The clever thing about this arrangement is that once the activity of a transcription factor gene is set, it tends to stay that way. Any desired pattern of gene activity can be produced with the precise amounts of different dimer combinations. Random small changes that affect the stability of the transcription factors can flip a cell from one state to another, but they are not taken seriously. The control system is flexible and robust because of this.
It was decided by Elowitz, Zhu and their team that they could build it in the cells of mammals. The model suggested that a control system built around these could put cells into three different states, one in which only the first and second genes were active, one in which both were active, and one in which neither was active. The stability of the factor and how likely they were to bind to each other were the factors that would determine which state was favored.
Modeling is one thing, but making something work in a living cell is another. The team was surprised when the genes for the initial test were introduced into the hamster cells and they turned into a colorful pattern of green, red and yellow. The system they named MultiFate seemed to work.
They added a third transcription factor to see if it would scale as predicted. The cells created a kaleidoscope of seven colors. The states persisted for over a month if they were left undisturbed.
The researchers watched how the cells responded to change. Alteration of the concentration of a chemical in the environment could cause the cells to move between states. The responses of the engineered cells were shaped by their histories. When the concentration of the chemical agent went from high to low, they switched states, but they didn't just go back to where they were.
In nature, cells that live through a time of scarcity may stay in a permanent state of hoarding energy. Resetting the environment does not wipe away the experience of the cell.
Ahmad Khalil, a professor at Boston University, co-authored a commentary about the Elowitz and Zhu paper for Science.
It's a great achievement, because whatever process led to the seething complexity of enormous multicellular organisms must have started off quite simple, and it likely relied on something basic and mutable. The system described by Elowitz and Zhu would have been sufficient to generate the variety we see in nature.
The E. coli system with four stable states was developed by Wang, who believes that the researchers drew on a branch of mathematics that deals with systems that often have complex, surprising outcomes. In biology, there is something else in there that makes it so complex but also so robust.
If you have a master network of eight transcription factors, you have the core machinery to form a human body. It should be possible to produce more than 1,000 steady states with just 11 transcription factors, according to the MultiFate paper.
On paper it is very easy to scale up. There is a lot that is unknown in biology. We might see something that we don't expect.
The MultiFate system could be used to control real aspects of a cell, not just its color. Cells could be introduced into patients to respond to their environment. He said that it was a cool idea that they might develop cancer in a diagnostic or therapeutic way.
For Elowitz, the system is a way to understand biology as more than just a Rube Goldberg machine. He said that the artist's contraptions, which performed simple tasks with the maximum number of steps, were the perfect embodiment of the design.
He said that natural systems may look like that because we don't fully understand what's going on.
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