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How researchers study the human brain in isolation from the body
How researchers study the human brain in isolation from the body

How scientists create models of the human brain and what ethical issues such research raises.

How researchers study the human brain in isolation from the body
How researchers study the human brain in isolation from the body

The journal Nature published The ethics of experimenting with human brain tissue, a collective letter from 17 leading neuroscientists in the world, in which scientists discussed progress in the development of human brain models. The fears of specialists are as follows: probably in the near future the models will become so advanced that they will begin to reproduce not only the structure, but also the functions of the human brain.

Is it possible to create "in a test tube" a piece of nervous tissue that has consciousness? Scientists know the structure of the brain of animals in the smallest detail, but still have not figured out which structures "encode" consciousness and how to measure its presence, if we are talking about an isolated brain or its similarity.

Brain in the aquarium

“Imagine waking up in an isolated sensory deprivation chamber - there is no light, no sound, no external stimuli around. Only your consciousness, hanging in the void."

That’s the picture of ethicists commenting on a statement by Yale University neuroscientist Nenad Sestan that his team was able to keep an isolated pig brain alive for 36 hours.

The Researchers are keeping pig brains alive outside the body report of a successful experiment was made at a meeting of the Ethics Committee of the US National Institutes of Health in late March this year. Using a heated pump system called BrainEx and a synthetic blood substitute, the researchers maintained fluid circulation and oxygen supply to the isolated brains of hundreds of animals killed in a slaughterhouse a couple of hours before the experiment, he said.

The organs remained alive, judging by the persistence of the activity of billions of individual neurons. However, scientists cannot say whether the pig brains placed in the "aquarium" retained signs of consciousness. The lack of electrical activity, tested in a standardized way using an electroencephalogram, convinced Sestan that "this brain is not worried about anything." It is possible that the isolated brain of the animal was in a coma, which, in particular, could be facilitated by the components of the solution washing it.

The authors do not disclose the details of the experiment - they are preparing a publication in a scientific journal. Nevertheless, even Sestan's report, poor in details, aroused great interest and a lot of speculation on the further development of the technology. It appears that preserving the brain is not much more difficult technically than preserving any other organ for transplant, such as the heart or kidney.

This means that theoretically it is possible to preserve the human brain in a more or less natural state.

Isolated brains could be a good model, for example, for researching drugs: after all, existing regulatory restrictions apply to living people, and not to individual organs. However, from an ethical point of view, many questions arise here. Even the question of brain death remains a “gray area” for researchers - despite the existence of formal medical criteria, there are a number of similar conditions, from which a return to normal life activity is still possible. What can we say about the situation when we assert that the brain remains alive. What if the brain, isolated from the body, continues to retain some or all of the personality traits? Then it is quite possible to imagine the situation described at the beginning of the article.


Where is consciousness hiding

Despite the fact that up to the 80s of the XX century among scientists there were supporters of the theory of dualism, which separates the soul from the body, in our time even philosophers studying the psyche agree that everything that we call consciousness is generated by the material brain (history The question can be read in more detail, for example, in this chapter Where is consciousness: history of the issue and perspectives of search from the book of Nobel laureate Eric Kandel "In Search of Memory").

What's more, with modern techniques such as functional magnetic resonance imaging, scientists can track which areas of the brain are activated during specific mental exercises. Nevertheless, the concept of consciousness as a whole is too ephemeral, and scientists still do not agree on whether it is encoded by a set of processes occurring in the brain, or whether certain neural correlates are responsible for it.

As Kandel says in his book, in patients with surgically separated cerebral hemispheres, consciousness is split into two, each of which perceives an independent picture of the world.

These and similar cases from neurosurgical practice indicate at least that for the existence of consciousness, the integrity of the brain as a symmetrical structure is not required. Some scientists, including the discoverer of the structure of DNA Francis Crick, who at the end of his life became interested in neuroscience, believe that the presence of consciousness is determined by specific structures in the brain.

Maybe these are certain neural circuits, or maybe the point is in the auxiliary cells of the brain - astrocytes, which in humans, in comparison with other animals, are rather highly specialized. One way or another, scientists have already reached the point of modeling individual structures of the human brain in vitro (“in vitro”) or even in vivo (as part of the brain of animals).

Wake up in a bioreactor

It is not known how soon it will come to experiments on whole brains extracted from the human body - first, neuroscientists and ethicists must agree on the rules of the game. Nevertheless, in laboratories in Petri dishes and bioreactors, the rise of three-dimensional human brain cultures are already growing “mini-brains” that mimic the structure of the “large” human brain or its specific parts.


In the process of development of the embryo, its organs are formed up to certain stages according to some program inherent in the genes according to the principle of self-organization. The nervous system is no exception. The researchers found that if differentiation into cells of the nervous tissue is induced in stem cell culture with the help of certain substances, this leads to spontaneous rearrangements in cell culture, similar to those that occur during morphogenesis of the embryonic neural tube.

Stem cells induced in this way "by default" differentiate ultimately into neurons of the cerebral cortex, but by adding signaling molecules from outside to a Petri dish, for example, cells of the midbrain, striatum or spinal cord can be obtained. It turned out that an intrinsic mechanism of corticogenesis from embryonic stem cells can be grown in a dish, a real cortex, just like in the brain, consisting of several layers of neurons and containing auxiliary astrocytes.

It is clear that two-dimensional cultures represent a highly simplified model. The self-organizing principle of nerve tissue helped scientists quickly move to three-dimensional structures called spheroids and cerebral organelles. The process of tissue organization can be influenced by changes in initial conditions, such as initial culture density and cell heterogeneity, and by exogenous factors. By modulating the activity of certain signaling cascades, it is even possible to achieve the formation of advanced structures in the organoid, such as the optic cup with the retinal epithelium, which reacts Cell diversity and network dynamics in photosensitive human brain organoids to light.


The use of a special vessel and treatment with growth factors allowed scientists to purposefully obtain Modeling human cortical development in vitro using induced pluripotent stem cells - a human cerebral organoid corresponding to the forebrain (hemispheres) with a cortex, the development of which, judging by the expression of genes and markers, corresponded to the first trimester of fetal development …

And scientists from Stanford, led by Sergiu Pasca, have developed Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture, a way to grow clumps that mimic the forebrain right in a Petri dish. These “brains” are about 4 millimeters in size, but after 9–10 months of maturation, cortical neurons and astrocytes in this structure correspond to the postnatal level of development, that is, the level of development of the baby immediately after birth.

Importantly, stem cells for growing such structures can be taken from specific people, for example, from patients with genetically determined diseases of the nervous system. And the advances in genetic engineering suggest that scientists will soon be able to observe in vitro the development of the brain of a Neanderthal or Denisovan.

In 2013, researchers from the Institute for Molecular Biotechnology of the Austrian Academy of Sciences published an article Cerebral organoids model human brain development and microcephaly, describing the cultivation of a "miniature brain" from two types of stem cells in a bioreactor, which mimics the structure of the entire human brain.

Different zones of the organoid corresponded to different parts of the brain: posterior, middle and anterior, and the “forebrain” even showed further differentiation into lobes (“hemispheres”). Importantly, in this mini-brain, which also did not exceed a few millimeters in size, scientists observed signs of activity, in particular fluctuations in the concentration of calcium inside neurons, which serve as an indicator of their excitation (you can read in detail about this experiment here).

The goal of the scientists was not only to reproduce the evolution of the brain in vitro, but also to study the molecular processes leading to microcephaly - a developmental abnormality that occurs, in particular, when an embryo is infected with the Zika virus. For this, the authors of the work have grown the same mini-brain from the cells of the patient.


Despite the impressive results, scientists were convinced that such organelles were incapable of realizing anything. First, the real brain contains about 80 billion neurons, and the grown organoid contains several orders of magnitude less. Thus, a mini-brain is simply not physically capable of fully performing the functions of a real brain.

Secondly, due to the peculiarities of development "in vitro", some of its structures were located rather chaotically and formed incorrect, non-physiological connections with each other. If the mini-brain thought anything, it was clearly something unusual for us.

In order to solve the problem of the interaction of departments, neuroscientists have proposed to model the brain at a new level, which is called "assembloids". For their formation, organelles are first grown separately, corresponding to individual parts of the brain, and then they are merged.

This approach scientists used the Assembly of functionally integrated human forebrain spheroids to study how the so-called interneurons are incorporated into the cortex, which appear after the formation of the bulk of neurons by migration from the neighboring section of the forebrain. Assembloids obtained from two types of nerve tissue have made it possible to study disturbances in the migration of interneurons in patients with epilepsy and autism.

Wake up in someone else's body

Even with all the improvements, the brain in a test tube is severely constrained by three fundamental conditions. First, they do not have a vascular system that allows them to deliver oxygen and nutrients to their internal structures. For this reason, the size of mini-brains is limited by the ability of molecules to diffuse through tissue. Secondly, they do not have an immune system, represented by microglial cells: normally these cells migrate to the central nervous system from the outside. Third, a structure growing in solution does not have a specific microenvironment provided by the body, which limits the number of signaling molecules that reach it. The solution to these problems could be the creation of model animals with chimeric brains.

The recent work An in vivo model of functional and vascularized human brain organoids by American scientists from the Salk Institute under the direction of Fred Gage describes the integration of a human cerebral organelle (that is, a mini-brain) into the brain of a mouse. In order to do this, the scientists first inserted a gene for a green fluorescent protein into the DNA of stem cells so that the fate of the developing nervous tissue could be observed using microscopy. Organoids were grown from these cells for 40 days, which were then implanted into a cavity in the retrosplenal cortex of an immunodeficient mouse. After three months, 80 percent of the animals had the implant engrafted.

The chimeric brains of the mice were analyzed for eight months. It turned out that the organoid, which could be easily distinguished by the luminescence of a fluorescent protein, successfully integrated, formed a branched vascular network, grew axons and formed synapses with the nerve processes of the host brain. In addition, microglia cells have moved from the host to the implant. Finally, the researchers confirmed the functional activity of the neurons - they showed electrical activity and fluctuations in calcium. Thus, the human "mini-brain" fully entered the composition of the mouse brain.


Surprisingly, the integration of a piece of human nerve tissue did not affect the behavior of the experimental mice. In a test for spatial learning, mice with chimeric brains performed the same as normal mice, and even had worse memory - the researchers explained this by the fact that for implantation they made a hole in the cerebral cortex.

Nevertheless, the goal of this work was not to obtain an intelligent mouse with a human consciousness, but to create an in vivo model of human cerebral organelles equipped with a network of vessels and microenvironments for various biomedical purposes.

An experiment of a completely different kind was staged by Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice by scientists at the Center for Translational Neuromedicine at the University of Rochester in 2013. As mentioned earlier, human accessory cells (astrocytes) are very different from those of other animals, in particular mice. For this reason, researchers suggest that astrocytes play an important role in the development and maintenance of human brain function. To test how a chimeric mouse brain would develop with human astrocytes, the scientists planted helper cell precursors in the brains of mouse embryos.

It turned out that in a chimeric brain, human astrocytes work three times faster than mice. Moreover, mice with chimeric brains turned out to be significantly smarter than usual in many ways. They were quicker to think, learn better, and navigate the maze. Probably, chimeric mice did not think like people, but, perhaps, they could feel themselves at a different stage of evolution.

However, rodents are far from ideal models for studying the human brain. The fact is that human nervous tissue matures according to some internal molecular clock, and its transfer to another organism does not accelerate this process. Considering that mice live only two years, and the full formation of a human brain takes a couple of decades, any long-term processes in the format of a chimeric brain cannot be studied. Perhaps the future of neuroscience still belongs to human brains in aquariums - in order to find out how ethical it is, scientists just need to learn how to read minds, and modern technology, it seems, will soon allow this to be done.

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