Modelling is an
essential part of the scientific method. A model enables us to learn about our
surroundings by simplifying complex observations. Through this means, a set of
operational or conceptual principles can be emphasised. Furthermore, statements
can be deciphered, tested and challenged to get the most of an initial thought
or proposal. The first recorded uses of an animal living model, were in a
faraway era when scientists can go hand and hand with a philosopher, would seem
to date from ancient Greece with Aristotle & Erastratus. Naturally, ever
since the animal modelling has evolved both scientific-wise and in the
guidelines that rule the field –ethics-. Past centuries observed an increase in
the number of species used for a wide variety of novel domains.
To keep it simple, scientists
rely on small-animals to study genetics and developmental biology, whereas
large living beings are used widely for therapeutic development. Lastly but not
least, cellular models –not the whole body- are tailored to study diseases and
develop medicines.
-The Organoid Model, an emerging
technology full of promises-
An organoid can be
defined by a miniaturised structure resembling whole organs at a
three-dimensional level. It can be generated from different sources such as
adult organ progenitors, e.g. tissue-resident adult stem cell, or from
different types of pluripotent stem cells such as induced pluripotent stem
cells (iPSCs) or embryonic stem cells (ESCs). This organ-like framework can
exhibit multiple cell types that are able to self-assemble and organise (organ
morphogenesis) on their own or driven in different ways. The resulting entities
are complex and mimic somehow their in-vivo counterparts.
Once generated from
progeny, organoids can be furtherly differentiated and matured following the
hallmarks of embryogenesis, organogenesis and even ageing. These features make
this model a unique and unprecedented tool to model an outstanding variety of
organisms, diseases and provide the opportunity to recapitulate human
development. Thanks to the origin of the cells that compose the miniaturised
organ, it turns that this model has acquired a prominent place in old:
Diagnostics, Drug Discovery and Drug Testing - and new fields: Disease and
Infection modelling, Precision/Personalised/Regenerative Medicine. Moreover, it
appears that this technology is also currently included in an extensive range
of clinical practice routine (Cystic Fibrosis, for example). Furthermore,
several leading laboratories envisage using organoids as alternative organ
replacement strategies (just like me).
In numbers of
instances, organoids come out to be an alternative to animal experiment;
capable of, at least, reducing the number of animals used in research. In fact,
this emerging tool allows us to address a large number of initial questions
thanks to characteristics such as the fantastic topology of cell-to-cell and
cell-to-matrix interactions as observed in vivo. Undergone with
animal cells at a first instance, the technology quickly moved towards human
organ modelling.
Nowadays, organoids
from the three germ layers have been developed from patient-derived tissues as
well as differentiated from pluripotent stem cells.
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| Embryonic germ layers |
Intestinal organoids
are recognized to be the first-ever launched by Prof. Hans Clevers. Benefiting
from the discovery of intestinal stem cells, his lab developed the first mouse
organoid in 2009 and human gut organoid in 2011. An outstanding amount of
publications and findings took roots from his work. I am one of those,
currently trying to develop a novel therapeutic solution for SBS (Short Bowel
Syndrome) patients in the context of a European collaboration –INTENS- via the
investigation of the development and functional maturation of human pluripotent
stem-cell-derived gut organoids. A myriad of other endodermal organs has been
developed since then such as liver lungs or the upper part of the
gastrointestinal tract.
In the same “vein”,
another organ has been modelled recently, the heart. Its development originates
from another germ layer, the mesoderm, giving rise to muscles, bones and the
circulatory system. It is astonishing to see the beats of the heart muscle, and
even more mesmerising still a full plate of beating heart cells!
As major representant of the last germ layer, the neuroectoderm, and
arguably considered as the most important organ of the human body, cerebral
organoids sprung up. Considering the complexity of the brain due to the
multiple issues towards its investigation, such tool as been wanted for years.
Lancaster, Knoblich and Muotri’s labs are leading the optimisations and
innovations within this pretty insane field. Among other unprecedented
experiments, mini-brains have been interconnected and seems to communicate,
microgravity brain impact has been accessed in space thanks to acollaboration
with NASA.
Other 3D structures are closely related to organoids but lack a compulsory
essence of the tool –to model an organ-, include gastruloids or
tumouroid. Organ-on-a-chip systems are also being developed. Overall it is
hoped these 3D cellular systems, in conjunction with organoids, could give
insightful and unique opportunities to unravel unanswered scientific questions.
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| Novel 3D cell culture, Source: Pasca, Nature |
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| Dylan's colleagues! |
Of note, the Ludovic Vallier
lab, part of the Cambridge Stem Cell Institute is undertaking responsive
research to COVID-19. Dr. Fotios Sampaziotis -Clinical Lecturer and
Hepatologist- and other members of the team resort to the organoid he developed
a few years ago, i.e. cholangiocyte ones,
to study the mechanism the virus is utilizing to enter the cells. The
Liver being the an organ of interest for this pandemic and the expertise of my
lab. You can watch an interview with Dr. Sampaziotis here .
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