Scientists take the first step to mastering an all-powerful cell type early in life

In the current study, Ding and his colleagues identified a cocktail of drugs that induces an almighty type of stem cell at will, a type of cell that can grow into an entire organism on its own. Researchers are also able to maintain the differentiation potential of the resulting cells in the laboratory, allowing a stable system for later researchers to demystify the creation of life. This alternative path – getting a clean slate of the first raw materials of life from more mature cells, instead of new sperm and eggs – can have a wide range of implications. “Such an alternative to the natural way of creating the beginning of life is a holy grail of biology,” Ding says.

The creation of life begins with a cell. Your blood, brain, and liver cells can all be traced to this one-celled embryo or zygote.

In nature, a zygote is produced when sperm and egg fuse together. And the event triggers an irreversible process where the zygote divides, forms new cells, and the new cells continue to divide and specialize more and more.

As specialization is acquired, something is lost along the way. Once the one-cell embryo divides and reaches the stage of two-cell embryo, the last cells will quickly lose the differentiation potential to give rise to all types of cells to generate a whole organism and its tissues of support like the yolk sac and placenta, becoming less potent stem cells.

Scientists call these all-powerful cells in the single-cell and two-cell embryonic stages totipotent stem cells. And there are pluripotent and multipotent stem cells further down the continuum. “Normally, after the totipotent cells, none of the other stem cells have the ability to grow into a life on their own,” Ding says.

To better study and control totipotent stem cells, Ding and his team implemented a system that achieves the induction and maintenance of these cells, and confirmed their identity with rigorous criteria.

With 20 years of work and understanding of cell fate and stem cell regulation by chemical compounds, the team has selected and screened thousands of small molecule combinations. Through several rounds of analysis, they identified three small molecules that could coax mouse pluripotent stem cells into cells with totipotent characteristics. The researchers called the molecules TAW cocktail. Each letter of TAW represents a molecule known to regulate a specific cell fate decision. But their combined effect was not known until the current discovery, Ding says.

Next, the researchers examined the cells receiving the TAW cocktail treatment in detail, both their totipotency and their lack of pluripotency. These cells have passed strict molecular testing criteria at all levels of the transcriptome, epigenome and metabolome. For example, the team found that hundreds of critical genes were turned on in TAW cells. These genes are typically found in totipotent cells and have been pointed to by other researchers in the field as the bar for determining totipotency. At the same time, genes associated with pluripotent cells were silenced in TAW cells.

To further prove that the resulting cells have a true totipotent state, the team tested their differentiation potential in vitroand also injected them into an early mouse embryo to see the differentiation potential live. They found that the cells not only behaved like true totipotent cells in a Petri dish, but also differentiated into embryonic and extraembryonic lineages. live. This is a typical feature of normal totipotent cells, which have the potential to develop both into a fetus and into the surrounding yolk sac and placenta, whereas pluripotent cells can only develop into a fetus.

Moreover, when the researchers used special culture conditions for TAW cocktail-induced totipotent cells, the following cells also showed similar totipotent traits. This observation suggests that the totipotency of TAW-induced cells can be maintained in a laboratory environment, and thus a stable system is established.

Such a system is important because it will allow many scientific investigations concerning the beginning of life. For example, scientists can use this system to manipulate totipotent cells to better understand the highly orchestrated process in early life. “Certain cells will have to appear at the right time and in the right place for life to occur,” Ding says, and you can’t study that without the proper tools.

In this sense, “this document is a first step and opens up tremendous opportunities”, he believes.

Moreover, having a deeper understanding and therefore control over totipotent cells will have a wide range of implications, such as gaining a second chance at the creation of individual life and even accelerating the evolution of a species.

Many possibilities will spark controversy, Ding acknowledges. It should be noted that even if these possibilities lie in the distant future, he mentions, it is difficult to predict what the ethical concerns of the company will be. After all, the scientific community hasn’t seen lighter restrictions around human embryo research in the past decade. But last year people started to seriously consider extending the shelf life of a human embryo in a Petri dish from the original 14-day rule.

Although the team is keenly aware of ethical considerations, Ding believes that as scientists their main job is to focus on discoveries in the present and lay the groundwork for future generations. Then the latter will have the knowledge and the tools to make decisions.

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SOURCE School of Pharmaceutical Sciences, Tsinghua University

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