Metabolic pathways SynBio is fighting a headwind of complexity, resource intensive product development and barriers to market. Image credit: U.S. DOE. 2006. Breaking the Biological Barriers to Cellulosic Ethanol: A Joint Research Agenda, DOE/SC/EE-0095 http://genomicscience.energy.gov/biofuels/
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Protein is the Killer App for Synthetic Biology

Engineering pathways is still an art, and commercializing the results can be difficult. The protein production pathway is a remarkable exception, scaling reliably and offering new kinds of functionality for products. With more examples of innovative commercial applications becoming available, protein is SynBio’s killer application.

With vivid images of petroleum bubbling to the surface of an algae covered pond, Synthetic Biology (SynBio) promises to be the philosopher’s stone of bioproduction— creating just about any material imaginable — plastics, fuel, flavorings, therapeutics, and bringing the trillion dollar petrochem economy to sustainability. Even so, SynBio has had a hard time delivering.

SynBio products have multiple barriers to market

Complexity is always the enemy of progress. In the case of SynBio, even modest increases in the number of enzymes in a pathway increases the work and time required exponentially. For each enzyme, additional variables like cofactors, competing pathways and cell viability enter the equation. When microbial strains that make any one of millions of compounds are created, they start by producing tiny amounts — often around a few milligrams per liter.

After adding the metabolic pathway, significant problems with getting a SynBio product to market can be encountered during the process of scaling a product in fermentation as well as navigating the sales chain of multi-ton markets for commodity chemicals.

Each class of compounds presents almost as a unique problem, and even for pathways of modest length, substantial time and resources must be brought to bear to discover new solutions.  

And yet even now, despite the obstacles, there are successful companies making biochemicals. Zymergen, among other companies, is an amazing example of an exception to the current rule of the struggling SynBio startup.

But if SynBio had a killer app  then the field could have greater impact. What I mean is an application that is so needful and works so consistently that it could establish biotech as a ubiquitous technology platform, opening the way for many startups to establish a broad, strong, and accessible market.

Protein production scales by a work function

When it comes to the issues of strain engineering, scale, and market, one type of pathway is a remarkable exception. Producing protein has proven to be a leading basis for a new generation of biotech companies and has enormous untapped potential.

Rapid protein turnover is related to cell survival, and so protein production can run in high gear in any organism. Protein-making strains can be nearly perfect factories — in some cases converting 90+% of the dry mass carbon of feedstock into product.

(Figure generated by author.)

This is good news, as a killer app must have, at its core, log scaling .  As production is scaled up, costs and efficiencies must change by orders of magnitude for the app to make business sense. The classic example of this reality is found in computing power and the software industry: in going from hertz to gigahertz, Moore’s Law scaled across eight orders of magnitude.

Scaling for protein production is a work function — the more work you put into a protein producing strain, the better the yield. In the crude estimate in the figure, I attempt to include both fermentation scaling and strain engineering costs over time. Typically over the course of 10+ years, the costs associated with producing a gram of protein drops by up to a factor of 10,000 and can fall to as little as dollars per pound. This has amazing implications for proteins as commodity, but the status of protein as a killer app also owes to the fact that proteins have new classes of functionality in addition to scale.

The Protein Tech Future

In terms of user adoption, proteins are only just starting to see their potential realized. Proteins and small molecules are the yin and yang of cellular function. Small molecules are synthesized and transformed by proteins, while proteins are activated and modulated by small molecules as well as by each other. In the end, though, the vast majority of biological function is performed by proteins.

Proteins are extremely versatile in their structure and function. Proteins can make available devices and materials that are both scalable and completely new, and were simply not possible before.  We can only begin to imagine what kinds of technologies will be brought about in the SynBio protein space.

Already many companies are breaking ground with enormous promise. Several are fashion and food companies, which represent previously unheard-of end markets for SynBio companies.

Bolt Threads, Spiber and AmSilk are making spider silk.The idea of making spider silk —which is  stronger than steel and lighter than cotton–commonly available  is mind-boggling. Millions of spiders were needed to produce a spider silk cape in 2009. The spiders were literally yoked and milked for their silk by hand. As the new spider silk companies edit and access the silk genes from the tens of thousands of spiders around the world, materials of differing adhesion, strength and elasticity will be possible. Imagine bulletproof outerwear, performance sportswear, or construction cranes that fold into a moving van.

GelTor, a company I helped to fund, is making vegan gelatin through fermentation strains, but more profoundly it is a biomaterials platform of incredible versatility. Collagen is already a material that is used nearly everywhere from food to cosmetics to reconstructive surgery.  Usually derived by boiling a livestock animal carcass in acid, GelTor can provide any of the millions of collagen genes from millions of animals and microbes in bulk. There are limitless new materials and applications whose cost will drop in time: performance pharmaceutical delivery systems, scaffolds for organ reconstruction, or biodegradable leather materials for building, fashion or consumer packaging.

On top of this, proteins are largely responsible for the texture and mouthfeel, flavor, and nutritional profiles of food. Clara Foods is discovering the direct connection between proteins and the many many culinary uses for eggs. Taking the various separate protein components of egg whites, they have made meringues that do not weep as well as pastas that are lower in cost but firmer in texture.  In french cuisine, the chef’s toque has 100 folds for the 100 ways to cook an egg.  Maybe with the help of SynBio it could be 300.

Use of proteins as a tech platform has been taken up by large companies already.  Hampton Creek has become a plant based protein materials company, as has Modern Meadow whose platform is based on a technology called collagen scaffolding.

The action and interaction of proteins will continue to astonish us as companies leap ahead in their discovery of new products rather than replacements for the ones we know, creating novel economic vistas.

Consider gluten. Although a humble wheat protein, it has generated cuisines across continents. It activates when wetted, forms networks that create bubbles, fibers, and the scaffold for many of the most appealing foods we know. Engineered gluten has the potential to mitigate allergic reactions, create new textures, and new categories of food. But can it also inspire building and fabrication materials? Bioplastics? Self-assembling devices? All of these possibilities are up-and-coming, and proteins can be scaled much more quickly from prototype to product than can a tech device.

Given all this, there is an incredible need for better tools. Already several platforms are being created to jumpstart protein production to a much higher initial productivity than a starter strain. Right now the best industrial strains have beaten 100 grams/liter in production. How can we reach those sort of results more quickly and consistently and for any chosen sequence?  Can we find even better systems and methods for protein production from the standpoint of sustainability and desirable post-translational modifications?

Indeed these are challenges, but they are ones that are quite possible to meet in the next few years.

Like the article? Read more of Ron’s writings on Medium: https://medium.com/@rshigeta

Ron Shigeta is the CSO of IndieBio. Ron did his academic training at Princeton, Stanford and Harvard Medical School and is a 15 year veteran of Biotech in the Bay Area, working at Affymetrix and as a serial biotech startup entrepreneur. Being an early adopter and scientific advisor to the Do-it-Yourself Bio (DIYBio) movement has influenced the flavor of lean startup models being created at IndieBio.

Ron is a veteran of the biotechnology industry in the San Francisco Bay Area and has built several startups during his industry career as employee, consultant and principal. Ron was a Scientist for Affymetrix, a bioinformatician, biohacker (at BioCurious) and co-founder of Berkeley BioLabs. He can troubleshoot or build anything in the lab, from cells to robotics! Ron received his PhD in Chemistry from Princeton University focusing in biophysics.

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Ron Shigeta

Ron Shigeta

Ron Shigeta PhD, CSO IndieBio. Ron did his academic training at Princeton, Stanford and Harvard Medical School and is a 15 year veteran of Biotech in the Bay Area, working at Affymetrix and as a serial biotech startup entrepreneur. Being an early adopter and scientific advisor to the Do-it-Yourself Bio (DIYBio) movement has influenced the flavor of lean startup models being created at IndieBio.

Ron is a veteran of the biotechnology industry in the San Francisco Bay Area and has built several startups during his industry career as employee, consultant and principal. Ron was a Scientist for Affymetrix, a bioinformatician, biohacker (at BioCurious) and co-founder of Berkeley BioLabs. He can troubleshoot or build anything in the lab, from cells to robotics! Ron received his PhD in Chemistry from Princeton University focusing in biophysics.

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