Diversity By Design
by Christina Agapakis, Scientific American
"The recent Nature paper from Jef Boeke’s group, “Synthetic chromosome arms function in yeast and generate phenotypic diversity by design,” begins with an appropriately futuristic sentence: “The first phase of any genome engineering project is design.” While there have been efforts to redesign viral genomes and chemically synthesize bacterial genomes, whole genomes of living cells are not yet something that can readily be designed from scratch. This new paper (excellently reviewed by Lab Rat a while back) approaches the design of genomes in a fascinating way; instead of trying to decide in advance what a good engineered/engineerable genome looks like or simply copying an existing genome, they designed the sequence of one arm of a yeast chromosome (about 90,000 base pairs) with built-in genetic flexibility, enabling future experiments and future evolution.
While the paper’s abstract states that “The ability to synthesize large segments of DNA allows the engineering of pathways and genomes according to arbitrary sets of design principles,” the principles they chose are hardly arbitrary. First, the synthetic chromosome arm must work in a living yeast without hurting the cell, and second, the new design should be free of any sequences that could make the strand unstable, which both seem reasonable enough. Third and most importantly, the genome should incorporate diversity by design. This design principle includes three useful and interesting sub-strategies:
- replacing all the TAG stop codons with TAA stop codons, to allow for coding a new amino acid
- including “tag” sequences that allow the researchers to track the parts of their synthetic sequence easily without sequencing the whole chromosome and
- adding sequences that can SCRaMbLE the genome.
SCRaMbLE stands for synthetic chromosome rearrangement and modification by loxP-mediated evolution, and is a method for large chunks of the genome to flip and recombine with each other, rapidly generating large sequence diversity. The sequence is therefore not fixed but designed to change, to mutate, to recombine, to evolve. Activating SCRaMbLE created many mutations that made the cell less able to grow in certain conditions, perhaps violating the first design principle but at the same time opening up interesting roads to study the genetics, genome structure, and evolution of yeast.
Activating evolution in the lab can be used to refine an important trait, like making enzymes more stable or making yeast that can tolerate higher concentrations of ethanol in brewing, or even create new behaviors through a combination of synthetic biology and directed evolution. George Church, a pioneer in genome engineering writes in a great essay in The Scientist that “Lab evolution and synthetic biology are about embracing the outliers and creating the occasional hopeful monster, just as evolution has done for millions of years.”
These outliers don’t come from nowhere, they emerge in evolution through chance mutations in the genome or recombination of chunks of DNA like a natural SCRaMbLE. These changes in the existing DNA allow evolution to explore what origin of life researcher Stuart Kauffman calls “the adjacent possible.” Steven Johnson, author of Where Good Ideas Come From: A Natural History of Innovation, writes in an excerpt in the WSJ that “the adjacent possible is a kind of shadow future, hovering on the edges of the present state of things, a map of all the ways in which the present can reinvent itself.” By constantly mutating, recombining, and refining, bumping up into the adjacent possible, evolution has brought us from inorganic molecules floating in water to the diversity and complexity of life that exists today.
The adjacent possible doesn’t apply only to the evolution of gene sequences and cells, but as the title of Johnson’s book suggests, it also applies to the recombination of ideas and the hopeful monsters of design and technology. Designers Anab Jain, Jon Ardern, and Justin Pickard of Superflux use the concept of the adjacent possible to discuss their approach to speculative “design futurescaping” in Blowup: The Era of Objects: “Positing an unevenly-distributed futurity, many of the components of our speculations as design futurescapers are already out there, in the wild. We visualise images of genetically-engineered bees, artificial clouds, and network cold-zones, and, as science-fictional novums, they seem plausible because so much of their technological and social underpinnings already exist, in however nascent a form.” Recombining all the weird and wonderful technological and social bits and pieces of our present world (many delightfully curated as Daily Idioms by Deb Chachra), we can better imagine and create a future one.
The very best synthetic biology ideas act by activating the adjacent possible in every sense, innovating by recombining ideas and parts shared openly between researchers but also activating the adjacent possible of evolution and the serendipitous recombination of genes, building diversity, evolution, and change into the very DNA of a design."
By Christina Agapakis