If you guys remember all of the big genome sequencing projects of the 90s and the early aughts, they’ve been continuing and the amount of raw data they have been giving back to us has exponentially accelerated. However, those of us trying to understand the biological realities of what all of those sequences actually mean were very quickly left behind and have been falling further and further behind as the advance of sequencing technology accelerates faster than we could ever hope to keep up with. The central problem is that while it turns out that we can get computers to do our pipetting for us if we pay engineers enough – we can’t get computers to do our thinking for us. Like mathematicians with some of the fanciest calculators imaginable, we can get the tools NCBI gives us to show us amazing things in amazing ways, but they can’t tell us what it all means. For the genomes we get to make any kind of sense a human being has to abstract meaning from it and communicate that meaning in understandable language – and there is no way around that limitation – there will only ever be ways to optimize it. This is really what synthetic biology is trying to do from its own weird and attractive but easily dangerously simplistic perspective.
E Andrianantoandro, S Basu, et al. Published 2006 in Molecular Systems Biology. doi:10.1038/msb4100073
Credit: Chuck Wadey, www.ChuckWadey.com
Synthetic biologists engineer complex artificial biological systems to investigate natural biological phenomena and for a variety of applications. We outline the basic features of synthetic biology as a new engineering discipline, covering examples from the latest literature and reflecting on the features that make it unique among all other existing engineering fields. We discuss methods for designing and constructing engineered cells with novel functions in a framework of an abstract hierarchy of biological devices, modules, cells, and multicellular systems. The classical engineering strategies of standardization, decoupling, and abstraction will have to be extended to take into account the inherent characteristics of biological devices and modules. To achieve predictability and reliability, strategies for engineering biology must include the notion of cellular context in the functional definition of devices and modules, use rational redesign and directed evolution for system optimization, and focus on accomplishing tasks using cell populations rather than individual cells. The discussion brings to light issues at the heart of designing complex living systems and provides a trajectory for future development.
If there is a God of creation that went around designing the genomes of all of the living things on Earth, they are the sloppiest, most frustrating, terrible programmer you could possibly imagine. The Intelligent Design proponents are particularly frustrating to me as a biologist having seen how fundamentally unintelligent the design of living critters actually is when you get down to the real moving parts. At least it is designed according to a sort of logic so fundamentally alien to our own that by any human standard we couldn’t help but call it stupid. Looking at life through the lens of Max Delbrück’s slowly fulfilled dream of a science of molecular genetics to replace the stamp collecting of Drosophila genetics1, the organization of information, regulation, and function in genomes makes precious little intuitive sense in terms of human logic. When you think about it; silly things like fundamentally unrelated systems being piled on top of each other such that one can’t be manipulated without messing up the other – necessitating otherwise functionless patches to the paired system whenever the other is modified, or Rube Goldberg-esque fragile systems of regulation that respond to all kinds of wrong stimuli, or systems of global regulation that are pretty analogous to reading the same giant program in either Python or C++ to produce one of two desired global results, or the kinds of systems that you can just tell are 99.9% amateur patch jobs are really what you would expect from systems designed exclusively by the entropic trial and error of evolution.
The end goal of the folks behind synthetic biology is pretty simple on the face of it. They want to turn biological systems into abstractions that can be manipulated by people who don’t understand the lower parts. While this might seem like a trivial goal, when you really understand what it means, it becomes clear that it has the potential to change the world in intensely profound ways and the very nature of life itself – that is if they can actually make that work in a functional way. At the moment genomes can only really be meaningfully understood or manipulated by folks like me with expensive and rare educations. This is because in order to create de novo anything like a solid grasp of how anything so beautiful as the lac operon works in E. coli one needs to have a pretty good understanding of how things like DNA-binding proteins work, how the structure of DNA relates to its function, how ligand binding works, how transcription initiation works, and how enzymes do their thing. Similarly, in order to have any hope of understanding how one would manipulate systems like that, you’d need to have a good understanding of how cell competency works and can be created, how to manipulate plasmid vectors, the anti-parallel nature of DNA , how to use antibiotics and resistance cassettes to select for desired strains, what TATA boxes do, how Shine-Delgarno sequences work, how RNA polymerases tend to like to bind, how to choose which regulation mechanism to use, and that doesn’t even include the technical skills necessary to actually do it yourself. Their idea is to turn genes, gene cassettes, and genetic systems into ‘BioBricks’ that their manipulators don’t need to understand to be useful (in a way analogous to how Perl programmers and Sys Admins don’t need to understand Assembly language to be useful) and can pay to have manipulated in industrially mechanized ways. At the moment the iGEM folks are using the levels of abstraction they can already create to harness to creativity of undergrads with their competition, but what may lie ahead is much much cooler.
Until this summer I did nothing but make fun of the nascent science of Synthetic Biology, having only been exposed to its many nuttier proponents. Maryr of Metafilter was absolutely right when she went all Mol Bio hipster and declared: “I heard of iGEM before it was cool. BioBricks is for people who can’t handle real cloning,” in this thread about what is still solidly iGEMs neatest project. BioBrick really is just a new name for gene cassette, things that have been actively studied and manipulated since the 60s. What convinced me that this could actually be really amazingly cool was a talk Drew Endy gave at the most recent Bacteriophage conference in Brussels about the research that is going on in his lab, the parts he needed from us, and why. (37:38) [Don’t be intimidated by the technical nature of the talk – even if you zone out during the technical bits you can totally still get the point]. In it, he describes his lab’s quest to create what amounts to a living computer – programmable systems architecture within E. coli. The current project involves using the architecture he is building to create a trivially readable clock that reads out in binary that would track the number of generations that a culture of bacteria has gone through – which would itself be amazingly useful. However, if created, these kinds of systems architecture combined with sensor proteins, enzymes, and regulator molecules understood as BioBricks could make life understandable by people who are to us as programmers are to hardware engineers. Here is another detailed talk focused more towards computer folks than biologists and here is another shorter talk he has given that is more geared towards laymen at a higher level of abstraction.
While I was sitting in that talk, knowing that the phage community does indeed have all of the parts he wants and then some, I couldn’t help but get goose bumps recalling one of my favorite stories from Science Fiction: The Nine Billion Names of God (part 2 ) by Arthur C. Clarke. Where suddenly I was, by way of analogy, a monk in his Lamasery slowly going about the task of annotating out the 10,000,000,000,000, 000,000,000,000,000,000 (1031) names of creation. If we really can systematize the genome of a living organism into neat little boxes like a well designed program according to the sensibilities and biases of human logic that would, in a very real and profound way, give us the ability to remake life in our own image in a way that very much evokes the line in Genesis that phrase comes from.
How cool would that be?
It is still however worth being very cautious about what promise synthetic biology may hold. There seems to be a whole cottage industry, particularly around the singularity movement, that has been set up to help people pretend they understand biology, and molecular genetics in particular, by calling it synthetic biology and making fanciful claims that people have different interests in being true. It preys on the scientific illiteracy of its audience counting on there being few enough people with the education to call them out on the sizable amount of fundamentally false false stuff they are communicating for them to get away with it. There are indeed huge limitations to this kind of thinking ever producing anything of meaningful value, which it has yet to do, that have nothing to do with a need for bigger computers or most anything else that singularity folks tend to point at as growing exponentially. The Singularity University is indeed an elaborate fraud run by folks with precious little understanding of biology.
1From the 1920s to the 1930s there was a mass movement of out of work physicists, having suddenly run out of things to do when we figured out to much of physics, to biology. They brought with them a mechanistic view of how the universe works that they used to cause massive transformations in how we understand and interact with biology. One of the most influential of these scientific interlopers was Max Delbrück who quickly reasoned that, if we were ever going to understand how life works, we would need to start with the simplest organism possible and work our way up. He isolated seven bacteriophages against E. coli B, originally just his lab strain, and named them in a series T1 through T7. The central idea was that he and his growing number of colleagues* would focus on truly understanding how these phages worked and use that knowledge to generalize to Escherichia coli, then the mouse, and then the elephant and us. An essential component of this was the “Phage Treaty” among researchers in the field, which Delbrück organized in order to limit the number of model phage and hosts so that folks could meaningfully compare results. What came out of their original focus, in many respects encapsulated in Erwin Schrödinger’s What is life?, has shed light on so much as to truly redefine our self-understanding, much less medicine
The Luria–Delbrück experiment elegantly demonstrated that in bacteria, genetic mutations arise in the absence of selection, rather than being a response to selection, that is in all of life.
The Hershey–Chase experiment showed once and for all that nucleic acids were in fact the heritable molecule in not just T2 phage and E. coli, but indeed all of life.
Easily the snarkiest, most badass, and likely most important published scientific paper ever, written as an accessible single page, about the double helix structure of DNA. Jim Watson changed majors from ornithology to genetics after reading What is Life and became Luria’s graduate student, while Crick was an older former physicist who also claimed inspiration from Schrödinger. The structure of DNA, and its relationship to function that they discovered, is true for all of life.
Soon afterwards the adapter hypothesis and central dogma, both of which are (at least simplistically) true for all of life.