Indeed, his precision-tooled temperament may
be a prerequisite for the kind of slog needed here,
to get an embryoid to trace the footsteps of a real
human embryo, in something the scientists call
recapitulation. It is only by mimicking the true-life
course that a dish-bound doppelganger can give test
results that are valid.
And that is a big ask, not least because there is
no gold standard; the ‘black box’ means there is no
definitive embryo library to provide reference points
for the journey. Then there are the endless variables in
embryoid research: the physical layout of the device,
when to add morphogens and chemical signals, and
countless other tiny details.
Which is where Fu took his Enterprise into
deep space. His embryoids reached the early phase
of another critical developmental stage called
gastrulation. When the furrow-like primitive streak
appears at 14 days, it signals that the cells below, a
little like the settling of ploughed earth, are falling
into three layers: the ectoderm, mesoderm and
endoderm, respective precursors of skin and brain,muscle, and internal organs. Their emergence heralds
the laying down of the body plan.
But Fu’s embryoids also showed something
else undeniably human. Budding off from those
furiously dividing balls were the barely discernible
outlines of germ cells. These define the male
and female sex – they are the cells that go on to
produce sperm or eggs.
Megan Munsie is Deputy Director of the Centre
for Stem Cell Systems at the University of Melbourne
and has been entangled with the stem cell story for
two decades, first as a researcher and now as an expert
on policy and ethics. The appearance of these sex cells
left a deep impression.
“This is a part of human development that we just
really can’t follow,” she says. “The start of the germ
lineage I think is absolutely fascinating.”
Nor was it the only aspect of Fu’s achievement
that gave her pause.
“When we looked across his images I found them
quite extraordinary,” she says. “In almost all the
clusters in the wells the patterning was consistent,
and as you can imagine in this area of biology there is
often quite a lot of inconsistency.”
That cookie cutter reliability is essential if you
want to screen a bunch of drugs for harmful effects;the substrate has to repeat faithfully across each test.
One example, of course, stands out.
“Thalidomide, who was expecting that? What
if we could develop a screening mechanism, that
is an adjunct to pharmaceutical development, that
enabled us to provide a safeguard for a new drug?”
asks Munsie.BARELY A KILOMETRE FROMMunsie’s office, across
Melbourne’s verdant and expansive Royal Park,
Andrew Elefanty is using stem cells to try to make
bespoke blood for people whose bone marrow has
failed, or is in overdrive making blood cells that don’t
work properly – the leukaemias.
It is the kind of medicine that shows just how
personalised the embryoid project could become.
In order to create the customised blood,
Elefanty’s team at the Murdoch Children’s Research
Institute takes blood samples from volunteers. The
immature red cells are removed and, with the help
of genes delivered in a virus, programmed back to a
pluripotent state – they become iPS cells.
In crimson culture
fluid in blue-capped flasks,
these iPS cells are then
urged by the team towards
the embryoid stage. But,
unlike Fu, the team halts
development at the point
of gastrulation, directing
the cells to become mesoderm alone.
Why? Because it is that layer, as Elefanty shows
me in a stunning photo, that fashions the seminal
version of our biggest blood vessel, the aorta, in
whose walls, at this rudimentary time, the red blood
cells are made.
Duplicate Elefanty’s process with the blood of
someone with leukaemia and the hope is that, one
day, you could make healthy blood for them that’s a
perfect match.
But I’m confused about something.
Since stem cells were first coaxed into tiny
3D brain-like structures in 2008, scientists have
produced a cornucopia of organoids. All of these- mini brains, hearts, kidneys and even blood cells
- can be made directly from pluripotent stem cells.
Why, then, would you want to push them through the
embryoid pathway first, which seems to be taking the
long way round?
“The way that works the best, if you like, is if
you try to direct them via a trajectory where you do
actually try to replicate some of the steps during
embryonic differentiation,” says Elefanty. “That’s the
road map that you’re following.”
The whole process is artificial, but there’s
something of a “nature knows best” adage at its
“
What if we could develop a screening mechanism,
that’s an adjunct to pharmaceutical development, that
enabled us to provide a safeguard for a new drug?”MEGAN MUNSIE
Deputy Director,
Centre for Stem Cell Systems,
University of Melbourne74 – COSMOS Issue 86
STEM CELL FRONTIER