The ethics of organoid research

Andrea Lavazza
CUI, Arezzo, and University of Milan, Italy
National Commission for Bioethics and Technoethics of Greece
Laboratory for the Research of Medical Law and Bioethics,
Aristotle University of Thessaloniki – March 28, 2024
Outline of the talk

1. Organoid revolution

2. Extrinsic ethical issues

3. Intrinsic ethical Issues

4. And the future?

The organoid revolution / 1
An organoid can be defined as an in vitro 3D cellular cluster
derived from primary tissue, Embryonic Stem Cells (ESCs)
or induced Pluripotent Stem Cells (iPSCs), capable of self-
renewal and self-organization, and exhibiting similar organ
structure and functionality as the tissue of origin.

Although the self-organizing capacities of human stem cells

have been known for decades in developmental biology, a
paper by Sato and Clevers published in 2009 can be
considered the first one on what we now call organoids.
The organoid revolution / 2

An organoid is a miniaturized and simplified version of an organ (lung, heart, liver, and kidney for example)
produced in vitro in 3D that shows realistic micro-anatomy. They are derived from one or a few cells
from a tissue, embryonic stem cells or induced pluripotent stem cells, which can self-organize in three-
dimensional culture owing to their self-renewal and differentiation capacities. Organoids are used by scientists
to study development, diseases and treatments.

Organoid formation generally requires culturing the stem cells or progenitor cells in a 3D medium. The 3D
medium can be made using an extracellular matrix hydrogel Matrigel. Organoid bodies can then be made
through embedding stem cells in the 3D medium. When pluripotent stem cells are used for the creation of the
organoid, the cells are usually, but not all the time, allowed to form embryoid bodies.

Those embryoid bodies are then pharmacologically treated with patterning factors to drive the formation of the
desired organoid identity. Organoids have also been created using adult stem cells extracted from the target
organ and cultured in 3D media. Cancer organoids have been created in order to have in vitro models..
The organoid revolution / 3
The organoid revolution / 4

Organoid technology can be taken to be a transformative one, as it constitutes

a revolutionary method to mimic human tissues in a dish. Organoids turn out
to be the recent most valuable tools for research and clinical care.

This technology promises to impact the entire biomedical innovation cycle,

with applications ranging from developmental studies to regenerative
medicine, including fields that are subject to ongoing hot ethical debate.

Organoid technology may give a new twist to the ethical debate, on one hand,
overcoming some old dilemmas.

But on the other hand, organoid technology can raise new important ethical
issues, and morally responsible innovation requires pro-active scrutiny of
the ethical challenges (cf. Boers, 2019; Lavazza and Massimini, 2018).
Organoid revolution and ethics / All going well?

Human Organoids (HBOs) can be considered a more acceptable form of

experimentation than that on human fetuses, animals and voluntary human
adults.

No living being is destroyed, damaged or put at risk in tests involving organoids, and
their level of scientific reliability might soon be equivalent to that of traditional
methods. So, there is no efficiency loss to the detriment of the ill awaiting a cure.

Also, organoids can be cheaper— both in terms of material and working hours—
than other forms of experimentation, and their use may make resources
available for other relevant uses in the biomedical field.

But we need to be careful in celebrating (from an ethical standpoint)

.
 Extrinsic ethical issues / 1

In organoid technology different biotechnological developments converge,

among which fields that are subject to ongoing ethical debate, the first one
being the use of stem cells (neither extrinsic nor intrinsic issue)
Types of issues Potential Solutions Remaining Concerns

Kinds of Donors Patients /Healthy adults Need of others donors

Informed Consent Different types of consent What’s the best one?

Privacy of Genetic Information Usual protection Apt for organoids?

Intellectual Property No patent for organoids Is that right?

Earnings distribution No monetary reward Gains only for profit companies?

Issues related to the use of stem cells

Human brain organoids can raise ethical (and legal)

problems for the use of embryonic stem cells if
their use leads to the destruction of embryos. As is
well known, there is an open debate as to whether
human embryos are a potential person who has the
same moral status and must have the same legal
protection as a born individual.
Stem cells lines created in the past are less ethically
concerning than stem cells directly derived from
human embryos
The use of induced pluripotent stem cells allows
overcoming the problem (although from a clinical-
scientific point of view the difference between cell
types may be significant)
Extrinsic ethical issues /General

Organoid technology is situated in an increasingly commercialized and globalized biotechnological field.

Financial resources coming from private parties are deemed necessary to sustain academic research
endeavors and biobanks, as public funding is limited or not well allocated (cf. Boers, 2019).

Collaboration with industry is regarded indispensable in bringing novel treatments from ‘bench to
bedside’ and the biotechnological field is increasingly positioned as a source of economic value.

This fact results in an increasing pressure to commercialize stem cell technologies, that is, to turn
research into marketable products or services. An example is the establishment of human stem cell
lines as either therapeutic solutions or research products.
Extrinsic ethical Issues /General / 2

As well as for cell lines, the problem holds for

organoid technology, where commercial interests
are growing. This is illustrated by the growing
number of patents, the establishment of
commercially oriented biobanks, and the uptake of
organoid technology by the biotechnological and
pharmaceutical industry.

The commercialization of human tissues and related

products, however, is ethically problematic and is
known to raise legal issues and of public trust.
Donors and Biobanks / 1

The storage of organoids in biobanks raises

questions about the type of consent required
from the donor for long-term use and for
applications for purposes not included in the
informed consent.
In order to achieve a constant production of
organoids, tissue donation is needed, which
entails possible problems in terms of
properties of the biological material that is
produced from the original tissues.
A broad and non-specific consent on tissues is
good for research but not for the donors.
Donors and Biobanks / 2

One proposal, by Bredenoord, Boers, et al., relates to using a consent

for governance model, which builds on a model previously used for
DNA banking, in which participants in organoid research give consent
to have a particular mechanism in place to arbitrate future decisions
about appropriate uses of their organoids.

The idea behind consent for governance is that it is difficult to inform

donors about the specific studies that will be done with the organoids
derived from their tissues, but it is possible to inform them about how
the biobank is structured, how it operates, and how decisions are
made regarding the use of organoids.
Donors and Biobanks / 3

A consent for governance model shifts the ethical emphasis from initial consent to ongoing
governance obligations for the biobank. However, such a model would require changes in
consent forms and legislation that may take substantial effort and time to implement.

Other scholars maintain that consent should always be as specific as possible. People should know
how their cells and tissues are being used. Obviously, this choice can slow down the procedure
or hamper the immediate availability of biological material.
 Donors and Biobanks / 4

Another proposal envisages an expert acting as executor of the donor's wishes. The donor
signs a general consent but also expresses to the executor her general criteria or the limits
she would like to place on the use of her biological samples. In this way, there is an
actualization of the donor's wishes without there being a lengthy procedure to recall and
question her again.
Of course, it is not the same thing to decide through an executor as to decide directly, but it
is probably better than a broad and non-specific consent.
Patients’ attitudes

There is very limited empirical research that has been reported to date. A very recent
interview study conducted in the US (MacDuffie et al., 2023) reported that donors
of biospecimens and parents of donors expressed high hopes in the use of brain
organoids. They felt positive toward HBOs research and deemed it more ethical
than other methods. Donors were comfortable with broad consent and accepted
deferring to research teams on what specific research was done with organoids.

Only a minority of interviewees showed some concerns (but they were not asked
about commercial uses, for example). Donors want to know the results of the
research; to allow transfer of decision-making authority over time; and to ensure
ethical boundaries are not crossed (HBOs experiencing pain and memory are not to
be grown; nor HBOs are to used beyond clinical settings).
Ethical Issues / Transplantation

In the future, organoids might also be used for transplantation, with the
aim of repairing damaged or ill brain. If clinical translation proceeds
through transplantation, it will be critical to attend to good
manufacturing processes to minimize risks and maximize benefits.

In addition, it will also be necessary to follow a conventional translation

cascade, moving from bench, to non-human animals, to first-in-human
clinical trials, each with appropriate oversight. This sort of work would
likely benefit from following related ethical guidelines, such as those that
have been issued so far for stem cell-based interventions (cf. Sugarman
and Bredenoord, 2019).
Ethical Issues /Special cases / Gastruloids

Gastruloids are three dimensional aggregates of embryonic stem cells (ESCs) that,
under appropriate culture conditions, develop an embryo-like organization.
Gastruloids contain elements of primitive streak formation and cells from each of the
three germ layers, and they recapitulate key steps in early embryogenesis.

Consequently, research with them may provide insights into early human embryo
development and early pregnancy loss. However, there have been longstanding
debates about the moral status of human embryos, which are in some ways similar to
gastruloids. Given their shared characteristics, gastruloids and embryo-like structures
should likely be considered somewhat analogously to embryos, but this needs further
conceptual ethics research.
Ethical Issues /Special cases / Gastruloids and the 14-day rule

Since gastruloids appear similar to early-stage embryos, ethical

concerns arise around the extent to which they are permitted to
mature. With human embryos, there has been a good degree of
international consensus that in vitro work with them should not
proceed beyond 14 days, which is about the time when the neural
streak appears, suggesting individuality.

Should gastruloids be held to the same standards? What if the neural

streak appears earlier in gastruloids than in human embryos?
Although the 14-day rule has been an internationally agreed upon
rule for decades, some suggest there are scientific, ethical, and
regulatory arguments to extend the 14-day rule.
Organoids + Gene-editing

The use of specific techniques, such as manipulating organoids

with new gene editing tools (CRISPR), is ethically sensitive,
but this is due primarily to ethical concerns regarding
genome editing in general and enhancement in particular.

The use of gene editing techniques in organoids grown for

clinical application—for example, in organoids designed for
transplantation—raises research ethics issues when we
consider the possibility of the responsible launch of a first-
inhuman trial, which could become a real possibility.
Scientists’ view

Personal attitude toward the ethical debate

Positive attitude toward the ethical debate Typical
Informed consent
Need of specific informed consent for donating for Typical
HBOs
No need of specific informed consent for donating Variant
for HBOs
Guidelines and regulations
Current guidelines are sufficient Typical
Current guidelines should be updated Variant
Impact of ethics over research
Concerns that the ethical discussion could slow Variant
research down
No concern that the ethical discussion could slow Typical
research down

[Lavazza and Chinaia, 2023]

Intrinsic ethical issues (related to human brain organoids)

Chimeric research

Emergence of sentience / consciousness

Moral status of HBOs

How cerebral organoids work

1 To have an organoid, a “3D in vitro culture

should replicate not only the complexity of
the cell types present in the organ, and the
processes of self organization of the tissue,
but also the main organization of the whole
organ (Kevala and Lancaster, 2016).
Cerebral organoids should replicate “the
appearance of different brain regions”
2 But so far there are significant
problems with their vascularization

3 Recently, there have been some first

signs of electrical activity
(communication between neurons)
and also presence of cells that respond
to light stimulation
 Assembloids

Assembloids are obtained by incorporating

different organoids into multi-region
assembloids, such as when combining dorsal
with ventral forebrain, cerebral cortex with
striatum, or cerebral cortex with thalamus;
integrating neural or non-neural cells, such
as microglia, immune cells and endothelial
cells, into organoids to create multi-lineage
assembloids; or combining organizer-like
cells with organoids (Pasca et al., 2022, Nat).
Cerebral organoids: the first uses

Mini-brains have already been used to With the patient's cells, there will be
1 study the microcephaly linked to the Zika 4 the possibility of creating parts to be
virus (Li et al., 2016), but they are also transplanted and models on which to
expected to be used for autism, Parkinson's test drugs and personalized therapies
disease, and multiple sclerosis.
2 Also, cerebral organoids pave the way
for a very detailed understanding of all
phases of cerebral development and its
abnormalities, in a way that was
hitherto unthinkable in vitro.

A model has been created to test the

3
toxicity of unknown substances based
on the response of brain organ genes
after exposure to known toxic and
non-toxic compounds.
Chimeric research / 1

A chimera is a single organism composed of cells with distinct genotypes. Various forms or
chimera research have been taking place without much ethical debate, such as
transplantation of human cancers cells into mice.

But we might wonder whether it is ethically appropriate to use in vitro

structures of human origin in chimeric research, especially when this

may ‘‘humanize’’ a non-human animal. It happens when we introduce

human early-stage organoids into the brain of animals.

A relevant concern seems to be that in the process of biologically humanizing a research

animal, scientists might inadvertently morally humanize the resulting chimera (giving them
a moral status or, at least, a special value they would not have had beforehand).
Chimeric research / 2

Substantial ethical concerns have been

raised by ‘humanized mice’, especially
concerning the central nervous system.

It has been suggested that the transfer of

HBOs into non-human animals should
be conducted through incremental
research and be closely monitored to
determine the physical and behavioral
changes that might occur in the host
animal.
Chimeric research / 3

Growing a human organoid in a non-human

animal can be difficult to evaluate ethically
both in itself and from the donor's point of
view.
Nonhuman-human chimeras probably have
some form of consciousness (especially higher
mammals) and the insertion of human tissue
while the animal foetus is developing or after
the birth of the animal may lead to unknown
results.
No specific guidelines exist for this kind of research
(cf. National Academies of Sciences, Engineering
and Medicine, 2021; ISSCR, 2021).
Chimeric research / 4

A statement from a
large group of
bioethicists and
scientists involved in
the field (Hyun et al.,
2022, published on
October 18)
But consider the paper
from Revah et al., 2022,
published just some
days before
Chimeric research / 5

Researchers transplanted 3D hCO derived from hiPS

cells into the primary somatosensory cortex (S1) of
immunodeficient rats at an early, plastic
developmental stage.
Neurons from transplanted hCO (t-hCO) undergo
substantial maturation, receive thalamocortical and
corticocortical inputs that are capable of evoking
sensory responses and extend axonal projections
into the rat brain that can drive reward-seeking
behaviours (through optogenetics)
[Revah et al., 2022]
THE PROBLEM WITH BRAIN ORGANOID SENTIENCE

“The dilemma? When we avoid unethical research by making living models

of human brains, we may make our models so good that they
themselves deserve some of the kinds of ethical and legal respect that have
hindered brain research in human beings. If it looks like a human brain and
acts like a human brain, at what point do we have to treat it like a human
brain — or a human being?”

“Human Brain Surrogates Research: The Onrushing Ethical Dilemma”

Greely, 2021
Brains in a vat

In a famous thought experiment, which draws on a long tradition starting from

Descartes, philosopher Hilary Putnam (1981) hypothesizes that a cruel scientist has
detached the brain from a person's body and immersed it in a vat filled with a
nutritive liquid that keeps it alive.

The brain’s nerve terminals are then connected to a supercomputer, so that the
person has the illusion that everything is perfectly normal. It will seem to him that
there are objects and people placed in an environment and he will have feelings
and perceptions corresponding to the actions he thinks he is doing.

But all that the person (brain) feels is the result of the impulses transmitted from
the computer to the nerve terminals.
Human brain organoids: the main ethical concern / 1
A (controversial) study has shown for the first time that brain
organoids generated by induced pluripotent stem cells can develop
periodic and regular oscillatory electrical activity that resembles the
EEG patterns of premature newborns.
This means that 10-month-old mini-brains, even in the absence of
external or subcortical inputs, can develop according to a specific
genetic program typical of all humans.
The most surprising aspect: an expert software trained with the EEG
data of preterm infants was able to evaluate with a good
approximation the age of cerebral organoids based on their
electrical activity (Trujillo et al., 2019).
New methods of cultivation of cerebral organoids have allowed to
generate diverse nerve tracts with functional output (Giandomenico et
al., 2019). Cerebral organoids have proved capable of inducing
movement, although not yet a purpose-oriented kind of movement.
 Human brain organoids: the main ethical concern / 2
Image: Gabriel et al., 2021
HBOs also show the differentiation of photoreceptor-like cells
endowed with proteins for light responsiveness. These photosensitive
cells ‘can respond to non-invasive, light-based sensory stimulation’
(Quadrato et al., 2017). Recently, optic vesicle-containing brain
organoids (OVB) have been grown (Gabriel et al., 2021).
These steps forward indicate that it is possible to transmit afferent
stimulations to brain organoids.
In another study (Sakaguchi et al., 2019), researchers have managed to
visualize in cortical spheroids synchronized and non-synchronized
activities in networks and connections between individual neurons.
Cells were capable of organizing themselves into clusters and form
networks with other nearby clusters. The manifestation of a
synchronized neural activity can be the basis for various relevant brain
functions.
The main ethical concern / 3 – Scientists’ view
General themes, domains, and sub-domains Frequency

On consciousness and moral status

Consciousness
Skepticism about consciousness emerging in HBOs today General
Skepticism about consciousness emerging in HBOs in the future Variant
Repercussions on the usage of HCOs if consciousness is Typical
detected
Consciousness in HBOs would be similar to that of flies or Uncommon
grasshoppers
Moral status
There is no ethically relevant difference between HBOs and other Typical
tissue products
There is an ethically relevant difference between HBOs and other Variant
tissue products
Human/non-human chimeras
Chimeras are no different compared to other animals without General
HCOs grafts
Personal ethical concerns
No personal ethical concern Typical

[Lavazza and Chinaia, 2023]

Sentience and consciousness
1 Subjective experience is a general category, within which
consciousness can be isolated as a more circumscribed
phenomenon: not everything that a living being feels is
necessarily conscious (inner speech is characteristic of
consciousness, for example). Consider pain or the so-
called primordial emotions, such as thirst (Denton, 2009).
These sensations impose themselves on experience and
cannot be ignored.

2 Some scholars hypothesize that these emotions are

experienced in a certain way only thanks to the
sophisticated processing typical of the nervous system
of mammals.

But it is not implausible to suppose that a living being

3
can feel pain and experience lack of air even without
having an inner model of the world or of itself
(Godfrey-Smith, 2018).
Human cerebral organoids: the main ethical concern / 1
1 2
The developmental
stages in which a
cerebral organoid
could begin to have
sensations of pain and
possibly a first glimpse
of consciousness are
critical, provided that
the consciousness
manifests itself
gradually.
3
To make this assessment,
we need a theory of
consciousness and the
possibility of measuring it
through instruments that
do not depend on any
kind of communication
from the conscious
subject.
A promising candidate to
do this is the theory of
consciousness as
integrated information,
measured with the PHI
indicator using the
complexity of the
electrical response to
signals sent to the nervous
system, whatever its
organization.
SENTIENCE IN BRAIN ORGANOIDS?

• Brain organoids do not (yet) display behavioral outputs

• Proposal: let’s look at the neural correlates of consciousness
(NCCs)
• Problem: different theories account for different NCCs

Image from: Reardon, 2020

THEORIES OF CONSCIOUSNESS and BRAIN ORGANOIDS

• Different theories provide a different account of consciousness and possible

NCCs

• Integrated Information Theory (IIT)

• Global Neuronal Workspace Theory (GNWT)
• Temporo-spatial Theory of Consciousness (TSTC)
• Embodied Theory (ET)

Zilio & Lavazza, 2023

THEORIES OF CONSCIOUSNESS and BRAIN ORGANOIDS

• Different theories provide a different account of consciousness and possible

NCCs

• IIT → consciousness = integrated information (Tononi, 2017)

• Global Neuronal Workspace → conscious access through broadly
distributed networks (Dehaene et al., 2011)
• Temporo-spatial theory → consciousness depends on the ability of the
brain to encode inputs in the spatio-temporal structure of its firing
activity (Nortoff & Huang, 2017, Northoff & Zilio, 2022)
• Embodied theory → consciousness is neurovisceral (dependent on
processing proprioceptive and interoceptive stimuli) (Park & Tallon-Baudry, 2014)

Zilio & Lavazza, 2023

THEORIES OF CONSCIOUSNESS and BRAIN ORGANOIDS

• Different theories provide a different account of consciousness and possible

NCCs

• IIT → consciousness = integrated information (Tononi, 2017)

• Global Neuronal Workspace → conscious access through broadly
distributed networks (Dehaene et al., 2011)
• Temporo-spatial theory → consciousness depends on the ability of the
brain to encode inputs in the spatio-temporal structure of its firing
activity (Nortoff & Huang, 2017, Northoff & Zilio, 2022)
• Embodied theory → consciousness is neurovisceral (dependent on
processing proprioceptive and interoceptive stimuli) (Park & Tallon-Baudry, 2014)

Zilio & Lavazza, 2023

THEORIES OF CONSCIOUSNESS and BRAIN ORGANOIDS

• Different theories provide a different account of consciousness and possible

NCCs

• IIT → consciousness = integrated information (Tononi, 2017)

• Global Neuronal Workspace → conscious access through broadly
distributed networks (Dehaene et al., 2011)
• Temporo-spatial theory → consciousness depends on the ability of the
brain to encode inputs in the spatio-temporal structure of its firing
activity (Nortoff & Huang, 2017, Northoff & Zilio, 2022)
• Embodied theory → consciousness is neurovisceral (dependent on
processing proprioceptive and interoceptive stimuli) (Park & Tallon-Baudry, 2014)

Zilio & Lavazza, 2023

THEORIES OF CONSCIOUSNESS and BRAIN ORGANOIDS

• Different theories provide a different account of consciousness and possible

NCCs

• IIT → consciousness = integrated information (Tononi, 2017)

• Global Neuronal Workspace → conscious access through broadly
distributed networks (Dehaene et al., 2011)
• Temporo-spatial theory → consciousness depends on the ability of the
brain to encode inputs in the spatio-temporal structure of its firing
activity (Nortoff & Huang, 2017, Northoff & Zilio, 2022)
• Embodied theory → consciousness is neurovisceral (dependent on
processing proprioceptive and interoceptive stimuli) (Park & Tallon-Baudry, 2014)

Zilio & Lavazza, 2023

 THEORIES OF CONSCIOUSNESS and BRAIN ORGANOIDS

Integrated Brain organoids could generate complex, non-stereotypical integrated

Information information through recurrent networks.
Theory

Global Brain organoids would need long distance connectivity and sufficient
Neuronal anatomical variability to broadcast information.
Workspace
Theory

Temporo- Need to access to the environment to develop a structure that can

spatial Theory organize the stimuli in a temporal and spatial fashion.

Embodied Need of a body → possible solution: connecting brain organoids with

Theory artificial environments or engrafting them into animals. (Zilio & Lavazza, 2023)
 Consciousness: what it is and how to identify it (a proposal)

1 • The theory of integrated information (G. Tononi, M.

Massimini, C. Koch) posits two phenomenic axioms that
give rise to postulates on the properties of brain
mechanisms that support consciousness.

• The axioms are: (i) conscious experience is informative

(each conscious experience differs in its specific ways
from countless other possible experiences); (ii)
conscious experience is integrated (every conscious
experience cannot be divided into parts). It follows that
a system has subjective experience to the extent that it
is capable of integrating information.
• This capacity depends on an optimal balance between differentiation (information) and unity
2 (integration), a non-trivial condition for a physical system. On the contrary, at first sight, it would
seem that these two properties are extremely difficult to reconcile.
How to measure consciousness (also in organoids) / 1

1 The IIT proposes a theoretical measure (PHI) and

empirical metrics to quantify the ability of a
system to integrate information.

2 The Perturbational Complexity Index (PCI) is

a parameter inspired by the main postulate
of IIT, namely that consciousness is based on
the joint presence of integration and
differentiation in the brain.
3 The calculation of the PCI locally involves
perturbing the cerebral cortex (by
transcranial magnetic stimulation, TMS) and
measuring the complexity of the electrical
response in the rest of the brain (by EEG).
How to measure consciousness (also in organoids) / 2
1 The basic idea is that the PCI is low if the interactions
between neuronal elements are reduced (loss of integration),
because the response induced by TMS is limited in space. The
PCI is low even if many connected areas react to the
perturbation, but they do so in a stereotyped way (with a loss
of differentiation), because in this case the response is wide
but not complex.
2 The PCI should only reach high values if the initial disturbance
is transmitted to a large network of neuronal elements that
react in a differentiated way.

3 As such, the PCI is independent of sensory processing,

executive function or motor behavior. For this reason, with
specific technologies, it could also be applied to cerebral
organoids.
ORGANOIDS AS A LIVING LAB FOR CONSCIOUSNESS?

• To study the emergence of consciousness

• To investigate its mechanisms and neural correlates
• Brain organoids could become a benchmark for different
neuroscientific theories of consciousness (Lavazza, 2021)

Problem: using HCOs that were conscious for research studies on

consciousness without evident clinical outputs would be a violation of the
requirement not to use sentient beings of human origin as pure means
WHY IS SENTIENCE / CONSCIOUSNESS IMPORTANT?

• Sentience/consciousness are deemed relevant for the attribution of

moral status - “moral status-qua-consciousness” (Kreitmeier, 2023)

• Proposal of a precautionary principle (Birch & Browning, 2021)

• Repercussions in research
WHY IS SENTIENCE / CONSCIOUSNESS IMPORTANT?

• Scientists do not seem concerned yet (Lavazza & Chinaia, 2023)

• Other stakeholders do not perceive consciousness as a current ethical
issue (ISSCR, 2021)

“I think that still, to me, it is similar to other organoids of other part of the
body, liver, pancreatic organoids, because the organization is too immature
to expect something more.” (P16)
Consciousness, moral status, and value

There are two questions about the presence of consciousness in HCOs and their possible moral status.

The first is strictly philosophical and concerns how to identify what consciousness is and what
characteristics attribute moral status to an entity.

The second is gnoseological and concerns how consciousness can be found and evaluated and the
characteristics that allow moral status to be given.

In the case of cerebral organoids, moral status is linked to the presence of forms of consciousness, so
that the identification of the characteristics capable of motivating the attribution of moral status
derives from the presence of evidence of consciousness.
Moral status and moral value

properties and, for living beings, can only be

Moral status is a condition for which a certain
attributed to entities that have subjective
entity receives consideration in the ethical
interests, i.e. interests in having or not having
sphere for being that entity and not only for
specific subjective experiences and interests
its relations with other entities (Jaworska
in not being harmed in a general sense.
and Tannenbaum, 2018).

Moral status is not equivalent to moral value, the

former being a basic condition that does not
determine the degree of the latter. Moral status
is attributed based on a being’s intrinsic
Granting moral status

Subjective interests are linked to certain subjective experiences, so to obtain moral

status it is (generally) necessary to have some form of consciousness.

Moral status can be attributed based on various justifications, the most relevant of
which include having a certain relevant moral characteristic, having a biological
affiliation o being similar to other entities already granted a moral status.

In the case of HCOs, the necessary premise seems to be the possession of subjective
interests and, therefore, of some even minimal form of consciousness, i.e.
sentience. If cerebral organoids possessed this characteristic, this would not
qualify them as entities with a moral status as such: they would probably have to
reach a certain threshold of complexity.
(Cf. Lavazza, 2021)
Moral status and value

Once an entity has been given moral status, this does not imply any
necessary consequences.

One may consider that there are different levels of moral status, which can
be for example partial or complete, or that moral status is a continuum,
based on the characteristics and complexity of the psychic life of the entity
under consideration. In fact, one must specify the moral hierarchy in which
the entity is inserted, what kind of rights it acquires through its new status
and what kind of obligations, if any, other moral agents have towards it.

This is based on the premise that obtaining a moral status in itself

neither implies the acquisition of specific rights
nor imposes specific obligations on other moral agents.
Consciousness, moral status, and value / 3

The dimensions of entities

Human Brain Organoids

From Koch (2019)

Are sentient HCOs already with us?

A statement from a large

group of bioethicists and
scientists involved in the field
(Hyun et al., 2022, published
on October 18)

But consider the paper from

Kagan et al., 2022, published
just some days before
Are sentient HCOs already with us?

1 In vitro neural networks from human or rodent origins are

integrated with in silico computing via a high-density
multielectrode array. Through electrophysiological
stimulation and recording, cultures are embedded in a
simulated game-world, mimicking the game “Pong”.
2 Applying implications from the theory of active inference
via the free energy principle, we find apparent learning
within five minutes of real-time gameplay not observed in
control conditions (Kagan et al., 2022).
3 Sentience as being «responsive to sensory
impressions» through adaptive internal processes
(Friston et al., 2022)
The foreseeble future

Front. Sci., 28 Feb 2023

 Biocomputing – Organoid Intelligence

1. Recent advances in human stem cell-derived
brain organoids promise to replicate critical
molecular and cellular aspects of learning and
memory and possibly aspects of cognition in
vitro. Coining the term “organoid intelligence” 3.
(OI) to encompass these developments, we
present a collaborative program to implement the
vision of a multidisciplinary field of OI. This aims to
establish OI as a form of genuine biological
computing that harnesses brain organoids.
sensory organ organoids (e.g., retinal organoids),
and are trained using biofeedback, big-data
warehousing, and machine learning methods.
In parallel, we emphasize an embedded ethics
approach to analyze the ethical aspects raised by
OI research. We anticipate OI-based
biocomputing systems to allow faster
decision-making, continuous learning during
tasks, and greater energy and data efficiency.

2. Technologies that could enable novel 4. Furthermore, the development of “intelligence-

biocomputing models via stimulus-response
training and organoid-computer interfaces are
in development. We envisage complex,
networked interfaces whereby brain organoids are
connected with real-world sensors and output
devices, and ultimately with each other and with
in-a-dish” could help elucidate the
pathophysiology of devastating developmental
and degenerative diseases (such as dementia),
potentially aiding the identification of novel
therapeutic approaches to address major global
unmet needs.
Some future issues

• An online conference organized by Frontiers on June 21, 2023.

• Hartung: gifted donors, no limitations of size, new
architectures, novel inputs, training schemes…
• Smirnova: microphysical systems also for food, cosmetic and
tobacco research…
• Gracias: integrating, interfacing and embedding HBOs
• Kagan: stimulation of HBOx in real time
(cf. Lavazza and Reichlin, 2023)
To conclude: more questions than answers

What should we do if cerebral organoids

presented a glimmer of consciousness in
the form of integrated information?
Will we be able to use brain organoids
to try to unravel the mystery of
consciousness?
Ultimately, do we need new and special
rules for the creation and use of human
cerebral organoids?
Thank you for your attention

lavazza67@gmail.com
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