IEEE PULSE presents

Next-Gen Gene Synthesis Enables Large-Scale Engineering in Biological Systems

Feature September/October 2015
Author: Devin Leake

As scientists make strides toward the goal of developing a form of biological engineering that’s as predictive and reliable as chemical engineering is for chemistry, one technology component has become absolutely critical: gene synthesis. Gene synthesis is the process of building stretches of deoxyribonucleic acid (DNA) to order—some stretches based on DNA that exists already in nature, some based on novel designs intended to accomplish new functions. This process is the foundation of synthetic biology, which is rapidly becoming the engineering counterpart to biology.
Synthetic biology, still a relatively new field, aims to alter existing organisms to function differently or to build completely new genetic elements or even whole organisms from scratch. Already, synthetic biology has been used successfully to tweak microbes to consume more oil—useful for treating oil spills in the ocean—or to process materials more efficiently to generate important components for biofuels or industrial chemicals. These advances offer tremendous promise for the goal of finding alternatives to petroleum-based fuels and materials.
Scientists using synthetic biology rely on custom-built DNA parts or small components that allow them to engineer a biological system. The field really began in 2000, with two separate achievements: teams at Boston University and at Princeton University developed the first genetic toggle switch and the first three-gene oscillator, respectively. While these may be just rudimentary engineering tools, they served as the first way to perturb a genetic network with excellent reliability and predictability. These first tools, and those created since, have been compiled by the BioBricks Foundation and the Registry for Standard Biological Parts as a freely available catalog of useful engineering widgets. Today, the parts registry includes more than 7,000 available genetic components.
These parts, and the broader synthetic biology work they serve, are built with gene synthesis. This field is innovating as well: a new approach to manufacturing synthetic DNA at higher capacity and lower cost is enabling much larger-scale synthetic biology work than has ever been possible.
This article looks at three major areas where synthetic biology offers significant value and impact, and describes new gene synthesis technology that is dramatically increasing the scale of engineering that can be applied to biology.

Therapeutics, Biofuels, and Sensors

Therapeutic development, biofuel production, and environmental sensor design have all seen marked improvement through synthetic biology. Alternatives to traditional techniques have led to cost savings, better efficiency, faster development, and other innovations.
Finding new ways to produce therapeutics is necessary for a number of reasons. For instance, the rise in antibiotic-resistant bacteria— especially in light of people who are allergic to broad classes of existing antibiotics—necessitates the rapid development of new antibiotics, but these have been few and far between with traditional pharmaceutical methods. Synthetic biology could offer a strong alternative for designing, screening, and testing new antibiotic candidates as well as for manufacturing validated ones more rapidly. For example, it is possible that scientists could make chimeric DNA constructs based on what is already known about antibiotics, insert those into engineered yeast, and mass produce new therapeutics.
Yeast has already been an important organism for the application of synthetic biology to the production of biopharmaceuticals. A yeast called Pichia pastoris has been engineered to add certain functions, so it can produce therapeutics it normally couldn’t. The first biopharmaceutical produced from Pichia, Dyax’s Kalbitor, was recently approved by the U.S. Food and Drug Administration.
Another therapeutic example comes from artemisinin, an antimalarial drug that has long been produced from plants in a costly and tedious method. Synthetic biology company Amyris engineered yeast strains to generate artemisinic acid, which can be turned into the therapeutic. Drug giant Sanofi recently announced that it implemented this approach for industrial-scale production of artemisinin, with the goal of manufacturing some 150 million treatments in its first year alone.
Synthetic biology has also been valuable in the biofuel industry, which found limited success in making alternative fuels from crops like corn that were already in high demand for food. The shift to engineering microbes to produce nonpetroleum fuels has provided a more sustainable and attractive approach for biofuels. Algae, E. coli, and yeast have been the most commonly used organisms, with research going into adjusting biological pathways to optimize fuel production and reduce unwanted byproducts.
For example, scientists have worked to boost organisms’, such as sunflowers, natural ability to process fatty acid feedstocks. One team streamlined the E. coli genome, removing competing biological pathways, so the microbe was dedicated to processing these fatty acids and producing ethanol, butanol, and other compounds at high yield. Another team used synthetic biology to transplant a useful genetic pathway from bacteria into yeast, where its presence helped the organism ferment sugars into ethanol with great efficiency. Other scientists have found that engineered algae can produce more yield per acre than plant-based biofuels.
Aside from industrial uses like therapeutic and biofuel development, synthetic biology has also been used to create an array of sensors for environmental toxins and more. These sensors, many designed by teams participating in an annual synthetic biology competition for undergraduates, show the broad potential for engineering with biology. Students have built sensors to detect arsenic in drinking water; cigarette toxins in air; phenol in marine environments, and much more. Most sensors use engineered bacteria to detect a specific element, and the biological activity of detection triggers a reporting signature, such as a color change or a fluorescent glow.

Scaling Gene Synthesis

For all of these synthetic biology efforts, gene synthesis—or the ability to design a new stretch of DNA and then have it custom-made so scientists can insert it into an organism and see how it functions in real life—is the foundational technology. Until recently, gene synthesis could only be done accurately for very short pieces of DNA; longer stretches required stitching snippets together in a tedious process that led to errors and required significant hands-on time. The uptake of synthetic biology for industrial-scale use depends on highly accurate gene synthesis for even the longest pieces of custom DNA.
A new technology developed by Joseph Jacobson at Massachusetts Institute of Technology, Drew Endy at Stanford University, and George Church at Harvard University provides the first truly scalable approach to gene synthesis. Commercialized by Gen9, the technology is based on silicon chips with a unique error-correction process that allows for the massively parallel construction of custom DNA. Accuracy, length, and cost are all dramatically improved with the first exponentially scalable gene synthesis approach, known as the BioFab platform.
This next-generation gene synthesis will allow scientists to use synthetic biology for much larger-scale projects than have been possible in the past. Future advances in therapeutic development, biofuel production, and sensor design stand to have even greater impact than they already have. These and industries as diverse as agbio, enzyme and chemical design, and electronics are poised for remarkable innovation as synthetic biology scales up.

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