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SUNDAY SCIENCE: HUMAN EMBRYO MODELS ARE GETTING MORE REALISTIC —
RAISING ETHICAL QUESTIONS  
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Smriti Mallapaty
September 11, 2024
Nature [[link removed]]

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_ Dozens of labs around the world are striving to grow models of
human embryos to study development, fertility and therapies. They are
entering uncharted ethical territory. _

Models of human embryos at the blastocyst stage, which are called
blastoids., Monash University

 

Under his microscope, Jun Wu could see several tiny spheres, each less
than 1 millimetre wide. They looked just like human embryos: a dark
cluster of cells surrounded by a cavity, and then another ring of
cells.

But Wu, a stem-cell biologist at the University of Texas Southwestern
Medical Center in Dallas, knew that these spheres were not what they
seemed. They were laboratory-grown models of embryos, and they were
far from perfect replicas.

Entire groups of cells were absent and others were there that didn’t
belong. And Wu knew that, eventually, the models would perish abruptly
and chaotically.

If embryo models were houses, then behind the facade they would have
uneven floors, distorting mirrors and ghosts in their closets.
Nonetheless, dozens of labs are competing to grow the best likeness
of a human embryo
[[link removed]].

There are as many models as there are groups making them, each
recapitulating slightly different aspects of embryo development in the
hope of uncovering new biology about the first weeks after conception.

This high-stakes, high-drama period “is shrouded in mystery”, says
Nicolas Rivron, a developmental biologist at the Institute of
Molecular Biotechnology of the Austrian Academy of Sciences in Vienna.
In the womb, these embryos are too small to be observed using
ultrasound. And in the lab, there are technical, ethical — and often
legal — limits to studying real embryos
[[link removed]] outside the body
beyond 14 days after conception.

Insights from embryo models could help to explain why about one-third
of natural embryos don’t make it past their first weeks. This could
help to address infertility, improve the success rate of _in
vitro_ fertilization and even prevent diseases that emerge early in
development. Models could also be used to test the safety of drugs for
embryos.

But as the models become increasingly complex, and reach symbolic
milestones, such as the first heartbeat, they raise tricky ethical
questions [[link removed]].
Ethicists, regulators and legal specialists are scrambling to keep up
with the pace of research.

Meanwhile, the field is fizzing with energy. In February, researchers
organized the world’s first scientific meeting entirely dedicated
to embryo models
[[link removed]].
And several scientists have launched spin-off companies to use models
to develop therapeutic molecules, test drugs and improve fertility
treatments. Embryo models are “pretty much the hottest topic right
now”, says Insoo Hyun, a bioethics consultant for the Broad
Institute of MIT and Harvard in Cambridge, Massachusetts.

EPIC SHOW

The meeting of egg and sperm triggers a process of rapid and precisely
choreographed cell division and differentiation. In the first week,
around 100 cells form a hollow circle known as the blastocyst. This is
made up of three distinct groups that eventually grow into the embryo,
the supportive yolk sac and the placenta.

Then the embryo implants itself in the uterus. From about two weeks,
embryos go through a process known as gastrulation, in which cells are
committed to becoming one of three cell types and organize into
layers. These layers differentiate further into lungs, guts, muscles
and other organs, in a process known as organogenesis.

“The embryo is never static,” says Naomi Moris, a developmental
biologist at the Francis Crick Institute in London. “It undergoes
these huge dramatic shifts.”

Researchers have attempted to recreate this epic show in a dish. These
efforts — often done in mice and then in humans — have typically
captured snapshots of the process.

In 2014, researchers coaxed human embryonic stem cells into three
distinct rings — precursors to cells that form the embryo and the
placenta1
[[link removed]]. Later
models featured amniotic cavities and yolk sacs, and some were 3D. By
2020, some researchers had recapitulated an aspect of gastrulation2
[[link removed]], in which
the embryo elongates into a tube-like structure.

But many of the early studies wouldn’t be considered models of an
entire embryo by today’s standards, says Wu.

COMPLETE MODEL

A major milestone came in 2021, when Wu’s group3
[[link removed]] and
another team4
[[link removed]] published
models that resemble the human blastocyst (see ‘Model
development’) — typically the stage at which embryos are
transferred to the uterus during _in vitro_ fertilization.

These models, called blastoids, contain cells that form the embryo and
those that will support it, called extra-embryonic cells, making them
the first ‘complete’ or ‘integrated’ models of the human
embryo.

“They’re not perfect,” says Marta Shahbazi, a stem-cell and
developmental biologist at the MRC Laboratory of Molecular Biology in
Cambridge, UK. But “they’re pretty good”.

Some groups have tried to capture even earlier stages of development,
using cells with the ability to turn into every cell type required for
embryonic development (most models use cells with more limited
abilities).

In 2022, Miguel Esteban, a stem-cell biologist at the biotechnology
company BGI Cell in Shenzhen, China, and his colleagues developed a
model resembling the eight-cell embryo that typically forms three days
after fertilization5
[[link removed]]. And this
June, Du Peng, a stem-cell biologist at Peking University in Beijing,
made similar blastomere mimics that eventually form blastoids without
needing to be doused in chemicals6
[[link removed]].

WRITING THE RULES

Ever since the first embryo models appeared, ethicists have been
striving to address the dilemmas that they pose. The International
Society for Stem Cell Research (ISSCR) developed guidelines in 2021
[[link removed]]; many countries are considering
their own guidelines and legislation.

Australia’s rules are some of the most stringent in the world. In
2020, biochemist Jose Polo, who leads a team based at Monash
University in Melbourne and the University of Adelaide, informed
Australia’s regulatory body overseeing embryo research, the National
Health and Medical Research Council, that he had developed blastoids,
and was asked to put the work on hold.

The regulator wanted to assess whether blastoids met the criteria to
be considered an embryo under the current laws, which define embryos
as biological entities with the potential to develop to a stage,
roughly two weeks in, at which a structure called the primitive streak
appears and the entity moves towards having a body plan.

Some five months later, the answer came back: they did, said the
agency, because of their theoretical potential to develop a primitive
streak. As a result, the same limits that apply to research on real
embryos would apply to blastoids.

It was a devastating setback, says Polo. His team had to get a
specific embryo licence, which bars the group from growing blastoids
to study later stages of gastrulation and organogenesis. “I think
that they made a mistake,” says Polo about the agency’s ruling.
The rules also limit the number of blastoids that can be made, and
require stricter consent from those donating cells to be used in them.

Every country is charting its own course. Some points of contrast are
how countries define an embryo, whether that definition extends to
embryo models and how permissive the rules are to research. Regulators
are often guided by rules and norms designed for research on real
human embryos when thinking about embryo models, says Megan Munsie, a
developmental biologist and bioethicist at Murdoch Children’s
Research Institute in Melbourne.

And these discussions often transcend the world of research, finding
relevance in other domains, such as reproductive health, abortion,
women’s rights and regenerative medicine, says Alfonso Martinez
Arias, a developmental biologist at the University Pompeu Fabra in
Barcelona, Spain. “Our echo chamber is very large,” he told a room
packed with his peers at the annual ISSCR meeting in Hamburg, Germany,
in July.

Human embryo models are trying to capture aspects of the development
of real embryos, such as this one at the 16-cell stage.Credit:
Bernardo Oldak et al./Nature

Because embryo models differ in lots of ways from the real structures,
most countries treat the two differently. In Spain, for example, the
definition of an embryo is based on fertilization, which excludes
embryo models, says Nienke de Graeff, a bioethicist at Leiden
University Medical Centre, the Netherlands.

Some definitions focus on the embryo’s potential to form or become
something else. The ISSCR has said that, based on their potential,
embryo models cannot be considered to be embryos, and most countries
take a similar view.

Some have proposed revising regulations concerning real embryos to
cover some types of embryo model. In the Netherlands, says Nienke, a
scientific advisory body proposed a ban on growing the models beyond
the equivalent of 28 days in real-embryo terms. France is considering
the same limit. Researchers in the United Kingdom did something a
little different in July: they published voluntary guidelines
[[link removed]] for embryo
models that do not set fixed limits on how long they can be cultured.
The guidelines could eventually lead to the passing of binding
legislation — as happened with similar voluntary UK guidelines
around embryo research several decades ago.

The UK guidelines and 2021 ISSCR guidelines do, however, forbid the
transfer of human embryo models into a uterus, and several other
countries, including Sweden and Japan, are considering introducing
similar restrictions.

SCIENCE ACCELERATES

Meanwhile, the science keeps moving at such a pace that regulators
have a lot to keep up with. In June 2024, the ISSCR announced that it
had set up a working group to assess the state of the science and
review earlier guidelines, in light of the models published since
2021.

In 2023, around half a dozen teams described models that recapitulate
the development of embryos just after implantation. Two models in
particular [[link removed]] were
widely covered by the media — one by Magdalena Zernicka-Goetz, a
developmental biologist at the California Institute for Technology in
Pasadena, and one by Jacob Hanna, a stem-cell biologist at the
Weizmann Institute of Science in Rehovot, Israel. They were described
as complete post-implantation models, but that title has been hotly
debated.

“These are not complete models,” says Rivron. The one by
Zernicka-Goetz’s group7
[[link removed]] doesn’t
have cells that behave like trophoblasts, which provide nutrition for
the embryo — and although Hanna’s8
[[link removed]] does
contain a trophoblast-like layer, it isn’t as organized as the real
thing, say researchers.

“It’s almost like a beauty contest — whose ‘model’ looked
better,” says Jianping Fu, a bioengineer at the University of
Michigan in Ann Arbor. “There’s a lot of excitement, but at the
same time, there’s some hype in the field right now.”

Some researchers question the value of chasing a complete model.
It’s a “pretty exquisite balancing act”, says Hyun. Researchers
want models to resemble an embryo closely enough that they provide
real insight into human development but not so closely that they
can’t tell the difference between the two, and so risk restrictions
to their work. “You want to skate as close to the edge as possible,
without falling over,” he says.

Some researchers try to avoid this ethical dilemma by intentionally
introducing changes to their embryo models that would make it
impossible for the model to result in an organism. For example, Hanna
has started working on models in which genes involved in brain and
heart development have been inactivated. He has inferred from
discussions with Christian and Jewish leaders in his community that an
embryo model lacking brain or heart tissue would not be considered a
form of person.

Fu has described a model9
[[link removed]] that he
says alleviates some of the ethical burdens because, although it
reaches gastrulation, it gets there without first forming the
primitive streak.

Such models can be insightful and useful, say researchers. One, first
published last December, has generated excitement because of how well
it reflects some aspects of real embryos10
[[link removed]], as well
as its direct implications for the clinic. When Mo Ebrahimkhani, a
stem-cell bioengineer at the University of Pittsburgh, Pennsylvania,
and his colleagues grew 3D models on a dish, they noticed the
appearance of tiny blood islands. Those islands held the first
progenitors of blood cells, including immune cells known as
macrophages, platelet-producing cells and cells containing
haemoglobin. As Ebrahimkhani has found in unpublished work, these
models could be used to produce large amounts of blood stem cells,
which could be useful for transplants in people with cancer or genetic
diseases.

ORGAN MAKING

At about three weeks, the embryo starts the momentous organ-growing
process that lasts more than a month. Several teams have homed in on
aspects of this organogenesis, growing models that resemble only
pieces of the embryo — this has potentially fewer ethical
constraints than modelling the whole structure.

One such model11
[[link removed]] recapitulates
the rhythmic process by which the body forms repeating segments known
as somites, which give rise to vertebrae. And earlier this year12
[[link removed]], Fu’s
team described a model of the neural tube, the progenitor of the
central nervous system, complete with a treasure trove of cells,
including the precursors to some neurons.

But even these models aren’t without controversy; those that contain
nerve cells raise ethical questions around the emergence of sentience,
says Hyun.

The next frontier for embryo-like models is to nestle them in
environments that more closely resemble the womb, and study how
embryos interact with its lining. Researchers have shown that
blastoids placed on cells that make up the lining of the uterus can
burrow in and fuse correctly. Co-culturing embryo models with this
maternal tissue could help models develop as natural embryos would.

Some scientists have gone even further using cells from other animals,
including non-human primates. For example, in unpublished work, Liu
Zhen, a developmental biologist at the Institute of Neuroscience at
the Chinese Academy of Sciences in Shanghai, has grown monkey
blastoids in a dish for long enough to reach early organogenesis.

In 2023, Liu transferred blastoids into eight monkeys, three of which
experienced the hormone surge observed in early pregnancy13
[[link removed]]. The
blastoids formed gestation sacs but then stopped developing
[[link removed]]. Cow and mouse
blastoids transferred into their respective species also don’t
survive long.

There are currently no rules prohibiting the transfer of non-human
embryo models into living animals, with the exception of humans, but
Hyun worries that if such transfers do lead to a live birth, that will
cause a backlash against the research and have a detrimental effect on
studies using human embryo models. The intellectual leap from monkey
to humans is easy to make, he says. “You don’t actually have to do
the human experiment to have a pretty major concern.”

WHEN IS IT AN EMBRYO?

Most researchers agree that today’s human embryo models are nowhere
near the real thing. The key challenge for researchers who are
developing guidelines is determining “when an embryo model would be
considered equivalent to an embryo”, says Amander Clark, a
developmental and stem-cell biologist at the University of California,
Los Angeles, who co-chairs the ISSCR’s working group on embryo
models.

Given that ethical norms prohibit the transfer of embryo models into a
uterus to see whether they can give rise to an organism, researchers
are coming up with other tests of their potential. Some groups are
developing tools to better compare embryo models with real embryos,
for example by looking at the cells’ RNA profiles. But even these
gene-expression exercises can miss key information, says Hanna, such
as the positions of cells in an embryo.

Assessing and improving models is important for science, as well as
for ethics, says Fredrik Lanner, a stem-cell and developmental
biologist at the Karolinska Institute in Stockholm. If the models
aren’t good, then they’re not useful, he says. It’s “really
critical now for us to not waste time on bad models”.

That standard setting is especially important as the field starts to
offer real insights into early embryonic development. There have
already been some surprises, says Moris. Most notable is the ability
of cells to switch personas — their plasticity — and their
capacity to self-organize, often without the aid of extra-embryonic
tissue.

Some models are even revealing new phenomena. Researchers have long
known that, in some mammals, embryos that are fertilized in the summer
‘hibernate’ and restart development later so that the young are
born in the spring. In unpublished work, Rivron and his colleagues
have been able to cajole human blastoids into this state of suspended
development.

But so far, he says, embryo models have not led to scientific
discoveries of societal value, and it’s not clear which models will
help researchers get there.

“There’s been a lot of debate, arguments, especially drama, in the
past”, along the lines of “my model is better than yours”, says
Wu. The reality is that every model is imperfect, but every one is
useful, he says. It just depends on what the question is.

_Nature_ 633, 268-271 (2024)

_doi: [link removed]

References

*
Warmflash, A., Sorre, B., Etoc, F., Siggia, E. D. & Brivanlou, A.
H. _Nature Methods_ 11, 847–854 (2014).

How the Higgs Field (Actually) Gives Mass to Elementary Particles
[[link removed]]
Matt Strassler
Quanta Magazine 
In this article adapted from his new book, "Waves in an Impossible
Sea," physicist Matt Strassler explains that the origin of mass in the
universe has a lot to do with music.
September 3, 2024

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