“With our technique, we are actually asking a mouse: ‘What did you look like so many days ago?’”, says Professor of Developmental Biology Joost Gribnau of Erasmus MC. “With the technique we can map the entire development from a fertilized egg to the development of all 350 cell types.” He expects this to be of great value to developmental biologists, who will be able to see for the first time which genes are active in all cells during development.The article about this research was published today in Nature Biotechnology
This new technique has now been proven with research in mice. In follow-up research, the researchers want to see whether they can study human stem cells in culture dishes.
It is important to know which genes are active when, because in order to produce a good mature cell, exactly the right genes must be ‘on’ at all times. Every person has about 25,000 genes, or pieces of DNA. Only a third to a half of those genes in a cell are active at a time. Depending on which genes are active at specific times during the development of a cell, a stem cell develops into a certain cell type such as skin cell, kidney cell, muscle cell or glandular cell.
Blood cells from the lab
With information about the gene activity, scientists can mimic the development of cells in a lab. “Take blood stem cells, for example,” says Gribnau. “If we know how a stem cell becomes a blood stem cell, we can mimic that in the lab.” You can donate those blood stem cells made in the lab to patients with leukemia, for example.
In leukemia, the production of white blood cells is disrupted. They divide uninhibitedly, or are deformed. Many patients receive chemotherapy and/or radiation. These treatments not only destroy malignant cells, but also healthy stem cells. Therefore, a stem cell transplant is often necessary. In the future, these cells may be made in the lab.
Active genes
To determine which genes are active, the researchers use an enzyme that plays an important role in the multiplication of DNA in the cell and in reading DNA to produce proteins. When the researchers add the enzyme to the mouse, it attaches a so-called methyl group (certain compound of molecules) to all genes that are active at that moment. Gribnau: “He hangs flags, so to speak, so that the marking remains clearly visible. The great thing is that those methyl groups remain, even if the cell continues to divide.”
In their experiments, the researchers followed the development from intestinal stem cell to intestinal epithelial cell; the cells that form the outer layer of the intestines and are in contact with the passing food slurry. Every day the researchers marked the active genes in a different group of mice. For example, they recorded the development from stem cell to epithelial cell on all days.
After a few days, development was complete, and the researchers were able to see which genes were flagged on each day of development. The flags used look different from the methyl groups that occur naturally in mice and humans, so the researchers can easily distinguish them. “With this technique, we travel through time, as it were,” says Gribnau. “We look back in time and see which paths the cells have taken.”
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“We have now applied the technique to map the differentiation process from intestinal stem cell to the intestinal epithelium in the mouse, but we want to do this for many more tissues and organs.” In follow-up research, the researchers want to see whether they can study human stem cells in culture dishes, for example in gastruloid research.
One of the phases that developmental biologists would like to know more about is the period in embryonic development when cells are sealed for their fate. This phase is called gastrulation. It is a crucial phase because if something goes wrong during this phase, for example due to an infection, medication, alcohol use or genetic predisposition, it can have major consequences. Scientists therefore want to know which genes are important in that development and determine what goes wrong in certain hereditary diseases.
It took Gribnau and colleagues 18 years to get the time machine technology up and running. For Gribnau, it shows how important it is to invest time and money in fundamental research. “I started with the idea that ‘this is high-risk research, but if we get it up and running then we can take very important steps with it.’ I have continued to put money into this on a structural basis and now you can see what that can yield: a technology that will soon be directly applicable in the hospital.”
