Focusing on the Essentials

New Emmy Noether Research Group "Cell-free synthetic Biology"

July 17, 2020

Synthetic Biologists aim to create new biological functions. Because artificial systems are supposed to be predictable, quantifiable, and modular, this requires engineering thinking. For Henrike Niederholtmeyer, newly appointed head of the new Emmy Noether group "Cell-free synthetic Biology", the focus is on gaining new insights: how much order does a cell essentially need? And how do biological networks function?

During her post-doc time in San Diego, Henrike Niederholtmeyer developed cell-like structures that can be programmed with artificial networks.

Henrike, can artificial systems teach us something about natural systems?

Well, biochemists have been carrying out experiments on isolated enzymes for decades and have learned a lot about the mechanisms and basic processes in cells.  We are actually trying to do the same thing - except that we are not just looking at individual biomolecules, but are building entire networks. In the course of our work we hope to gain a better understanding of how regulatory networks operate and control when and where biochemical processes occur in a cell.

One thing that synthetic biology in cells teaches us for sure is that we still have a lot to learn. The problem is that predictability is often lacking - biological systems are simply too complex. This is where cell-free systems come into play. We bring together a number of well characterised elements in a test tube. So you only use parts that you understand.

So how does this look like? Everything mixed together in one test tube, like the "primordial soup"?

Yes, a little bit. For example, you can put together the more than 30 components necessary for transcription and translation in one test tube, and it works. But in our work, the goal is not the production of a protein, but the regulation of it. In order to do this, we assemble genetic networks similar to those found in nature, but in a simplified form. The components can come from very different organisms. Artificial networks have the advantage of being not too complicated, and that we can program them according to our wishes.

Working with networks, isn't that very physical/mathematical? Do you come from mathematics?

No, I studied biology, but I have always found it exciting to quantitatively understand biological processes and develop technology. That is how I came to work with microfluidics.

Microfluidics, that means: you were looking for alternatives to the "primordial soup".

Yes, more complex systems do not work well in a test tube. For example, I am doing research on genetic oscillators, their expression is rhythmic and dynamic over a long period of time. In a test tube, the reaction time is limited. Products accumulate, ATP is consumed, and after two or three hours nothing works anymore.

That is why I developed a microfluidic reactor during my doctoral thesis, in which molecules are pumped in and out through tiny valves. It holds 30 nanolitres, a tiny reaction volume that is more controllable than a test tube, and above all, this device extends the reaction time. Our work resulted in a microfluidic chip for the characterisation of biological networks. This chip is a slide with a transparent polymer piece glued to it, which we produce ourselves. It contains 100 micrometre channels with valves that can be opened and closed selectively. The expression of fluorescent proteins enables us to follow what happens in the cell-free reaction in the chip.

And what are you working on now? What are your plans?

In my post-doctoral period I turned to artificial cells where certain reactions can be localised in compartments. I have developed artificial cells and organelles to create a spatial order.

We call this artificial cell, but it doesn't really have much in common with a living cell. Natural cells divide and grow. Our artificial cells don't do that, which makes things easier. Because we also work with synthetic materials, our artificial cells are more stable, we can control the parameters and make specific changes.

What I would like to do now is to program these artificial cells with genetic networks and see how they work together in communities. I am interested in how patterns are created in cell communities – like, for example, in embryonic development, where patterns emerge.

What did you find attractive in Marburg as a research location?

A lot of things go well together here: Tobias Erb’s group works with biochemical cell-free systems, Victor Sourjik's group is working on regulatory networks and Sean Murray and Knut Drescher, for example, are developing mathematical models for pattern formation. And in general, SYNMIKRO brings together many groups with an interest in synthetic biology. This is a great environment for my group.

Which disciplines are relevant for your group?

It would be best to have a good mixture, because we need methods from all fields. We work with the basic methods of molecular biology and biochemistry. But interest in the development of microfluidic technology and modelling is also helpful.

What is it that you like best about your research area?

What I like is that it's so creative. You can put together biological and non-biological components in completely new combinations and create new functions. There's just so much to develop in this field.

And then you follow the path of the possible?

Yeah, you try a lot of things. And a lot of things don't work at first. (laughs). But what's cool is that you now have access to an almost infinite number of sequences from a wide variety of organisms, and you can combine these biological building blocks with artificial materials. For example, we have used polymers that are particularly stable and porous. You take what works best. That`s possible, since our synthetic systems do not have to live, grow and divide.

What do you hope for in the next few years?

 That we will be able to take another step from the test tubes to cell-free systems where regulatory networks can be used to control what happens,  and that we will be able to use materials to bring more order into the "soup". At some stage in the future we might be able to reflect the complexity of a cell. It is not yet known how much order a cell really needs. These kind of questions can be explored in a synthetic system.

 Now back in Germany, after four and a half years in California, is that hard for you?

No, it`s ok… In California, everything is rather dry, here there`s so much green! I always liked that when I visited my parents in Germany.

Henrike, thank you for the interview!

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