Emerging platforms for organism engineering

Synthetic biology 5.0 wrapped up a couple weeks ago and attending the conference reinforced for me that the field has developed sufficiently over the past few years that we are now seeing different platforms and/or schools of thought in how to engineer organisms start to coalesce.

Chris Voigt gave a nice talk about how his lab harvests large, functional operons from nature, like the nitrogen fixation gene cluster, and goes through a process of refactoring to standardize the control and gene expression elements in order to gain complete control over the pathway. (The refactoring approach was first pioneered by Drew, Sri and Leon.) Unfortunately, refactoring currently appears to lead to a gene cluster that has less activity than what nature provided, but yet there is less concern over unknown or cryptic biology. Interestingly, Chris says that in all his lab’s refactoring efforts (which involves several years of design-construction-debugging by Karsten), they never really discovered new or interesting biology but rather tended to get tripped up by errors in the sequence databases or incorrectly annotated start sites for genes.

John Glass and Dan Gibson both gave talks about genome synthesis and genome upload technologies that came out of JCVI (see PMIDs 17600181, 18218864, 19073939, 19363495, 19696314, 20211840, 20488990, 20935651). The JCVI/Synthetic Genomics platform might be thought of as combining (meta)genome sequencing and genome synthesis to make organisms from scratch.

Zach Serber discussed the Automated Strain Engineering (ASE) platform at Amyris. They are able to build 1500 yeast strains start to finish in 3 weeks (though they do pipeline their process). They have a library of 12,000 parts which they draw from to make up to 6 gene constructs using sewing PCR and then integrate into yeast. He didn’t go into their assay platforms but briefly mentioned that they do a combination of high-throughput screening and ‘omics analysis.

Doug Densmore, Jake Beal and Ron Weiss are working on Bio-Design Automation: namely, the ability to translate a high-level functional specification to successively lower abstraction levels (i.e. devices, parts etc.) until you get the actual DNA sequence that you then construct using automated DNA assembly.

And while it wasn’t presented in detail in a talk at SB5.0, Jef Boeke, Jean Peccoud and collaborators are developing a platform for yeast chromosome redesign. Finally, of course there is the Tom Knight/iGEM/Registry of Standard of Biological Parts approach to synthetic biology which inspired aspects of many of the above platforms.

I imagine that at least a fraction of the would-be biological engineers out there might find the platform or tools aspects of synthetic biology mundane and prefer to focus on the organisms that they can design and build. But I’d argue that every synthetic biologist should care deeply about what the platforms look like. There’s a better than even chance that the future of synthetic biology lies in decoupling design from fabrication and testing. If so, the organism engineers in the future will submit their designs to centralized facilities where designs get batched, fabricated on robots and then [maybe] undergo a preliminary analysis. Hence, the platforms that get designed today are going to dictate the design constraints to which organism engineers will be forced to adhere tomorrow. Over time, the relative merits of each platform’s design constraints will be judged based on the complexity and utility of the engineered organisms that they produce.

Given all the above, you might be asking, what exactly is Ginkgo’s platform for organism engineering? I’ll cover that in a subsequent post …

Posted By: Reshma Shetty