22 October 2018

Brain to order

The receptacle of the mind was grown from cells

Alexey Aleksenko, Forbes, 21.10.2018

The new technology allows the mammalian embryo to replace its own brain with a new organ grown from the stem cells of another creature. The method opens up great opportunities for the study of the nervous system.

Researchers from the University of California (San Francisco) and the Howard Hughes Medical Institute (Harvard, Massachusetts) have proposed a way to grow a mammalian brain from stem cells (Chang et al., Neural blastocyst complementation enables mouse forebrain organogenesis //Nature 2018).

To begin with, apparently, it is necessary to explain why they might need it. The idea of growing a new brain for yourself, if the old one does not suit you (or your employer) for some reason, may seem attractive only at first glance. However, in fact, this scientific work opens up new perspectives mainly for researchers studying brain development and the functions of various genes in this process.

The traditional approach of geneticists to studying the function of any gene is to try to change or even destroy this gene and see what will change in the life of the organism or in the functioning of some of its organs. Of course, such experiments are carried out not on humans, but on laboratory model organisms, for example, mice. Usually, the study of a mammalian gene, including a human, begins with the breeding of a line of mice in which a similar gene is changed. How to get such a line?

Mammals are multicellular organisms originating from a single cell, and it would be logical to start obtaining a genetically modified organism from this cell. However, genetic manipulation of a fertilized mammalian egg is quite difficult. Therefore, in practice, researchers most often go the other way: the required genetic changes are made to embryonic stem cells growing in culture. Then these cells are injected into the developing mouse embryo at the blastocyst stage – a hollow ball of cells (the human embryo passes this phase on the fifth or sixth day after fertilization, even before attachment to the uterine wall). Stem cells become part of the embryo, and as a result, a "chimeric" organism is formed: some of its cells are descendants of a genetically modified line introduced into the blastocyst, and the rest trace their history from a fertilized egg.

Then, in order to obtain an organism consisting entirely of cells of the required genotype, mice are crossed among themselves to obtain a clean line. This method is quite time-consuming. To facilitate the procedure, Dr. Frederick Alt (one of the co-authors of the work in question here) proposed an elegant solution a quarter of a century ago. If the cells of the embryo, from which one or another organ will later develop, are destroyed, then their place can be completely occupied by injected stem cells genetically modified for research purposes. Thus, all cells of this organ (and not part of them) will carry the required genetic features, and there will be no need for a laborious stage – several rounds of crossing mice.

Then, in 1993, Frederick Alt demonstrated this possibility on cells of the immune system. Later, this approach was used to regenerate the genetically modified lens of the eye, kidney, heart and pancreas. Finally, 25 years later, it came to the brain. This experiment was staged by the same Frederick Alt with the participation of his Californian colleague Bjorn Schwer, as well as their employees.

Researchers have developed a line of mice in which the cells of the embryo – those that were destined to give rise to the forebrain – died at an early stage of development. They were killed by a diphtheria toxin produced at the command of a gene specially injected into mice. After the death of these cells, the developing mouse embryo was doomed to be born without the forebrain (that is, the cerebral cortex, hippocampus and other important parts). But such a fate awaited him only if the researchers did not inject stem cells into the blastocyst in advance. Once in the embryo, these cells willingly assumed the function of their dead colleagues and developed into a normal brain. If the researchers genetically modified these stem cells to carry a specific mutation, then all mouse brain cells also inherited this mutation.


Figure from the UCSF press release Building a Patchwork Brain to Study Neurological Disease – VM.

The mice obtained in this way had a completely normal mouse brain. Moreover, in all behavioral tests, they behaved exactly the same as their fellow tribesmen, whose brains developed in the usual way. At the same time, all the brain cells of these mice carried the genetic markers that the researchers wanted to insert there. For example, scientists have introduced into the mouse brain a mutant gene for doublecortin, a protein that controls, in particular, the migration of neurons during brain development. In humans, such a mutation causes a severe developmental anomaly. Mice whose brains were grown from modified stem cells showed corresponding abnormalities in the development of the hippocampus.

Thus, the proposed method can be used to model hereditary human diseases. Obviously, a more straightforward approach is also possible: the mouse brain can be directly replaced with human stem cells in order to obtain an interspecific "chimera" – a mouse with a brain grown from human cells. It should be noted that at present such experiments – the production of chimeric organisms using human tissues – are considered ethically controversial, and certainly the idea of using forebrain cells as a human component should cause serious objections. In addition, purely technical difficulties await researchers on this path.

Nevertheless, according to experts, this scientific work gives neuroscientists a powerful tool for studying the development and evolution of the mammalian brain. In addition, the method will expand the possibilities of studying the mechanisms of neuropsychiatric disorders and human neurophysiology.

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