Cellular tragedies, part 4
Who to be?
Polina Loseva, "The Attic"
The inner life of the cell is eventful no less than the human one. It is full of passions and dangers and just as inevitably ends in death. Polina Loseva understands what plots occur in the fate of cells and how their development affects you and me. We have come to a key event in everyone's life, be it a cell or a person – self-determination and the choice of a life path.
"Cellular tragedies" is a large series of articles about cells, which continues to be replenished. Read other texts about the difficult life of cells: they tell about deaths and suicides, stress and shock.
Most cells in an adult organism are differentiated, that is, they are specialists in a specific narrow field. And if a person's professionalism is determined by a set of specific skills, knowledge and experience, then the specialization of a cell depends on its protein composition (skills), a set of genes working in it acts as knowledge, and experience (as in humans) – this is the story of her interactions with the environment. How does the body educate a professional in a cell? Can we borrow from him some pedagogical methodology for modern cellular technologies? Let's watch.
Narrowing the horizons
Cells devoid of specialization are called undifferentiated, or stem cells. Let's imagine the most non–specialized cell in the world - the zygote, from which the whole organism will then develop. Any knowledge is available to her and her closest descendants, that is, any genes can be started in them. They are – let's use a metaphor from a neighboring text here – like middle school students. Everyone has the opportunity to study any discipline and choose any profession. He has books (genes) in all possible directions in his bookcase (core). However, time passes, and under the influence of parents and teachers "dripping on the brain", the student begins to specialize. He chooses a profile in which some subjects will be studied more intensively than others. If the profile is, say, natural science, then the humanities cease to be necessary for him and he pushes the corresponding books deep into the closet. This knowledge is no longer available to him. At the cell level, this means that the DNA regions carrying information about "unnecessary" genes are twisted, and the cell can no longer read this information. For example, a cell faces a choice: to become part of a bone or muscle. If a cell chooses the path of bone, then it will not need muscle proteins, and therefore, the genes encoding them will not be needed. Then the DNA section with these genes will tightly curl up and become inaccessible.
Germ cells consistently make a series of "decisions", each of which narrows the range of genes available to them. Specialized classes at school are followed by more narrowly focused examinations to higher educational institutions, and there you already have to choose the final profession. And as a result, we have narrow specialists who possess only a small set of knowledge, and textbooks on all other disciplines are pushed deep into the bowels of the cabinet. Therefore, differentiated cells can be easily distinguished from stem cells in photographs by dark nuclei in which a significant part of the DNA is twisted.
Small cell lung carcinoma. Tumor cells (indicated by arrows) are easily distinguished from lung cells by the size and color of the nucleus: differentiated cells have small and dark nuclei. Image: Yale Rosen, Flickr, CC BY-SA 2.0
Parenting Manual
Modern medicine is very interested in learning how to purposefully educate professionals, i.e. to obtain specific types of cells from stem cells. But what should I do, what keywords should I say so that the student chooses the right specialty exactly? For more than a century, the search for factors under the influence of which cells differentiate during the development of the embryo has been going on. So far, we have learned to influence the fate of cells in the following ways.
1) Bring to the workplace. We take the student by the hand and bring him to a room equipped for work. Now you're in the shop, here's your machine, and you'll figure out what to do yourself.
Most cells in the embryo are attached to something, and usually it is a matrix, an extracellular molecular network. It sets the shape of the cell (round or flattened), and by changing its hardness, different tissues can be obtained from stem cells. Recently, cell cultivation in a three-dimensional matrix has become popular (that is, schoolchildren are brought not to a separate workshop, but to a real factory). It is believed that this better simulates the real situation in the body.
2) Hook up with colleagues. You don't know who you are yet and why you're here, but the person on your left is cutting tomatoes, the person on your right is rolling out dough in circles. You start to suspect something.
Cells in an adult organism are surrounded by neighboring cells of both their own and other types. Therefore, it is possible to achieve differentiation in the right direction by cultivating stem cells together with already specialized cells.
3) Hand over the working tool. Hold the violin, hold the bow, half an hour of convulsions – and maybe something will turn out.
In addition to the matrix scaffold proteins, there are constantly many molecules secreted by cells in the intercellular space. These can be products of their metabolism or signaling molecules. The exact list of these substances is usually unknown. However, it is often found that they affect the differentiation of stem cells. Therefore, you can first grow a culture of specialized cells, for example, neuroglia (accompanying cells of nervous tissue), after a while collect the culture fluid and act on stem cells with it, simulating interactions in the tissue.
4) Make motivational speeches (aka "drip on the brain"). Sometimes it is enough to choose the right words to achieve the desired effect. With due passion to ask: "Have you signed up as a firefighter?" – or something like that.
In some cases, we know exactly the signaling molecules that trigger cell differentiation. If their concentration is quite high, then they can be isolated from the tissues of the developing embryo and determine the composition. For example, retinoic acid (a relative of vitamin A) is used in the differentiation of nerve cells.
However, it is worth remembering that any upbringing works only in the appropriate context. Retinoic acid, already familiar to us, can lead to the formation of not only neurons, but also endothelial cells (vascular walls) and pancreas, depending on other signals used. If you have armed a future professional with a knife, then he will start cutting, but he will turn out to be a cook, a surgeon or a cutter – it depends on the environment.
During differentiation, cells change greatly even externally. From left to right: (1) embryonic stem cells, (2) nerve cell precursors, (3) nerve tissue. Images: Nissim Benvenisty (Vojtech. dostal retouching); National Institutes of Health (NIH); GerryShaw / Wikimedia commons / CC BY-SA 3.0
Tips for parents
So, we have already armed ourselves with a set of pedagogical techniques. It remains to understand how to combine them. Imagine yourself in the place of a parent concerned about the future profession of a child. You really want to raise, say, a doctor. But what and in what sequence should I tell the child and where to take him so that he definitely decides to become a doctor? You can find a doctor among your friends, find out what exactly influenced his life choice, and try to repeat this path with a child. This is roughly how classical laboratory differentiation protocols are arranged: we observe the processes that occur in the embryo, sequentially isolate the factors acting on cells, and then reproduce the process in cell culture. This pathway is now called indirect differentiation, since in this case the cell goes through many intermediate stages. Let's say your doctor friend Vasily told his life story: he graduated from school, went to college to become an electrician, then did not find a job, served in the army, returned, did not find a job again, worked as a taxi driver, then got a job as an ambulance driver, Vasily liked it there, and he learned to be a paramedic. Should a child go through all these stages to achieve a result? So the cell does not have to fully repeat the ways that its analogues follow in the development of the embryo.
Recently, scientists have begun to actively develop methods of direct differentiation, that is, accelerated cell learning. If we study the mechanisms of determining cell fate for a long time, we can identify key transcription factors for each cell type – proteins that trigger the work of a whole group of genes. Under the influence of these proteins, an area of DNA with information necessary for a particular type of cell begins to be actively used, and the rest is twisted for uselessness. The essence of direct differentiation is to forcibly start the work of these factors in cells. A convenient way is to introduce the genes encoding these factors from the outside – then they will work more actively. That is, the parent needs to put a specific thought into the child's head – "You will be a programmer!" – and repeat it every day, like a mantra, until the child comes to terms with this fact and actually becomes a programmer. And despite the fact that pedagogy tends to distrust such methods of working with young people, at the cellular level, as it turned out, they work perfectly and allow you to achieve your goals faster and more efficiently. So it's good, perhaps, that we are not cells.
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