Rodents of Science
Mice with human lungs will help to find protection from COVID
Maria Nedyuk, Izvestia
Scientists from the USA have proposed a method for creating mice with humanized (consisting of human cells) lungs and an immune system. In their opinion, researchers currently do not have a suitable animal model that could shed light on how SARS-CoV-2 behaves in the human body. Ferrets, non-human primates and transgenic mice, on which bets were placed, show unsatisfactory results in experiments. They either die early or do not show the necessary symptoms. Russian experts highly appreciated the potential of this proposal, despite its complexity and cost. They believe that even if the coronavirus infection recedes soon, the creation of such models will greatly advance science.
Humanize mice
Scientists of the Center for the Dynamics of Infectious Diseases and the Institute of Biological Sciences. Huck (The Center for Infections Disease Dynamics and Huck Institutes of the Life Sciences) published a review article describing ways to create mice with humanized lungs and immune system.
Such individuals are necessary to test the safety and effectiveness of vaccines against the new coronavirus. As experts explained, humanity is now in search of a suitable animal model that could help to understand how SARS-CoV-2 behaves in the human body. But so far it has not been possible to find her.
As the article says, transgenic mice, which scientists from all over the world hoped for (Izvestia wrote about them in the article "Mice will be caught: rodents are sold for $ 3 thousand to test the vaccine"), die by the sixth day of infection, while showing only minor symptoms of COVID-19. Ferrets, whose lung physiology is similar to that of humans, are poorly susceptible to coronaviruses. And it is expensive and difficult to work with lower primates.
Any animal model has a so–called translational potential - the probability with which the results obtained on it can be transferred to humans, Vladimir Popov, head of the Laboratory of translational Medicine at the Moscow State University named after M.V. Lomonosov, told Izvestia.
– For ordinary laboratory mice, it is quite small: within 10-15%. The creation of a transgenic mouse model, even if the introduced genetic construct is a human gene, increases it slightly. After all, tissues, organ systems, and the whole body as a whole remain mouse–like, the expert is sure.
Transgenic models, according to the scientist, are needed when studying the molecular mechanisms of some already described physiological processes, when studying the pathogenesis of diseases caused by the breakdown of one (or a few) genes. But they are of little use in the study of systemic pathologies, which, apparently, include the disease caused by SARS-CoV-2. From this point of view, the ability to cause the development of human lung tissue and immune cells in mice is an obvious step forward," Vladimir Popov believes.
Two possible models
Humanized mice with human lungs will allow us to study precisely human immune responses. A common cause of death in COVID-19 patients is acute respiratory distress syndrome caused by excessive release of inflammatory cytokines, Andrey Nedorubov, head of the Center for Preclinical Research at Sechenov University (the university is a participant in the project to increase the competitiveness of education "5-100"), told Izvestia.
– In modern clinical practice, there are drugs based on monoclonal antibodies (created in the laboratory of clones) that are able to block this cytokine storm at the earliest stages of its activation. But the problem is that most of these drugs block only human cytokine activation pathways. And they are not active on laboratory animals due to evolutionary and species differences," the expert explained.
It is with these limitations that humanized mice are able to cope.
Scientists have described two possible methods for creating such laboratory rodents. In the first case, mice are offered to inject human hematopoietic stem cells. These are the precursors of B cells necessary for the production of antibodies and activation of the humoral immune response (when substances with protective functions are formed).
Also, rodents will need to plant an embryonic human liver and thymus, which produce T cells and carry out their maturation and selection to obtain a cellular immune response. A fragment of human lung tissue is transplanted into mice in a special capsule subcutaneously. Thus, the most important elements of the human immune system are assembled inside the animal like a puzzle and allow it to function normally according to the laws of the human body.
– As a result, in the first model there is a localized human lung, which preserves the structure and viability, and the main branches of human immunity, which are responsible for the body's response to an alien invasion, – explained Andrey Nedorubov. – The mouse's own protective system does not affect these components, since mice are genetically modified and deprived of immunity in order to avoid organ rejection.
In the second case, scientists suggest using the method of blastocyst complementation (blastocyst is the next stage of embryo formation after the zygote. – "Izvestia"), the head of the laboratory of genomic engineering at MIPT Pavel Volchkov told the publication. With this technique, embryonic stem cells must be inserted into the blastocyst of a mouse in which the genes responsible for the development of an organ are "turned off", from which the same organs of another type can later develop. In this case, human lungs.
– However, it should be understood that so far no one has experimentally injected human cells into animals. There is an ethical contradiction here, which is due to the fact that an animal can develop not only lungs, but also, say, nervous tissue. In this case, the question remains to what extent it is an animal, and to what extent a person," the scientist explained. – However, this is a very promising model that needs to be worked on.
Both described methods are suitable for studying both the human immune system and the work of the lungs. And each of them has its pros and cons, the expert noted.
Expensive, but promising
However, such experiments require large financial investments. The cost of transgenic mice can be up to several thousand dollars per core (several animals from which you can get offspring), and humanized models are even more expensive. However, if they really reproduce the pathogenesis of COVD-19, similar to the disease in humans, as well as the development of immunity against SARS-CoV-2 and other similar infections, these costs will be fully justified, Anastasia Efimenko, head of the laboratory of the Institute of Regenerative Medicine of the Lomonosov Moscow State University, is sure.
– Often in publications, humanized mice are called transgenic mice that have been injected with a human gene or several. Although this is not quite correct. At the level of the body, the introduction of human genes does not mean the development of human reactions, for example, to infection," the specialist said. – This article describes precisely humanized mice, in which a significant part of the lung and blood cells are human. And their response to the virus should correspond to those that occur in patients.
Experts say that even if the coronavirus infection recedes soon, the creation of such models will greatly advance science. However, there is a downside to the coin: if we talk about the creation of man-made viruses (and talk about the laboratory origin of SARS-CoV-2 does not subside), then the development of humanized animal models can accelerate the process of pathogen transition from animal to human, some scientists warn. Therefore, it is necessary to strictly control the work with such animals.
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