking
on a NASA podcast about the study.
In order to draw meaningful relationships
between a particular exposure like spaceflight
and a change that you might see,
you have to have multiple individuals
and then show that there's statistical significance;
in other words, that you see changes
in the space travelers compared to non-space travelers
that are greater than the variation
that you see within the group of space travelers itself.
You can't do any of those statistical
tests in a study like that,
so the main importance, I think, of the study,
is that it shows how you can do such work
and that is not trivial.
So understanding how to do genomics in space
is not an easy thing to do.
>> One of the limitations of our study
is that we only have two individuals
and so with that, we really can't attribute
the changes that we see,
we can't ascribe them to a level of significance
where we would expect to see them
every time an astronaut goes to space.
What we have instead is we have observations
that say hey, maybe there's a perturbation in this pathway,
or these genes, that would be interesting
to follow up on in future studies.
What we have in Scott could just be an outlier
and we would never see that change again
if we looked at 50 astronauts,
and because we don't have other data,
we can't distinguish an outlier from a true signal
that's gonna change no matter who goes into space
for that length of time.
>> Now that we know that you can see changes
and measure them in astronauts;
we did not know that that would be the case.
We don't the significance of that
because we haven't studied enough.
The real question is can we use this kind of information
to predict what's going to happen to people
when they go on long-distance missions to Mars?
So I think the right kind of study
would be to look at many astronauts,
maybe all of them, really, if we could get them to agree,
if we could work that out,
who are going on short missions of three months,
longer missions of six months, missions of a year,
and use some of the same methods we developed in our study.
We could apply them in order to project
what are the changes that you're gonna see
over that sort of time that are likely
to then continue to progress
as you go out to a multi-year mission.
If we could do that, we might be able to anticipate
in astronauts individually or as a group
what sort of health problems they might run into.
We won't have the problem of a single set
of observations then, we'd have a much larger number.
We might be able to make statistically
meaningful conclusions about what changes
we see during spaceflight that are related to spaceflight
if we did such a study,
but we also might be able to make predictions
about what's going to happen to individual astronauts
and then prepare for that; not necessarily
exclude or select astronauts based on this analysis,
but have the right kind of either medicines
or anticipate the kind of problems they might have
so that they're able to remediate those problems
when they're on Mars for a longer period of time.
I think that might actually be possible
and in fact, I think the most important part of our study
was that it inaugurated really
the genomic era of space travel.
Although we can't draw statistically
meaningful conclusions about space travel from them,
we showed it can be done and how to do it
and now, I think that that sort of study,
that sort of analysis, can be included
within the armamentarium of biological and medical data
that are collected on astronauts
so that we can mitigate the health problems
they have on long-term spaceflight.
>> The next directions are clearly to include
more astronauts in these types of studies.
I think one of the great strides that our study takes
is showing that we can do this kind of genomic work
on the Space Station with this population, these astronauts,
and given that we've already kind of laid out the roadmap
of how the logistics of this could work
and the kind of data that we can generate,
we can now do this across every astronaut
that flies to the Space Station for any length of time
and by generating all of this data,
together we can then start to build a picture
of what happens to the human body
over any duration of spaceflight.
So again, just more data needs to be generated
on more astronauts so that we can start to
reach that level of significance
where we can really point to the things
that we should be on the lookout for
and have astronauts and the Space Station be prepared
for any medical issues that may arise
and we can maybe even predict what medical issues
may arise during a longer duration space mission.
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