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Creative Use of Molecules - What Is Synthetic Biology?

By Michael Reth

Before the opportunities and risks associated with synthetic biology can be discussed, it is first necessary to understand the principles of how it works and how it came to be. One of the most important questions is why this new research area is developing so rapidly at this particular time. Insights into the research field of synthetic biologists.

Creative Use of Molecules - What Is Synthetic Biology?© Dietmar Klement - iStockphoto.comSynthetic biology - a new field of research with great potential
Synthetic biology has established itself as a new biological teaching and research subject. Like everything new, it is regarded with great hope, but also with concern. But synthetic biology is not only playing an increasing role in biotechnology, it could also become an important way of generating new findings, and thus an irreplaceable part of current biological research.

In July 2009, the German Research Foundation (DFG), acatech, the German Academy of Science and Engineering, and the German Academy of Natural Scientists Leopoldina highlighted the great potential of this new field of research in a joint position paper on the opportunities and risks of synthetic biology, and demanded public discourse on the subject. According to the position paper, scientists from the fields of biochemistry, molecular biology, genetics, microbiology, immunology, chemistry and physics, from the engineering sciences, the humanities and the social sciences are involved in synthetic biology. In the medium term, the authors see possible applications in the development of vaccines and medications, but also fuels and new materials.

A long warm-up

The origins of synthetic biology are closely connected to the methodical development of molecular biology. On 3rd October 1979, the Frankfurter Allgemeine Zeitung published an article by Dr. Barbara Hobom titled "At the threshold to synthetic biology. Unlimited possibilities of coupling genes in vitro / Evolution through natural gene recombination". In her article, the author refers to the restriction enzymes discovered at that time.

These now made it possible to cut open DNA molecules at a specific location and purposefully create new gene combinations, she wrote. Barbara Hobom was one of the first to use the term synthetic biology for this surgical incision into DNA, but it was to take another 30 years before a biological field of research adopted the name. The precise definition of this young field is still in flux. So far, it is generally accepted that synthetic biology on the one hand consists of reassembling biological systems from individual parts, and on the other hand also includes the development of entirely new molecules that do not exist in this form in nature. The discipline pursues strategies from the engineering sciences, for example dividing systems into functional units and recombining them into larger complexes, and all this in the nano range of cellular components.

After such a long warm-up phase, why is synthetic biology developing so rapidly just now? First of all this is due to new methods, which have advanced from cutting and recombining to writing DNA molecules. The cost of DNA synthesis has only recently dropped significantly, and it is now standard to have entire gene sequences newly synthesised. The increasing attractiveness of synthetic biology is also based on the fact that it indicates alternative ways of approaching one of the main issues of modern cell research, namely "How do we deal with the enormous complexity of living systems?".

Sequencing the genomes of many organisms has provided a wealth of genetic information, but the hope of thereby arriving at a comprehensive description of a living system has not been fulfilled. Life is created only through the implementation of genetic information and the interaction of biological molecules with each other and with the genome. Due to a wide range of modifications and coupling reactions this leads to enormous complexity. Modern biology is now asking itself the fundamental question: "How can this enormous complexity be comprehended?"

Systems biology or synthetic biology

A promising approach is that of systems biology, which aims to arrive at an almost complete description of a living system by means of modern analytical "high throughput" procedures and mathematical modelling. Synthetic biology on the other hand relies more on human creativity than on expensive machines. In its attempt to first divide a cell into functional subsystems, its keywords are simplification, decoupling, functional description. Synthetic biologists are now both systems engineers and molecule designers. As the former they work from the admittedly ad hoc assumption that biological molecules behave like parts of a machine and can thus also be described functionally. As the latter they are guided by a playful, creative use of biological materials.

They reach into nature's so very diverse and colourful construction kit and create new biological machines from the isolated biological components known as "biobricks". In its research approaches synthetic biology thus partly mimics the developments seen in chemistry, which also evolved from natural chemistry to analytical and then synthetic chemistry. Historically, synthetic chemistry turned out to be not only a method for creating new materials and substances, but also a significant instrument to generate findings. Only when the de novo synthesised substance behaved identically to the material isolated from nature was its structural formula considered proven. Synthetic biologists reconstruct systems from individual "biobricks". Only when this system behaves as intended can each component be assigned a role, thereby allowing a far greater understanding of the way the involved molecules work. Synthetic biology has therefore adapted the words of nuclear physicist Richard Feynman: "What I cannot create, I do not understand".

Assembling a signal chain

Any molecular biologist who hopes to explain the vital processes within a cell by describing the involved molecules faces a problem. The molecules, e.g. proteins, can never be seen directly or observed in their dynamic behaviour. Modern optical microscopes enable a view into the living cell, but they cannot resolve individual molecules. The researcher is like a reporter who observes a playing field but cannot see the players on it. How could one come to understand the game under those circumstances? Genetic knockout or knockdown techniques have become a very popular approach in recent years.

In these processes, one or several genes are removed from the organism; the resulting defects allow conclusions to be drawn regarding the function of particular components in the system. Synthetic biologists take the opposite route. They first pick a suitable playing field and then place individual players into this area. The playing field is either an in vitro system in a test tube or an evolutionarily remote cell that lacks the players under investigation. It is important that the subsystem to be examined can be created and its functions studied largely in isolation from the influence of the overall system. Synthetic biology calls this decoupling of a subsystem orthogonality. For example, components of the signal chain of a mammal cell can be rebuilt step-by-step in a cell of the model organism fruit fly.

To illustrate, let's look at how B cells, an important component of our immune system, are activated by pathogens. In addition to the B cell antigen receptor, at least five different signalling pathways and up to 200 different molecules are involved in activating these cells. How could anyone ever make sense of that? The researcher first of all rebuilds the antigen receptor from its four known functional components and discovers: in the system she has chosen, a cell from the fruit fly Drosophila, the receptor alone cannot send out signals. Now the search for the partner proteins begins. These are often kinases, that is, enzymes that transfer a phosphate group from the energy carrier ATP to other proteins and change the activity of the target protein through this modification. Of the tested kinases, only one is capable of sending out signals together with the receptor. However, these signals are constitutive and therefore not properly regulated. Now our researcher looks for the missing regulative principle.

She determines that the receptor controls not only kinases but also phosphatases, that is, enzymes that split phosphate groups off proteins. This takes place through what is known as a negative feedback which deactivates the signal on the receptor again. Such an iterative strategy allows our researcher to gradually determine the essential players of a signalling subsystem.

Once a functional subsystem has been successfully reconstructed, the synthetic biologist's work is far from over. Now comes the creative part, which also involves manufacturing innovative molecules that do not occur in nature, such as controllable signal switches or signal detectors. To do so, our researcher uses "biobricks" that enable her to equip the receptor and its signal partner with new functionalities, resulting in, for example, receptors that light up yellow when they exist in a particular form, or red when they send out a signal. The latest results of this creative form of research include the finding that the activation model of the B cell antigen receptor as explained for the last 15 years in all the world's teaching literature is fundamentally wrong. Synthetic biology has many new findings, new methods and applications in store for us yet. Once particular signalling systems are understood in detail and ways have been found to reprogram them through controllable switch proteins, particular cells in our body could for example take on new functions.

Our immune system has a highly developed and sophisticated system for detecting and eliminating intruding pathogens. This system is basically also very well suited to removing abnormal tumour cells. The ability to reprogram cells via synthetic switches and detectors may make it possible to transform immune cells into anti-tumour killer cells and thus develop new therapies to fight tumours. It would not be the first time that extremely useful applications were derived from creative research. Nature too takes what is available and 'plays' with it over the course of evolution.

A conference transcript on the subject, edited by J. Boldt, G. Maio and O. Müller and including an article by Michael Reth, is about to be published.

About the author
Professor Michael Reth is the speaker of the BIOSS (Centre for Biological Signalling Studies) Excellence Cluster at the University of Freiburg and works at the MPI of Immunobiology in Freiburg.

From Forschung und Lehre :: August 2010