We are used to thinking of ourselves as a finished product. The finish, perhaps, is not exactly what we would like, but there is no getting around it. From one fertilized egg, we develop in the process of sequential formation of cells and tissues until we come to this world, tearing ourselves up in screaming and drooling. And from that moment on, a long and ordinary story begins, which ends without teeth, "without eyes, without taste, without everything."
But this old-time Shakespearean story about withering, decrepitude, decay and, as a result, oblivion is no longer an accurate reflection of reality. We now have the means to repair and replace damaged tissue. I speak from personal experience. Over the past few months, I have watched as a piece of my flesh that was cut from my hand turned into a structure called an "organoid," a miniature organ. In my case, it has become what some call a mini-brain - it is about the size of a frozen pea and exhibits many of the hallmarks of a real brain that grows in an intrauterine fetus. I have seen evidence that neurons in such tissue can fire flashes, sending signals to each other. It would be too poetic to call these signals thoughts,but they are the "substance of thought."
My flesh could be something else if scientists made that decision. It could become an organoid of the kidney, or a structure similar to some part of the heart or pancreas. It could turn into a light-sensitive tissue like the retina. Based on the available evidence, it has been established that she could become an egg, or a sperm, or something like a real embryo, the beginning of a living being. She could become any part or all parts of "me". Consequently, there is a technology that allows you to stir up fantasies and plant a tempting idea to cheat death by restoring a sick organism or even creating a new one, grown in the laboratory, "to replace" the old one.
In the year of the 200th anniversary of the release of Mary Shelley's novel Frankenstein, it would be easy to imagine everything grotesque, if not apocalyptic. Let's say we imagine people grown to order in flasks like the Central Hatchery in Aldous Huxley's dystopian novel Brave New World. But my mini-brains (there are several of them) were grown for a good cause. They are part of the Created Out of Mind project, funded by the Wellcome Trust, an independent international charity, which aims to expand our knowledge of dementia and the principles of caring for those who suffer from it. The researchers who created these organelles are studying the genetic basis of the neurodegenerative disorders that cause dementia. My mini-brain will be used in this study, which means it will probablywill someday help slow down the process of brain shutdown in other people.
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There are animals, such as the salamander, that are able to restore an entire lost limb, consisting of tissues of many types. Our human body is able to regenerate skin when small wounds heal, but otherwise, it is at best able to create only separate small "patches" of rough scar tissue. But if an organ fails, it cannot be restored and dies. We can survive with a donor graft or with a mechanical prosthesis. But growing tissue to obtain various types of cells and, possibly, as a result, whole miniature organelles now makes it possible to make the ability of regeneration, which, for example, a salamander has, available to humans. These techniques not only have overwhelming potential in medicine, but they also refute the beliefs that have been formed over the years.
If this sounds horrible and discouraging, it is only because we have not internalized the truth that Frankenstein forced us to look into the eyes of. This truth is that we are made of matter, and that matter somehow transcends itself and creates a mind peeking out of its shell. We still do not know where in this creature, made of flesh, is his essence, his "I". The new sciences of "cellular reprogramming" are shaking ideas about it like never before - in the form in which they are ingrained in my consciousness, literally intuitively.
Last July, scientists at the Institute of Neurology at University College London (UCL) excised a small piece of soft tissue from my right shoulder. This was done under mild local anesthesia and I felt nothing. Cells from the subcutaneous layer were an important element of this biopsy. They are called fibroblasts and are the main "sources" of connective tissue in the body. They form the skin and are key cells involved in wound healing. UCL neuroscientists Selina Wray and Christopher Lovejoy took fibroblasts from me and placed them in small petri dishes with red solution containing nutrients necessary for cell growth to reproduce.
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Two months later, I was able to look through a microscope at a fibroblast colony growing from the dark mass of a piece of tissue in my hand. These elongated cellular structures sprout out of the tissue in even rows, as if aiming somewhere.
So how truly new was what I saw? In our time, the basic ability to grow cells in culture is an art long known. It should be admitted that it was once considered a miracle of particular mystery. When in 1912 the French surgeon Alexis Carrel first announced that he had grown "immortal" cells from the tissue of a chicken heart, newspapers began to print sensational articles that death was no longer inevitable. These sensational articles turned out to be grossly exaggerated. But growing a "mini-brain" from cells taken from my skin is a completely different undertaking from the usual cultivation of harvested cells.
Ray and Lovejoy will have to transform my skin fibroblasts into neurons - brain cells. They do this in two steps. First, they will turn them into a cell that can create any tissue during development, and then direct them so that they turn into cells of the required type. To understand how this happens, you should know that all living cells in the human body contain the same complete set of "instructions" - encoded in DNA, which are located in 23 pairs of chromosomes and are divided into sections called genes, each of which performs in our biochemical processes a specific function. Basically, each cell has the same complete code as all the others. Of course, in a mature organism, different types of cells actually perform different tasks. For this, different genes are “turned on” and “turned off”. It is with such a switch that a cell of one type is formed (brain, skin, muscles, liver cells, and so on), and not another.
Much of this gene switching (or "regulation") is carried out by protein molecules called transcription factors. They are themselves encoded in genes: that is, the genome itself contains instructions for creating the transcription factors that regulate it. To regulate the activity of genes, our cells create different transcription factors all the time. Due to this, different types of cells behave differently. In addition, by switching genes, one fertilized egg can turn into an organism composed of many different tissues.
The earliest cells in a growing embryo, called embryonic stem cells, can evolve into any kind of tissue: they are said to be “pluripotent,” and we can say that they still contain all their genetic potential. But as the embryo develops into a fetus, and then into a child, cells begin to differentiate into cell types with a specific function - heart, liver, brain cells - in an organized way and in the right place.
We can interfere with the programming of cell behavior. For example, in the case of gene therapy, the goal of which is to fix a “defective” gene by adding to the cells an additional, small piece of DNA that encodes a normally functioning form of that gene.
But growing a "mini-brain" from tissue cut from my hand requires something more impressive than just "fixing" some of the cell's genetic instructions. This process begins with a complete "reboot" of the cell's program - most likely, resetting all those on / off switches that define the cell's specific purpose. It turns out that this can only be done with the help of a few specific transcription factors. Ray and Lovejoy insert genes that encode and produce these factors - small pieces of DNA - into cells taken from my hand using weak electric fields. Under their influence, holes are formed in the cell membranes for some time through which additional DNA can slip.
With the help of these biochemical "messages" sent by Lovejoy and Ray to my fibroblasts, these cells returned to the state of stem cells, similar to cells of an early embryo, capable of transforming into tissues of any type. They are called induced pluripotent stem cells. Scientists have been obtaining them from human cells since 2007. Until then, most experts considered it impossible.
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The person who changed the mind on this problem was the Japanese scientist Shinya Yamanaka. He did not work in the field of cell biology, but in clinical medicine and, probably, that is why it was easier for him to think about something incredible and think about whether it is possible to reprogram already differentiated cells into stem cells.
As early as the 1960s, experiments on frogs provided the first data indicating that cell fixation could be canceled. British biologist John Gurdon took frog eggs, removed chromosomes from them and inserted chromosomes taken from cells of adult frogs. These eggs, as it turned out, then could be fertilized and grown from them tadpoles and frogs. Chromosomes, which in adult cells were regulated (by all these chemical switching on and off) to perform certain functions, apparently rejuvenated inside the eggs, so that they could again direct the growth of all kinds of new animal tissues. This method of transferring chromosomes from adult cells was used in 1996 to clone Dolly the sheep.
Given the previously successful results, Yamanaka began to analyze the transcription factors that were produced in embryonic stem cells. Perhaps, instead of figuring out what exactly happened to the chromosomes of differentiated cells, capturing specific patterns of their gene activity, and then trying to reverse all this, it is enough just to add a new dose of these factors to "convince" the cells that they are stem cells? This hypothesis seemed speculative, but it worked. Yamanaka discovered that if genes encoding some of these factors were added to differentiated human cells (in the end, it turned out that only four were enough), these cells returned to a state similar to stem cells.
Thanks to this discovery, it became possible to create tissues and, possibly, entire organs in the laboratory. If you grow tissues or organs from the recipient's own cells (say, from fibroblasts in a tissue sample taken from my hand), then no problems that arise due to the rejection of the donor graft by the immune system will not arise. Moreover, it would be possible to test drugs for toxicity on artificially grown human tissues - without conducting tests on animals. The fact is that animal tests not only give ambiguous results, they also cannot always be applied, since other living organisms are not always suitable for testing a human response.
The practical potential of this discovery was enormous. But besides this, Yamanaka discovered a more important truth. Our tissues and bodies are more flexible than we thought. Your soft tissues and bones can be transformed into other types of tissue. Bone can be created from breast cells, and brain from blood cells. It suddenly became clear that the entire immutability of the structures of the human body was questioned.
Take your time though, something even weirder is waiting for you.
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Just before Christmas, six months after the start of our experiment, Ray and Lovejoy showed me stem cells obtained from my fibroblasts. Those oblong formations that I saw before have disappeared. There were now compact clusters of smaller cells in the nutrient solution dish. Using molecular markers that stick to specific proteins and glow in different colors when light is directed at them, scientists were able to show that genes specific to stem cells are now turned on. The first stage was completed; the next step was to get the cells to turn into neurons.
Typically, stem cells should be targeted to transform into a specific type of tissue using chemical triggers - for example, by adding more transcription factors specific to the target cells. But creating neurons is relatively easy, as they seem to be the default: if stem cells in the laboratory begin to differentiate spontaneously, the chances are high that they will turn into neurons. In fact, I saw some signs of this even in my own tissue sample. Here and there, one could see single cells detached from the compact cluster. I noticed that one of these lone cells began to sprout - long, thin branches that nerve cells have and that usually end in synapses, where these neurons transmit electrical signals to each other.
If these induced stem cells simply turned into clusters of identical neurons, there would be little reason to call the resulting tissues "mini-brains". Our brains are not like that at all. They are complex structures containing several different types of neurons that produce electrical signals. Other brain cells are not neurons - for example, glial cells that help structure the brain and perform supporting, protective, trophic, and other functions. There are also neural stem cells - partially differentiated stem cells that are focused on creating different types of brain cells that provide the brain with the ability to adapt to changing circumstances - and sometimes partially restore impaired functions.
Along with the question of the diversity of cells in the brain tissue, the question arises of how they all work. The brain contains various structures and, remarkably, the mini-brain replicates some of them. This organization of tissue suggests that neurons and other types of brain cells themselves "know" how to organize themselves to form the brain. Sometimes this alignment of cells involves the actual movement of the cell: cells move around each other to find their correct place - usually next to other cells of their type. But such “self-assembly” requires landmarks, and the organs developing in the embryo use the surrounding tissues as a system of landmarks. Brain cells, for example, need such signals in order to know where the brain stem should "grow", or to distinguish the forebrain from the back.
The mini-brain has a certain structure, but it does not take on quite the correct shape. For example, it forms medullary tubes - but if only one of them appears and moves down the spine in a real embryonic brain to create a central nervous system, the mini-brain forms several tubes at random - it is as if it is looking for a spine that does not exist.
For this reason, some scientists rightly object to calling a neural organoid a "mini-brain." But if organelles are not brains in the truest sense of the word, they "do" everything they can to become them. And the scientists involved in creating them are likely to create structures that are truly more like the brain, once they find ways to mimic some of the "orientation" directions in a petri dish.
My mini-brain has no such advantages - it will be just a rough sketch of the brain. But, one way or another, he is alive. And neurons can communicate with each other by sending electrical signals. Ray plans to demonstrate this using special methods to detect bursts of calcium ions released at the junctions of synapses, similar to those seen in the tissue of the real brain. I personally don't care that these are "thoughts." What worries me more is that everything currently happening in my (real) brain is the result (as far as we know) of just such a process.
Growing organelles such as mini-brains outside the body is potentially only the first step in the body's regeneration. The ability to grow tissue in the laboratory seems useful and even vital - imagine a pancreas grown in a laboratory from diabetic cells, but genetically "edited" and capable of producing insulin. But fully formed organs need blood supply, and we do not know how to provide it in cell culture in the laboratory. And some tissues grown in cell culture, such as brain tissue or heart muscle, cannot be simply put in place - they must be fully integrated into existing cell systems. And we also don't know how to do this.
True, now scientists are studying the possibility of growing new tissues directly inside the body. To do this, one could use the same methods that are used to reprogram cells to return to a state similar to the state of stem cells, and then direct them to acquire new characteristics. This "in vivo reprogramming" has already been carried out in experiments on mice - liver cells are converted, for example, into pancreatic cells, or cardiac fibroblast cells - into pacemaker cells.
But the two-step process of converting a normal cell into a stem cell, and then into another type of cell, proposed by Ray and Lovejoy, is fraught with risks if you do it directly in the body. Stem cells, which are capable of converting into various tissues, can be prone to converting to cancer cells. But, remarkably, scientists found that with the right combination of transcription factors and molecular signals, they could "skip" the stem cell stage, that is, the pluripotency stage, and switch one type of mature cell directly to another. Let's say create neurons directly from blood cells. Instead of delaying the development of cells and then restarting their development in a different direction, you simply jump to the side and switch to another type of tissue. Animal testing is encouragingand now the question of conducting clinical trials on humans in the regeneration of damaged heart muscle is being resolved.
The possibilities for this kind of reprogramming of cells within the body are staggering. Our body will someday acquire the ability to regenerate - like those salamanders that restore their lost limbs. Areas of the brain damaged by trauma or disease, such as Alzheimer's, can be repaired by selecting non-neuronal brain cells (such as glial cells) and converting them into functioning neurons. And since these cells are created in the place of their original localization, at least it is possible that they will integrate better into the surrounding cellular system. In any case, this happens when the heart muscle is reprogrammed - it contracts in sync with the rest of the heart.
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In addition to the potential applications in medicine, these discoveries suggest the need to reconsider your understanding of a living organism. If the liver can become a muscle, blood can become a brain, and skin can be turned into bone tissue, how should we then think about our mortal life and departure to another world? Of course, wounds can heal, hair can grow back - but we have already come to believe that we have only one body. But when cells become fully universal and able to adapt, it is no longer entirely clear if this is actually the case.
What, then, is the human essence - the biological "I"? This is clearly not what genetic testing companies like 23andMe insist that “makes you who you are,” but your unique genetic sequence. You have become who you are only because of the way in which this genetic sequence in different cells was limited and selectively activated: the process of disclosing, interpreting and modifying genetic information. Keep in mind that your genome lacks the information that completely defines “you,” with all your quadrillions of unique neural connections, formed by unforeseen circumstances and experiences as you develop and grow.
Do I really have multiple "brains" or at least "brain-like structures" now? I still don't know how to relate to this. I believe that I could, in principle, have a "spare" heart or liver created in this way. But, in my opinion, the brain is too tied up with experience, memory, emotions and character to consider any other organ other than my own as the container of my “I”. The idea of a "second brain" (even if you don't take into account the extremely "abnormal" nature of my mini-brain) is not very clear and does not make much sense.
I think this is a relief. After all, once these organelles have fulfilled their role in Ray's research, they will be thrown away. And I do not think that I will feel that any part of my "I" will disappear with them. However, it is still strange and disturbing to observe what a part of me, chosen quite randomly, can turn into in laboratories in central London. It's hard for me not to come to the conclusion that there is a kind of "meta-me", that is, all the tissues that could be created from this very first fertilized egg, which revived in the womb in October 1962 (in my case) … I am just one of the incarnations of this "meta-me". My boundaries of personality seem to be a little more blurred than then.
What if the process of growing a mini-brain becomes even more perfect even before we can provide it with the blood supply and coordinates to properly organize it into a coherent whole - before we can create something very similar to a full-fledged brain? At the moment, this is purely (forgive me) thought experiment: we simply have no opportunity, let alone motivation or moral justification. But it is certainly possible. What moral and ontological status would a brain have in a Petri dish? If the person whose cells were used to create it died after that, would they “live on” in the Petri dish? Should we at some point ask ourselves the question: who is there?
Philip Ball