Self-awareness of organoids
Can a brain grown in a laboratory have consciousness?
Can lab-grown brains become conscious?
Sara Reardon, Nature
Translation: InoSMI.Ru
Some experiments prompt scientists to ask the following questions: can groups of cells be intelligent? And the brain, separated from the body? And if "yes", how will scientists find out about it?
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In the laboratory of Alisson Muotri, hundreds of miniature samples of the human brain, like sesame seeds, float in Petri dishes, showing electrical activity.
These tiny structures, called brain organoids, are grown from human stem cells; it is common to see them in laboratories studying the properties of the brain. Neuroscientist Alisson Muotri from the University of California, San Diego (UCSD) has found some unusual ways to investigate this problem. He connected organoids to walking robots, modified their genomes with the help of Neanderthal genes, launched them into space aboard the International Space Station and began using them as models in order to develop artificial intelligence systems more resembling human ones. Like many other scientists, Muotri has now temporarily switched to studying COVID-19, using brain organoids; he would like to test exactly how drugs fight the SARS-CoV-2 coronavirus.
But one experiment attracted more attention than the others. In August 2019, a research group led by Muotri published an article in the journal Cell Stem Cell, reporting the creation of human brain organoids that were the source of coordinated waves of activity similar to those observed in premature infants. These waves manifested for several months before the team of scientists stopped their experiment.
This type of coordinated electrical activity of the brain is one of the properties that indicates the presence of consciousness. This discovery prompted ethicists, along with other scientists, to ask a lot of moral and fundamental questions about whether we have the right to grow organoids that have reached such a high stage of development at all? Are organoids "possessing consciousness" subject to some special regime of legal regulation and some special rights that do not apply to other cellular structures? Is it even possible, so to speak, to construct consciousness?
Many neuroscientists and bioethicists have repeatedly turned to the idea of an autonomously existing and self-aware brain. For example, just a few months ago, scientists from Yale University in New Haven, Connecticut, announced that they had managed, at least partially, to bring back to life the brains of pigs killed a few hours before the experiment. By removing the brain from the pig's skull and treating it with a special chemical composition, scientists restored the cellular functions of neurons and their ability to transmit electrical signals.
Other experiments were also conducted, for example, attempts were made to implant human neurons into the brains of mice. However, such experiments continue to raise questions for us, and some scientists, along with ethicists, argue that such experiments should not be allowed in any way.
These studies have paved the way for a discussion between those who oppose any attempts to construct consciousness, and those who believe that complex organoids are a means to study severe human diseases. Alisson Muotri and many other neuroscientists believe that with the help of human brain organoids, scientists will be able to better understand the mechanism of such pathological changes in the human body (for example, autism and schizophrenia), which cannot be studied in detail in mouse models. Muotri argues that in order to achieve this goal, he and other scientists may need to specifically create intelligent structures.
Currently, scientists are calling for the creation of a set of guidelines similar to those used in animal research for the humane use of brain organoids and other experiments that could lead to the construction of consciousness. In June, the National Academies of Sciences, Engineering and Medicine of the USA (NASEM) began conducting scientific research to identify potential legal and ethical problems associated with brain organoids and chimeras of humans and animals [chimeras are organisms consisting of genetically heterogeneous cells, – approx. transl.].
Concerns about growing the brain in the laboratory also highlighted the following "white spot": there is no agreement among neuroscientists on how to understand the concept of "consciousness" and how it should be measured. And since there is no working definition, ethicists fear that the experiment will be impossible to stop before the forbidden line is crossed.
The abundance of behavioral experiments can pose a difficult question for us: "If scientists suddenly notice that an organoid has suddenly gained consciousness, then they may have to hurry up and offer a hypothesis that would explain how this could all happen," says cognitive neuroscientist Anil Seth from Sussex University, located near the city of Brighton, United Kingdom. But if, according to some hypothesis created by scientists, Anil Seth continues, one of the organoids will be considered endowed with consciousness, and the other is not, then in the case of such a dual interpretation of "consciousness", we no longer have the right to claim that we have really created some kind of entity with consciousness. "All our confidence largely depends on which hypothesis we believe in. As they say, the circle has closed," adds Seth.
States of reasonableness
Creating an organoid system that has intelligence may be much easier than defining it precisely. Scientists and doctors give different definitions of the concept of "consciousness" – i.e. depending on the specific goals; however, it is difficult to combine these definitions into a single clear and working definition that could be used in relation to a lab-grown brain.
Usually, doctors talk about the presence of consciousness in one degree or another in patients who are in a vegetative state, based on the following signs: whether he blinks, whether there is a reaction in response to local pain or to other stimuli. For example, using electroencephalogram (EEG) readings, scientists have also learned to detect the brain's response to an electrical impulse. If the brain is conscious, then it demonstrates a much more complex and unpredictable electrical activity, which cannot be said about the brain in an unconscious state – its EEG is characterized by simplicity and regularity.
But such tests for the presence of consciousness may not give us an adequate answer to the question of whether a person has consciousness or not. In the course of studying the brains of people in a coma or vegetative state, scientists have shown that the brain of a person who does not respond to external stimuli is able to show some activity that somewhat resembles consciousness (for example, if a person is asked to think about walking, then activity is recorded in the motor cortex of the brain).
In any case, standard medical tests designed to determine the presence of consciousness in humans are difficult to apply to brain cells grown in laboratory conditions, or to the brains of animals separated from the body. When Alisson Muotri hypothesized that the activity of organoids grown in vitro is as complex as that of premature babies, scientists did not know how to react to it all.
According to some experts, the brain activity of a premature baby is not complex enough to be classified as conscious. If we talk about organoids, they cannot blink or react in any other way in response to a painful stimulus; that is why they will not pass a clinical test for the presence of consciousness.
On the contrary, it is much more likely that the intact brain of a slaughtered pig has all the necessary structures indicating the presence of consciousness in it, as well as neural connections formed as a result of those memories and experiences that the animals experienced during their lifetime. "Just imagine a brain filled with all these structures! The brain is hardly empty. I don't know what conclusions they came to about thinking, but it definitely cannot be reduced to zero," says philosopher and neuroethicist Jeantine Lunshof from Harvard University in Cambridge, Massachusetts. When we try to look for some semblance of life in a dead brain, as the above-mentioned team of scientists from Yale University did, then here we may also encounter attempts to regain consciousness at least in some form; however, scientists – with the help of special chemicals that block brain activity – have applied great efforts are being made to prevent these attempts.
Scientists agree that they need to take seriously the prospects that open up as a result of these studies. In October 2019, UCSD held a conference attended by about a dozen neuroscientists and philosophers, as well as students and members of the public. The purpose of the conference is to develop and publish ethical principles on the basis of which similar experiments on organoids should be carried out in the future. But the publication of the article was postponed for several months, partly due to the fact that some authors could not come to an agreement on the main issues concerning the concept of "consciousness".
Extremely difficult
Almost all scientists and specialists studying ethics agree that so far no one has managed, so to speak, to construct consciousness in laboratory conditions. But they ask themselves what they should pay close attention to and which theories of consciousness may be the most relevant. For example, according to the so-called theory of integrated information, consciousness appears as a result of an increase in the number of interactions between neural networks of the brain. The more neurons interact with each other, the higher the degree of consciousness (it is designated by the Greek letter "F"). If the "F" is greater than zero, then it is considered that this organism has consciousness.
According to this theory, most animals reach this level. Christof Koch, president of the Allen Institute for Brain Research in Seattle, Washington, doubts that any of the existing organoids can reach this threshold, however, Koch admits that a more advanced organoid may well reach.
Other competing theories of consciousness suggest the presence of sensory input or some features of coordinated electrical activity in many areas of the brain. For example, according to an approach known as the global workspace theory, it is claimed that the prefrontal cortex of the brain functions like a computer, processing sensory signals and interpreting them in order to form certain feelings of life. Since organoids do not have a prefrontal cortex and they cannot receive information from the outside, therefore, they are not able to possess consciousness. "Neurons can communicate with each other in the absence of input and output signals, but this will not necessarily mean that we have received something resembling human thinking," says developmental biology specialist Madeline Lancaster from the University of Cambridge in the UK.
However, connecting organoids to the organs of living organisms can be quite a simple task. In 2019, Madeline Lancaster's team connected an organoid of the human brain with the spine and back muscles of a mouse. After the nerves of the human organoid connected to the spine, the dorsal muscles began to contract spontaneously.
Most organoids grown in the laboratory reproduce only one part of the brain – the cerebral cortex. But if they are allowed to grow for a long enough time in a special nutrient medium, then human stem cells begin to spontaneously recreate many other parts of the brain, which then begin to coordinate their electrical activity. In an article published in 2017, it is reported that molecular biologist Paola Arlotta from Harvard University managed to turn stem cells into brain organoids consisting of many different cell types, including photosensitive cells similar to those found in the retina of the eye. Under the influence of light, the neurons of the organoids began to activate. But, according to Arlotta, the fact that the cells were activated in the experiment does not mean at all that the organoids have acquired the ability to see the world around them and process visual information. Here we can only say that organoids are able to form the necessary chains.
Arlotta and Lancaster believe that the organoids they have grown are too primitive to have consciousness, because they lack the anatomical structures necessary to obtain an EEG of a complex shape. Nevertheless, Lancaster admits that if we talk about more advanced organoids, then everything depends on what definition is given. "If you think that a fly has consciousness, then it is likely that this can be attributed to an organoid," says Madeline Lancaster.
However, according to Lancaster and most other scientists, an object resembling the brain of a pig, which was revived in the laboratory, is much more likely to have consciousness than an organoid. A team of scientists who studied the pig brain, led by neuroscientist Nenad Sestan, tried to find new ways to revive organs, rather than construct consciousness. The scientists managed to make individual neurons or groups of neurons activate, while the researchers tried to avoid the situation in which the waves produced by the brain would propagate in a wide front. However, as soon as Nenad Sestan's team noticed something resembling coordinated EEG activity in one of the laboratory brain samples, the scientists immediately stopped the experiment. Even after the neurologist confirmed that this EEG activity does not indicate the presence of consciousness at all, the scientists performed brain anesthesia as a precaution.
Nenad Sestan also contacted the US National Institutes of Health (NIH) to consult on further actions. The neuroethics group from this institution, which included Lunshof and bioethicist Insoo Hyun from Case University of the Western Reserve District in Cleveland, Ohio, analyzed the course of the experiments and agreed that Sestan should continue the procedure for brain anesthesia. But the commission did not engage in the development of any universal regulatory rules and regulations; in addition, the commission usually does not analyze projects involving the use of organoids from the point of view of bioethics, since the members of the commission believe that consciousness cannot be constructed. In addition, the NIH has not defined the concept of "consciousness". "It's so elusive that everyone insists on their own definition," says Hyun, "and the lack of clear definitions becomes a big obstacle to scientific discussion."
Fuzzy definitions
Some people think that it is useless even to try to fix some glimpses of consciousness in the brain studied in the laboratory. "It is impossible to say anything definite about such brain cells - whether they are able to think or perceive the world around them or not. And all because we don't understand the nature of consciousness," says neurologist Stephen Lauris from the University of Liege (Belgium), who was the first to use some visualization methods based on measuring consciousness in patients who are in a vegetative state. "We shouldn't be too presumptuous." According to Stephen, further research should be carried out with great caution.
According to Lauris and other scientists, the perception of the surrounding world by an organoid will probably be very different from the perception of the world by a premature baby, an adult or even a pig, they cannot be compared at all in the full sense of the word. Moreover, the internal structures of the organoid may be too small for their activity to be accurately measured at all, and the similarity between the EEG of organoids and the brain of premature babies may be accidental. Other scientists who study brain organoids agree with Lauris that the question of the presence of consciousness in a particular organ may remain open. Many scientists do not take this topic seriously at all. "I do not know why we are asking this question at all, because organoids are not the human brain," says neuroscientist Sergiu Pascha from Stanford University in California. – They are made up of neurons, neurons have electrical activity, but we have to think carefully about how to compare them."
Alisson Muotri wants the organoid systems he has grown to be comparable to the human brain – at least comparable in some sense. This is necessary in order to be able to study human diseases and find ways to treat them. Alisson is personally interested in this, since his 14-year-old son suffers from epilepsy and autism. "He's having a hard time," Muotri says sympathetically. Brain organoids are a promising direction, since they can be used to reproduce the process of forming connections in the brain at the earliest stages of development, because it is clear that it is simply impossible to study these processes in a human embryo. But, according to Alisson Muotri, studying disorders of the human brain and not using a fully functioning brain is like, say, studying the pancreas, which does not produce insulin. "To understand all this, I need a model of the brain organoid, which would really resemble a human one. I may need an organoid that has consciousness."
Alisson Muotri says that he does not know how consciousness can be detected in an organoid. According to Alisson, with the help of organoids, scientists could even understand the mechanism of consciousness generation in the brain. For example, mathematician Gabriel Silva from the University of California in the USA studies the neural activity of organoids obtained by Muotri in order to develop an algorithm describing the mechanism of consciousness generation. The goal of his scientific project, which is partially funded by Microsoft, is to create an artificial system that would work in the same way as human consciousness.
At the moment in The United States or in There are no rules and regulations in Europe that would prevent scientists from constructing consciousness. A group of national academies plans to issue a report early next year, which will give an overview of the latest scientific papers and decide whether it is necessary to specifically regulate research in this area. The members of the group plan to consider, for example, issues such as obtaining a person's consent for brain organoids to be grown from his body cells, as well as questions about the humane study and disposal of organoids. The International Society for the Study of Stem Cells (ISSCR) is also developing guidelines on organoids, but it does not deal with the consciousness of living beings, because it does not believe that science has already come close to this issue.
According to Insu Hyun, no proposals have yet been sent to the NIH Commission on neuroethics concerning the creation of complex organoids with consciousness, for which it would be necessary to develop some new guidelines. According to Alisson Muotri, Hen knows nothing about anyone trying to intentionally create such organoids, although some rather complicated organoid could, from the point of view of some definitions, accidentally turn into an organoid with consciousness.
Nevertheless, Alisson Muotri and other experts claim that they would accept some recommendations with approval, for example: the requirement for scientists to justify a certain number of human brain organoids taken for study; in addition, scientists should use them only in laboratory studies that cannot be carried out in any other way, as well as limit the painful effect on the organoid and dispose of them in a humane way.
The presence of such recommendations will help scientists to weigh in advance all the cons and pros associated with the creation of entities with consciousness. Many scientists emphasize that such experiments have great potential from a scientific point of view. "We do have patients with neurological disorders who are not receiving treatment," says Madeline Lancaster. "If we stopped all these studies because of our philosophizing, it would have an extremely detrimental effect on ordinary patients, for whose treatment it is really necessary to use new therapies."
However, new treatment methods can still be tested on brain organoids obtained using mouse stem cells, or on conventional animal models. In addition, such experiments will initiate a discussion about the ethics of using human organoids. For example, Insu Hyun would like scientists to tackle the problem of comparing the EEG of mouse brain organoids with the corresponding EEG of the brain of living mice; thanks to this, specialists will finally be able to judge how adequately human organoids reproduce the human brain.
For his part, Alisson Muotri does not see much difference in the study of human organoids and laboratory mice. "We work with animal models that have consciousness, and there are no difficulties here," says Alisson. – We need to move forward. And if it turns out that they suddenly have consciousness, then, to be honest, I don't see that as a big problem."
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