'Stripe' manual provides fresh insights for tissue and organ development

Scientists have created a complete manual of the processes that tell developing cells to form 'stripes'.

Genetic 'stripes' instruct cells to carry out specialised functions, such as forming the different parts of the body. Their formation is an important process that turns a fertilised egg into a complex and fully functioning embryo made up of different tissues and organs.

In a new study published in the journal Nature Communications, researchers exhaustively mapped thousands of possible stripe-forming networks. They hope their findings will help researchers design new biological tools that could one day instruct cells to form useful stripe patterns and build artificial tissues. The work is an important step forward for understanding how to grow and repair damaged tissue or organs.

Stripes are generated by signalling molecules called morphogens, which govern patterns of tissue development by forming concentration gradients across cells. Cells read the concentration levels and convert them into stripe patterns that look something like a French flag.

Depending on whether the cell detects a high, middle or low concentration level of morphogens, a genetic program inside the cell then decides whether to turn the stripe genes on or off.

While scientists have previously known that many genetic programs form flag-like stripe patterns, they have not systematically explored all the possible ways of doing this. In a new study, biologists based at Imperial College London used bacteria and sugar signalling molecules to test an exhaustive list of thousands of different gene networks that have the potential to form a central stripe, similar to the white part of a French flag.

They discovered four simple stripe forming networks. Their research demonstrates how each works in a different and distinct way to form a stripe.

 
Engineered bacteria make green fluorescent protein ring patterns  

Lead researcher Dr Mark Isalan from the Department of Life Sciences at Imperial College London says, ''Stripes are the very reason that a single cell ultimately becomes a baby. Without stripes, our cells would not know how to create different tissues or organs. They are essential for creating everything in our bodies, from the tops of our heads right down to the tips of our toes."

''At this stage our research is very theoretical, but we believe that this work will ultimately help scientists to design biological systems that can build tissues and organs just by telling cells how to make patterns,'' adds Dr Isalan.

Previous research has successfully built and modelled some stripe-forming gene networks, but this study is the first to systematically build all the basic networks, completing what the scientists call the network 'design space'.

The scientists first used a complex computational model to identify thousands of possible gene networks that could create a stripe. Results showed four simple mechanisms could successfully do this – each mechanism included activators and inhibitors that turn genes on and off to generate a stripe, but each connected them in different ways.

They then used E. coli bacteria and an artificial sugar gradient to test their computer predictions. They built each of the four separate gene networks in the bacteria and connected them to a green fluorescent protein that made bright green stripes.

At high sugar concentrations the morphogen made inhibitors which turned genes off so no green stripe was made. At middle sugar concentrations activators were produced, which in turn made a green stripe. But at low sugar concentrations not enough activators were made to produce a stripe.

When scientists injected sugar into the middle of a petri dish containing millions of E. coli bacteria they saw a green stripe form a green ring, or a 'circular stripe' at a mid-way (middle) distance from where the sugar was originally injected.

The results could prove promising for researchers involved in regenerative medicine, as Dr Isalan explains, ''Nobody has systematically built all the basic stripe-forming mechanisms until now. On the computer, we found some new networks that we thought might work, but we couldn't be sure until we tried them. And while we are still far away from building an organ from scratch using our understanding of stripes, by successfully replicating our computer predictions we now have a much better understanding of how to engineer different mechanisms precisely.''

The study was carried out in collaboration with the Centre for Genomic Regulation in Barcelona, and was funded by the European Research Council.