Living prehistoric fishes, the key to designing artificial organs?

A living prehistoric fish, known as “a living fossil,” has helped researchers understand the basics of stem cells. This is a quantum leap within stem cell research.

To be able to design artificial organs you first have to understand the function of stem cells and the genetic instructions that govern their remarkable properties. Professor Joshua Mark Brickman and his team have managed to unearth the evolutionary origins of a master gene that acts on a network of genes instructing stem cells.

A coelacanth, a living prehistoric fish. It has fins shaped like limbs and is therefore thought to resemble the first animals to move from the sea onto land.
A coelacanth, a living prehistoric fish. It has fins shaped like limbs and is therefore thought to resemble the first animals to move from the sea onto land.

“The first step in stem cell research is to understand the gene regulatory network that supports so-called pluripotent stem cells. Understanding how their function was perfected in evolution can help provide knowledge about how to construct better stem cells,” said Professor Brickman at reNEW’s Copenhagen node.

Pluripotent stem cells are stem cells that can develop into all other cell types. For example, heart cells. If we understand how the pluripotent stem cells develop into a heart, then we are one step closer to replicating this process in a laboratory.

A ‘living fossil’ behind the findings
The pluripotent property of stem cells is something that has traditionally been associated with mammals. Now Professor Brickman and his team have found that the master gene that controls stem cells and supports pluripotency also exists in a fish called coelacanth. In humans and mice this master gene is called OCT4. reNEW’s researchers found that the coelacanth version of the master gene could replace the mammalian one in mouse stem cells.

In addition to the fact that the coelacanth is in a different class from mammals, it is known as a ‘living fossil,’ since it developed into the form it has today approximately 400 million years ago. “By studying its cells, you can go back in evolution, so to speak,” said Assistant Professor Molly Lowndes. “The central factor controlling the gene network in stem cells is found in the coelacanth. This shows that the network already existed early in evolution, potentially as far back as 400 million years ago,” Assistant Professor Woranop Sukparangsi added.

And by studying the network in other species, such as this fish, the researchers can distill what the basic concepts that support a stem cell are. “The beauty of moving back in evolution is that the organisms become simpler. For example, they have only one copy of some essential genes instead of many versions. That way, you can start to separate what is really important for stem cells and use that to improve how you grow stem cells in a dish,” says PhD student Elena Morganti.

Sharks, mice and kangaroos
The researchers also learned how evolution modified the network of genes supporting pluripotent stem cells by analyzing stem cell genes from over 40 animals, including sharks, mice and kangaroos. They were selected to provide a good sampling of the main branch points during evolution.

The researchers used artificial intelligence to build three-dimensional models of the different OCT4 proteins. They noticed that the general structure of the protein is maintained during evolution. While the regions of these proteins known to be important for stem cells do not change, species-specific differences in apparently unrelated regions of these proteins alter their orientation, potentially affecting how well it supports pluripotency.

“This a very exciting finding about evolution that would not have been possible prior to the advent of new technologies. You can see it as evolution cleverly thinking, we do not tinker with the ‘engine in the car,’ but we can move the engine around and improve the drive train to see if it makes the car go faster,” Professor Brickman explained.

Additional information can be found in the following article “Evolutionary origin of vertebrate OCT4/POU5 functions in supporting pluripotency” published in nature communications.

What are stem cells?
Stem cells are non-specialized cells found in all multicellular organisms. They have two properties that distinguish them from other cell types. On the one hand, stem cells can undergo an unlimited number of cell divisions (mitoses). On the other hand, they have the ability to mature (differentiate) into several cell types. A pluripotent stem cell is a cell that can develop into any cell type, such as a heart, hair or eye cell.

Stem cell research is part of a broader research field called synthetic biology. This is basically about gaining an understanding of the biological building blocks, such as stem cells. The perspective is to design and build biological systems that, among other things, can produce cells for specific functions.