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Category Archives: Biological engineering

Synthetic biology is not engineering, it’s a programming

Vierpunktlager, geteilter Innenring, zerlegbar...

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Topic of this post has been sitting in my head for the very long time, but I couldn’t come up with a good enough opening. I’ve found it recently in the comments thread under the post on systems biology by Derek Lowe over at In the Pipeline. Citing Cellbio:

A trick of the human mind has us believe that if we rename something, we have changed the fundamental nature of the beast, but we have not.

I have taken it out of the context, but it applies very well to current situation in synthetic biology. My enormous frustration with this field comes from the fact that most of so-called synthetic biology is nothing else than genetic engineering with more systematic approach. The whole engineering meme has stuck in people’s head and many of them seem to care more about characterization of the system than about understanding how it works.

If we take a bearing from a car and from a bike, both will differ in shape and very likely one couldn’t be replaced by the other. However, their role and mechanism of work is the same, no matter in which machine we put it (this is BTW what I tried to say in my previous post on BioBricks, but judging from the comments I failed). Mainstream synthetic biology doesn’t seem to be interested in understanding how car and bike works – it’s interested in taking both of them apart as fast as possible, puting labels on the parts and pretend that now we understand how they work. And while this approach can be succesful to a certain extent in engineering, biology, especially synthetic biology, is not engineering, it’s rather a programming.

If we look at the particular component of conserved signalling pathway in two different organisms, its sequence most likely will differ. And for some pairs of organisms sequences of this component stop to be freely exchangable: they need to be mutated to fit particular chassis. Repository of information what works where is a great starting point, but it’s about the time to move further. It’s about the time to express biological systems as sets of functional roles and to build a compiler that transforms an abstract description of biological system into sequence understandable by the particular architecture (organism). This is what I think synthetic biology is all about. It’s designing by understanding.

Formalized language of biological processes sounds like a domain of systems biology, but a compiler certainly doesn’t, so such programming framework could use the best of both worlds. Can you imagine “Hello world” equivalent of a living cell? Or how would you debug program in such language? Sounds like lots of fun.

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BioBrick as a functional role

Genetics

When I initially saw The MIT Registry of Standard Biological Parts, I just fell in love with the idea. However, after closer inspection I realized that it’s not what I hoped to find. The Registry collects an interchangeable functional modules that can be assembled into novel biological systems. And it does it as good as it sounds, but to a certain extent. Pedro wrote some time ago about unavoidable complexity and potential issues with collected parts. I completely agree with his arguments but I have even more doubts about the Registry’s current approach.

First of all, my feeling is that DNA-centric view of life starts to limit us in understanding what is happening at a molecular level. It moved forward science a lot and it is still extremely useful, but with genetics we are not going to understand and avoid emergent properties of biological systems. DNA, RNA, proteins at a sequence and structure level are all interacting with each other. This properties are encoded in DNA, I agree. However, as Pedro pointed out, we have no way to predict what happens after transferring a part to other organism. It is possible to select for mutations that will render this part usable in the other organism, but I don’t think this approach would be of much use if we deal with organisms that are hard to grow (imagine you want to insert a specific system into extremophile organism). And what is more, it’s not necessarily practical if we transfer the part to an organism which already has a similar element encoded in the genome.

In my humble opinion, the Registry can be extended in two directions, transforming parts into a containers that have a specific functional role and include sub-gene elements, like domains or tectons. Let me describe both in more detail.

Currently a BioBrick is assigned a function and a sequence. I would rather see a functional role, that can be fulfilled by many different sequences. For example, if we have an enzymatic function the BioBrick would include not only single DNA sequence from a single organism, but also a protein sequence, domains, sequence motifs and a structure (whatever is available), and all these should be available for all organisms for which we can assign reliably this information. To clarify, I’m far from populating the Registry with BLAST results. I would rather have it done manually, or at least in the way The SEED allows experts to create subsystems and assign a functional roles to proteins. In this way we could just take a gene from a target organism instead of mutating the original one. Having a container would mean that we could include there different flavors of the same gene (for example, after optimization).

For the second thing, I’m a big fan of creating novel functions out of existing elements. That’s a reason why I believe the Registry should include building blocks of proteins as well as other fancy things, like riboswitches. One of the obvious example would be a signal transduction element, where one can attach different receptor domains to the same membrane component. This has been done already thousands of times – why not to standardize it?

Maybe with these two changes maybe we could finally connects some dots and make a complexity of biological systems more understandable or at least traceable. Future directions of the Registry are not very well defined, so I believe there’s a space for at least discussion about such ideas.

 

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Peptide and Protein Building Blocks for Synthetic Biology – EHC Broomley et al.

With my background in protein sequence analysis and recently increasing interest in synthetic biology/biological engineering, Deepak’s post about BioBrick project immediately caught my eye. However, after spending some time around registry of standard biological parts I realized that using full natural proteins as modules wasn’t very appealing to me. My thoughts oscillated in area between nanotechnology at a atomic level, and BioBrick approach – my idea for “a brick” was something from supersecondary structure elements to protein domains.

While I was trying to figure out what was done in this area, here’s what appeared in Google Reader: Peptide and Protein Building Blocks for Synthetic Biology: From Programming Biomolecules to Self-Organized Biomolecular Systems by E.H.C. Broomley, K. Channon, E. Moutevelis and D.N. Woolfson (DOI: http://dx.doi.org/10.1021/cb700249v). It’s not an open access paper, but you can download it from Dek Woolfson lab page. This review summarizes several different approaches to synthetic biology focusing specifically on peptides and proteins as a prime component of newly engineered machines. Why actually peptides and proteins? Here are some points from the paper:

  • efficient, reproducible and spontaneous folding with all information usually encoded in the polypeptide chain
  • organization of the folded structures, including secondary structure elements (referred there as tectons), which naturally limits the possible number of folds, but gives enough different structural scaffolds to display many biological functions
  • frequently observed self-assembly of folded structures into higher-order complexes/nanomachines

The review gives examples of selected protein folding motifs (like collagens or zinc-fingers) that can be used in designing novel fibrous materials, but describes in great detail various assemblies made of protein coiled-coils.

Being pretty familiar with coiled-coil structures, I was rather more interested in general view on the field – and I wasn’t disappointed. Below I copied first figure from this paper (for its legend see the original paper) – it’s a beautiful breakdown of different methodologies in synthetic biology. You can place on this graph most approaches people are taking in this area (from Venter’s bacteria, through BioBricks, to DNA cubes).

Peptide and Protein Building Blocks for Synthetic Biology - EHC Bromley et al.

 
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Posted by on February 4, 2008 in Biological engineering, Papers, Synthetic biology

 

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