November 24, 2006
Stem Cell Regulatory Circuitry Mapped

Using mouse embryonic stem cells Harvard researchers funded by the Howard Hughes Medical Institute have created a first draft map of how a set of proteins interact with each other to maintain embryonic stem cell state.

Howard Hughes Medical Institute (HHMI) researchers have created a map that charts the largely unexplored protein landscape that regulates a stem cell's ability to differentiate into multiple types of mature cells.

Understanding this protein network in greater detail could give stem cell biologists a new set of tools to coax mature cells to revert to an embryonic state, said the researchers. Reprogramming adult cells in this way could provide an alternative source of stem cells to use in regenerating tissues damaged by disease or trauma, rather than employing embryonic cells, they said.

HHMI investigator Stuart Orkin and his colleagues at Children's Hospital Boston and Harvard Medical School published their findings November 8, 2006, in an advanced online publication in the journal Nature.

They've also shown that depletion of concentration of a few of the proteins causes the cells to start showing signs that they are becoming more differentiated (specialized) to become cell types that carry out specific functions.

All these proteins will become targets for drug development to block or enhance their effects in order to shift cells into other states. Scientists will build on this work to create more detailed maps of how these proteins interact to control cell state. Likely still other proteins will be found to also interact with these proteins to control cell state. An increasingly more detailed map of relations between these proteins will provide a guide for where to intervene to control stem cell state. This report is a great foundation for further work along this line.

Orkin hopes the map will help guide the development of improvements in methods to better control reprogramming of cell state.

Orkin said that thus far experiments aiming at reprogramming mature cells into a stem cell-like state have yielded cells that imperfectly resemble embryonic stem cells. “However, with this new understanding of the network of regulatory factors, it might be possible to refine this approach to reprogramming,” he said.

He's being overly modest here. Of course this map will be useful for development of techniques to control cell state.

Note how these researchers think of the proteins in cells as forming complex circuits just as computer chips have complex circuits.

The regulatory network that maintains a stem cell's ability to become many different cell types - a characteristic called pluripotency - also prevents the cell from inappropriately differentiating into a mature cell, while keeping it poised to undergo maturation when required. This precise control relies on intricate circuits of interacting proteins that both regulate one another and govern the activity of genes.

While I sometimes write posts about promising individual stem cell treatments no one announcement of a promising treatment or even a dozen such announcements will amount to much of a breakthrough given our current deficient state of knowledge on how cells work. The real breakthroughs that will provide us with the most power to produce treatments are going to come from the development of knowledge on how cells control their differentiation (i.e. how cells specialize to become heart muscle cells or liver cells or other specialized types). So this announcement is much more important than the average report about stem cell advances.

Once scientists understand the complex circuitry governing cell differentiation the next set of real important breakthroughs (though mostly invisible to the general public) will come. Scientists will seek to intervene in those cellular circuits and to do so they will develop techniques to tweak those circuits in highly precise and controlled ways.

Cells in the embryonic state are several state changes away from any other state such as muscle cell or artery lining cell or liver cell. Once we have detailed knowledge of the circuits that control cell state the need for embryonic stem cells will go way down. It will become possible to start with a cell in any state and tweak it to shift into any other state.

Previous research has shown that the Nanog gene is a key regulator of whether a stem cell acts like an embryonic stem cell. Orkin's team used this previously discovered knowledge about Nanog to use it as a starting point to map the cell differentiation regulatory circuitry.

As the jumping-off point of their mapping effort, Orkin and his colleagues used a protein called Nanog, which other researchers' experiments had indicated was central to regulation of stem cell pluripotency. The researchers first tagged Nanog so that when they removed it from cells, they would simultaneously remove any proteins that were attached to it.

These experiments enabled them to identify numerous proteins that interact with Nanog, including some already known to regulate pluripotency. To confirm that the proteins they had found functioned to maintain stem cell pluripotency, they depleted the levels of several proteins in embryonic cells and observed that the cells then expressed markers of differentiation.

Drugs could emulate the depletion of a protein by blocking its activity. So each of these several proteins are obvious targets for drug development. To change stem cells into specialised cells or vice versa we need drugs that will bind to these regulatory proteins to turn them on or disable them. Scientists will gradually assemble large toolsets of molecules that can bind to regulatory proteins and by using them in different combinations and orders they will be able to change any cell type to any other cell type.

The researchers have created an initial map of how the proteins interact to maintain embryonic stem cell state.

Next, the researchers created a protein interaction map that showed the relationships among the various proteins. The map will provide stem cell biologists with an important guide for future studies, said Orkin. “Even though some of these factors were known to be important in pluripotency, exactly how they work and who they talk to and interact with was completely unknown,” he said.

This research is important for another reason: These scientists did not try to study one or two proteins at a time. If they did we'd have to wait another century before rejuvenation therapies become possible. The development of assay tools which allow measurement of many proteins or many genes at once has allowed scientists to study complex networks of interactions. Since cells contain many kinds of components functioning in complex networks this ability to collect more data about more target cell components at once is essential if we are to have a chance of benefitting from stem cell therapies.

Share |      Randall Parker, 2006 November 24 07:38 AM  Biotech Stem Cells

Joe said at November 27, 2006 1:03 PM:

Coming from a computer science background this kind of sounds like a finite state automata (FSA). An FSA is a map that defines a network in which each node represents a state and a token moves between the states as defined by the map. By definition their are a finite number of states, but their can be multiple tokens.

In CompSci you should be able to define any program or routine by an FSA. The token moving between the states is the thread; if there are multiple threads you get multiple tokens.

You can prove all sorts of things with FSA. You can prove that you will never enter an infantine loop, that a multi-threaded program will never run into a race condition, ect.

I am very lay when it comes to biology, but it seems to me that this map is very much like an FSA and their are all sorts of tools for analyzing FSAs in computer science. Just another example of how the silicone revolution will speed up the bio revolution.

I will let you draw your own conclusions from this Randall and others, but I thought I would just throw it out there.

Randall Parker said at November 27, 2006 6:29 PM:


I write software for a living and see cells the same way. Yes, they are state machines. The methylation patterns on the DNA backbone and concentrations of some proteins and other chemicals and how they are bound to each other determine what state a cell is in.

One of the reasons I've argued that the human embryonic stem cell debate is a distraction is that I think we need more money to figure out the cellular state machine far far more than we need scientists to be able to work with human cells that are in one particular state.

Once we figure out the states (and the vast bulk of this work can be done in other species) then we'll see ways to change from any starting state to any other state. So what state we start with will not matter. This latest result is far more important than 100 human embryonic stem cell studies because it is a big step in the direction of mapping out the states of cells and what proteins and genes keep them in states and shift them to other states.

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