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0:00If you're a human like me,
you started your life as a single cell,
0:04which replicated over and over until that
one cell turned into around 30 trillion.
0:09Most of these cells look like that diagram
you see in a biology textbook.
0:13A blob encased by a membrane
with a bunch of smaller blobby
0:17structures inside, like the nucleus,
where your DNA gets stored.
0:20And most of these cells are very,
very small.
0:23But at some point in your life, somewhere
between that one and 30 trillion,
0:28your body produced a cell
that in less than a year grew so big
0:32that its surface spanned around 13m².
0:35That's almost twice
the size of a king bed sheet.
0:39If you're thinking, how
could I possibly fit that inside of me?
0:42Well you didn't. It grew outside of you.
0:45Unless you also belong to a certain subset
of the human population,
0:49in which case they do
also grow inside of you.
0:51But we'll get back to that weirdness
later.
0:53For this huge cell
to form, billions of individual cells
0:57had to fuze together,
sort of like a big Ole slime monster.
1:02Naturally, scientists
have a lot of questions
1:06about how a cell that size can even exist.
1:09One of the people at the forefront of this
research is Hannah Yevick
1:12at Brandeis University.
1:14And to appreciate how amazing her work
is, you kind of have to see it.
1:18That's why we created this new series
called SciShow Field Trips.
1:22Each episode,
we get out of the studio and visit
1:25a lab where cutting edge
science is happening, like Yevick’s.
1:29We sent our friend Jada Elcock
to Boston to meet the biophysicist
1:33and learn about her obsession
with this massive, mysterious cell.
1:42The physics department
might seem like a weird place
1:44for someone who's interested
in cell biology to hang out, but
1:47Yevick studies biomechanics,
specifically how cells fold and grow.
1:51And her path through academia
has always involved more than one subject.
1:54You have all these diverse backgrounds.
1:56How does that influence the way
that you work,
1:57the different tools that you use
and things like that.
1:59I did an undergraduate
research experience in dark matter.
2:03Oh, wow. Which was actually amazing.
2:05I spent a summer in Italy in this lab
that's underneath a mountain to look at.
2:10Look for dark, dark matter.
2:12And, you know,
I think through through each research
2:15experience, you you develop
sort of new tools, new perspectives
2:19on how to see scientific questions,
how how to ask the questions,
2:23and also what kind of tools
you can use to answer them.
2:26who has been asking all kinds of questions
about the world to fuel her curiosity.
2:30She recently found an old childhood
journal of hers stuffed full of them.
2:34I've always been really fascinated
with just asking questions.
2:37And so, yeah, as a child,
I was always asking so many questions
2:40to my parents that they're like,
okay, well, write them down in a journal.
2:42And they're all, you know, kind of silly,
silly kid things like,
2:45I was wondering about,
you know, if you have a penny
2:49and it gets run over by an airplane,
is it going to get, like, more dense?
2:53Did chickens make good pets?
2:56I don't know what that question
is supposed to really mean.
2:58And that curiosity about the world
would eventually include a sense of wonder
3:02In fact, you have discovered the subject
of her current research project
3:05when she was pregnant.
3:06She was reading about the transformation
3:08her body was going through
and became interested in the placenta.
3:11That's the organ that provides
3:12oxygen and nutrients to the fetus,
among other things.
3:15Now, some of you may be thinking, well,
what does the placenta have to do with me?
3:19I do not, nor have I ever possessed
the bits necessary to gestate a baby.
3:23But the thing is,
every single person once had a placenta.
3:26The placenta is made by the fetus,
not the parent.
3:29Its cells have the DNA of the child.
3:32I did not know that the fetus was making
its own placenta, which is really cool.
3:35But what exactly does that mean
for studying this type of system?
3:39I think what's interesting in your
reaction, and I think is pretty common, is
3:42that people don't know that the placenta
is really a fetal tissue.
3:46And so that means that you can have male
or female placenta.
3:50I think the placenta has largely
been kind of put under this
3:53umbrella of women's health, you know,
and that it's kind of gross.
3:58And people don't want to think about it.
4:00And as a result has led
to sort of a huge amount of understudied,
4:04and sort of like blind spots
in terms of our understanding
4:07of placental development.
4:08Reading about the placenta, you ever came
across an even more mindblowing fact.
4:13It contains a single massive cell
in the outermost layer
4:16called a syncytiotrophoblast.
4:18This cell has many folds,
4:20but if it were laid out flat, it would be
big enough to cover a pickup truck.
4:24She was immediately fascinated.
4:26The placenta is like a vascular tree.
4:28Yeah, a sort of these villi.
4:30And this single cell covers
over this entire vascular tree,
4:34forming a surface area of 12 to 13m².
4:39I didn't believe it for a while.
4:40And then I was like, this is crazy.
4:41How how do you go from,
you know, cells in some tissues being,
4:45you know, tens of microns to a cell
that reaches a surface area of about 13m².
4:50But what exactly does it do
beyond just being a really big cell,
4:54which I thought was fascinating,
but acts like multiple
4:58kind of separate organs
that are in the human at term.
5:03You have about 600ml of blood
that's moving,
5:07every minute between the mother
and the fetus.
5:10And that brings oxygen to the fetus.
5:13So it's acting like a lung.
5:15It has really important
hormonal functions as well.
5:18So it's secreting hormones.
5:19And so it's acting sort of liver functions
and help filtering out toxins.
5:24It helps with sort of protecting, from
viral infection or pathogen infection.
5:29And so it's really amazing
because it's acting with all
5:31has all these different diverse functions.
5:33But yet it's sort of one single continuous
5:38kind of like pool, a cytoplasmic pool
and one single cell.
5:42But even though this huge cell
is universal to all placental mammals,
5:47the syncytiotrophoblast
can be pretty tricky to study. After all,
5:50the placenta is a temporary organ.
5:52It only exists
for the nine months of pregnancy.
5:54There isn't a lot of research
5:56about the placenta in general,
let alone its amazing giant cell.
5:59And there's a lot more we want to learn.
6:01That's where Yevick and her team come in.
6:03They're looking to answer
how the syncytiotrophoblast
6:04manages to stay strong
and hold itself together as it grows
6:08bigger and bigger throughout pregnancy,
despite all the stress it's under as well
6:12as, you know, just understand
the cells structure more generally.
6:15We're really interested in how things span
multiple length scales.
6:19How you how does a cell go from having one
nuclei to 2 to 10
6:23to 20 to 1 billion,
covering all of those orders of magnitude?
6:28some basic fundamental principles,
something that, like determines
6:32the length scales that pop up over
and over again, something that determines
6:36how they're able to hold their size
as they get bigger and bigger and bigger.
6:40And also when they fail.
6:41So when does it not manage to hold it
size?
6:43When does it start to fail, get
too big start, you know, rupturing itself.
6:47These are all things that we're able
to probe
6:48with our model system, which makes it
a really good experimental tool for us to use.
6:53But for reasons
we'll explain in a minute, it's
6:55hard to grow that huge
placental cell in a lab.
6:58So the team is currently forcing
a bunch of your traditional
7:01bio textbook cells with one nucleus
to all fuze together
7:04that turns them into a single multi
nuclear cell called a syncytium.
7:08And syncytia are far from a placenta
exclusive feature in the human body.
7:12Consider your skeletal muscle cells,
which have long organized fibers
7:16made of fused cells that help you contract
your muscles over bigger distances,
7:21like the hamstrings in your thighs
or the biceps in your arms.
7:24Meanwhile, your cells can also form
sensation when things aren't
7:28Certain viruses and cancers cause them.
7:30So, for example, during viral infection,
you can get cells that
7:34form syncytia or multi nucleated cells.
7:37In tumors, you can have larger cells
with multiple nuclei.
7:42was that the placenta was most sort
of a drastic example of giant cell.
7:46And so that really sort of sparked
my excitement to try and understand
7:50how is it even possible
to get such a huge size cell.
7:53Obviously,
it's not ideal to have these big cells
7:56formed randomly in our bodies
where they're not supposed to.
7:59But this virus induced fusion could be
a big part of what makes us, well, us.
8:05In rare cases, when a virus infects
a cell involved in reproduction
8:08but doesn't cause lasting damage,
that viral DNA gets transferred
8:12to the infected persons offspring.
It becomes incorporated into their genome
8:17They're called endogenous retroviruses,
and the leftovers
8:21from their infections
make up an estimated 8% of our genome.
8:25They also make the syncytiotrophoblast
possible.
8:27The reason why placental cells
can all fuse together at all
8:31is the one two punch of proteins
called Syncytin-1 and Syncytin-2,
8:35both of which owe their existence
to two separate endogenous retroviruses.
8:39This is really cool because the placenta
is really very intimately related to who
8:44It allows fetuses to develop
over the course of nine months
8:48and access a huge amount of blood
and a huge amount of nutrients,
8:51and that could have only happened
if, you know, this
8:54virus insertion
happened into the human genome.
8:57So we kind of are who we are
because of viruses.
9:00Viruses are also helping
9:02Yevick and her team grow
the biggest possible cells in the lab.
9:05They figured out a way to make cells
fuse together
9:07using a protein from the influenza virus.
9:09These epithelial cells
9:10don't have exactly the same proteins that
made the giant placental cell possible,
9:15but they're a good model when the goal is
just to create super big cells to study.
9:19So epithelial cells are, quite a good so,
type to use.
9:25They're easy to work with
9:26and they're able to, fuse together
to form multi nucleated cells as well.
9:30So what we do is that we artificially put
this influenza virus,
9:34fusogenic protein
on the surface of our cells.
9:37And then with a pH shock what happens
is that it it opens up
9:41and kind of allows it to fuse
with neighboring cells inside the tissue.
9:45How close have you gotten to that
30 meter squared goal?
9:49We're still
I mean, we're still in like millimeter.
9:52It's ongoing. And it's also,
9:55it's interesting because it's actually
9:57the cells are quite unstable
at that size scale,
10:01which in and of itself,
I think has given us some interesting
10:03scientific questions about like,
why are they so unstable?
10:07Yevick’s team can't reach the 13m²
of a typical syncytiotrophoblast,
10:12they can still explore the organization
of all the nuclei, as well
10:15as other stuff like how those big cells
managed to stay together.
10:19Meanwhile, in cancers,
multi nuclear cells can form
10:22because the internal machinery is
well kind of broken.
10:25Normally many of our cells
make exact copies of themselves
10:28through a process called mitosis,
which involves copying the DNA
10:32inside the nucleus and then dividing
into two identical cells.
10:35But cancerous cells are abnormal.
10:37They have some sort of mutation or damage
that causes them to grow out of control,
10:42including replicating their
genetic information without dividing.
10:45This can lead to a bunch of nuclei
accidentally getting wrapped up in one
10:49cell membrane, better known as
say it with me, syncytia!
10:52Those are human cells,
but they're carcinogenic, so those also
10:57they act a little bit
more like the syncytiotrophoblast cells,
11:01but they're a little weird
because they're cancer cells now.
11:03They fuse spontaneously
unlike our really artificial system.
11:07They can be stimulated
to fuse more readily. Right.
11:09But even with that, we've only been able
to get them to form syncytia
11:13with about the size of tens of nuclei
inside them at most.
11:19And so the goal really is to work
11:20kind of synergistically
between our different systems.
11:22Why don't those immortalized cells
get as big?
11:26Yeah, that's a great question.
11:27And it's something
that we don't really know.
11:29When we started this work, you know,
me and my students, we did a lot of,
11:33literature research
trying to find in the literature
11:36what is like the biggest picture
of a syncytia, placental syncytia
11:40that we could find. In the literature
too typically you see, you
11:43know, if you even see us in this issue,
they're not really that big.
11:46So inside our cell incubator right here,
we have a couple more flasks
11:52So these in this dish, these are cells
11:56that I already have shocked with a pH shock.
12:00So remember what
the cells looked like before.
12:02They had these like regular
kind of geometric patterns in them.
12:06And now for this one you'll see regions
where you still see those patterns here.
12:10And then you'll see regions where things
look totally different. Right.
12:13And the regions where they're totally
different is one continuous large cell.
12:17So if you look close,
those are actually nuclei
12:21So all of these circles with little black
specks in them.
12:25Those are all the nuclei
of all the cells that have fused together.
12:28And then we have
just like these islands of unfused, Yeah.
12:31So they didn't make the cut
for some reason.
12:33They were not invited
to the party of the giant cell.
12:36So so this is now
really, really zoomed out.
12:38So you can see the cells there are small.
12:41You can start to get a sense of scale
here.
12:43The giant cell doesn't look too happy,
12:46There's there's regions of it where
there's just holes inside the big cell.
12:51But yet it manages to to keep going.
12:53This thing is alive, even though
there's some random holes in it,
12:57and it's holding a really weird geometry.
12:59Okay, quickly,
before we get into the science,
13:01I have such an important question.
13:03Why is there a cat on your microscope?
13:06The namesake of the microscopes.
13:07He is a grad student in this lab’s cat,
actually named after Erwin Schrödinger.
13:12This microscope is a little different
13:14from the one
we were looking at in the cell room.
13:15Okay, because this one, in addition
to being able to look at things
13:19just, you know, in the black and white
that we were seeing before,
13:21it has the ability
to control the wavelength of light.
13:25So now we can excite a particular dye
that we've put in our sample.
13:28And then we can see
the signal out from that dye.
13:30So now what we're doing is we're looking
around one of these giant cells.
13:36The regular
shapes are the mononuclear cells.
13:39And I'm going to switch our wavelength
13:44Track the exposure down.
13:48And now we can see that that cell is
in fact made up
13:50of a whole bunch of nuclei
all packed together.
13:55Still, it's useful
to see how placental syncytia are different
13:59from the epithelial ones,
which can teach us more
14:02about the structure of big cells
with multiple nuclei.
14:04In general,
the team thinks the syncytiotrophoblast
14:07might be supported by filaments
connecting lots of nuclei together,
14:11making the nuclei act
sort of like pillars supporting a bridge.
14:14But their hypotheses are still evolving
with every experiment they do.
14:18This is a frozen cell.
14:20It's called a fixed cell.
14:22We have frozen it in place
with paraformaldehyde, so it's dead.
14:27But with this dead cell,
we can start packing in dyes
14:29that are really, really specific
14:30to different parts of the cell
that we might be interested in.
14:33One thing I want to highlight,
which I think is really cool,
14:36are these really long,
sharp bands of actin?
14:40We think that's one way
that the giant cell is able to hold
14:44its shape
is that it develops these giant bands,
14:48you know, maintain its integrity.
14:50To examine the structure of these cells,
14:53Yevick is actually going back to her
interdisciplinary roots.
14:56I really love bringing in ideas
from all different disciplines
14:59and kind of mixing and matching.
15:01And so a tool that I developed during
my postdoc was actually
15:06to take this, filamentous tracing algorithm
from astronomy and use it
15:12to trace this filament to structure
inside the developing fruit fly embryo.
15:17What this algorithm allows us to do
is to take a highly noisy image
15:23the peaks in it and sort of the ridges
that connect those peaks
15:26together, which are the filaments
themselves, to use these new techniques.
15:30Yevick plans to work with nearby hospitals
to get healthy placental cells to study.
15:34In many cases, placentas are discarded
after the babies are born.
15:37But scientists can also save them,
15:39including the cells that make up the syncytiotrophoblast for further research.
15:43So what are the goals when you finally get
to the point of studying
15:46living healthy placental cells?
15:49Human placental cells.
15:50Yeah. There's a lot of people doing work
like this.
15:52I think we're specifically interested in
15:55taking the approach
of looking at it as an organoid.
15:58So instead of
just having a flat quasi 2D layer,
16:01now we're going to introduce some
curvature or some ability for the cells
16:05to exist on an external matrix, you know,
that has some kind of preset shape
16:10or, you know, having the cells be
in some kind of, you know, maybe a sphere,
16:14a ball of placenta cells.
16:15They still have a limited complexity,
16:19but they approach them closer and closer
to something that is like a real organ.
16:23It opens the door to ask
really interesting questions about, okay,
16:26if you have syncytia inside,
more sort of physiological shape.
16:30So kind of curved structures,
16:32how does that impact fusion
has the impact mechanics of those cells.
16:36As a woman forging a career in biophysics.
16:38Yevick has gravitated towards questions
16:40around the biology of human health,
especially women's health.
16:43And she hopes
this research will help us understand
16:46the placenta better and improve
medical outcomes in difficult pregnancies.
16:50We're about to talk about preeclampsia,
16:52which is a complication
that can occur during pregnancy.
16:54If that is something
16:55you'd rather not hear today,
you can skip to this time stamp on screen.
16:58But what exactly is preeclampsia
and how does that relate to the syncytiotrophoblast?
17:04Preeclampsia is a very common
pregnancy complication that can develop
17:08in different ways, sort of early stage
or late stage preeclampsia.
17:12But basically it's all united by this idea
that the placenta
17:16is not getting enough blood. Okay.
17:18And this can trigger
sort of a stress response in the syncytiotrophoblast
17:22that sends signals
to kind of the mother that can
17:27wreak havoc on, for example, blood
pressure, maternal blood pressure.
17:31And typically we can just
17:32the only thing we can really do
is deliver the baby
17:34at that point to sort of
bring the blood pressure back down.
17:37We really don't know how to,
17:40effectively despite the fact
that it's really ubiquitous.
17:44So with a better understanding
of the syncytiotrophoblast,
17:46doctors might have a better idea
of what can cause preeclampsia
17:50and be able to develop treatments for it.
17:51But Yevick hasn't just thought about what
this research could one day mean
17:55for the fields of obstetrics and women's
health.
17:57Remember,
her lab is in the physics department.
17:59Yevick mentioned there's another lab at
Brandeis that's engineering biomaterials.
18:03And she could imagine lots of ways
that growing a giant sheet sized
18:07cell could have really interesting
material science properties
18:10from filtering the air to protecting the
development of something underneath it.
18:13Can you take a giant cell sheet
and use that for kind of try
18:18to engineer that in a system
that could be sort of bio inspired, right.
18:22Can you use it to cover over kind of
an implantable device inside a human?
18:27One of the exciting parts
18:28of a relatively unexplored
field of research is that questions
18:32don't just lead to answers,
they lead to even more questions.
18:35Questions
are so foundational to to science,
18:39and I almost see like questions
as being more
18:41important than answers,
because I feel like when you do research,
18:45you know, firstly, like the more research
you do, the more experience you have.
18:49I feel like the better
your questions get like,
18:51oh wow, this is more and more interesting,
but then also, at least personally,
18:55when you find the answer,
18:56it's almost just like springboard
to the next interesting question.
18:59With all of the interesting questions
you have been uncovering lately,
19:02maybe it's time for her
to add to that childhood journal.
19:07SciShow Field Trips are made with our friends
at HHMI Tangled Bank Studios.
19:11We've come together
to bring you face to face with researchers
19:14at the cutting edge
of scientific discovery.
19:16You can watch more of Tangled Bank’s science
content at tangled Bank studios.org.
