June 15, 2016 (Vol. 36, No. 12)
GEN’s Expert Panelists Discuss Technologies and Products That They Are Developing and Share Their Visions of Where Synbio Is Heading
According to Synberc, a multi-university research program established in 2006 with a grant from National Science Foundation, synthetic biology draws on multiple academic disciplines to stage a coordinated advance toward two goals: 1) The design and construction of the core components of new biological entities such as enzymes, genetic circuits, and cells. 2) The redesign of existing biological systems.
Synthetic biology is progressing rapidly, so GEN recently interviewed several “synbio” experts to get a better sense of the technologies and products that they are developing. GEN also asked the experts to share their visions of where synbio is heading.
GEN: What synthetic biology projects are you currently working on?
Dr. Collins: We are working on engineering microbes to serve as living diagnostics and living therapeutics for a variety of infections and complex disease conditions. We are also developing paper-based synthetic biology diagnostic platforms, including a rapid, low-cost diagnostic test for Zika.
Dr. Gibson: Some recent projects are the creation of JCVI-syn1.0, the first bacterial cell to contain a completely synthetic genome, and JCVI-syn3.0, which (currently) contains the smallest genome of any self-replicating organism, with just 473 genes. For the first time, we’re writing and not just editing the genetic code of a cell. These synthetic genomes are platforms that allow us to investigate the fundamental essence of cellular life.
What are the applications of these synthetic organisms? JCVI-syn3.0 can be used as the starting point for adding and manipulating metabolic pathways for functional analyses. Future applications include the design of organisms for discrete purposes, for instance, the one-day production of medicines. The field of whole-genome design, analysis, and application is emerging from its infancy.
Dr. Golding: We are developing reporters for measuring gene activity at unprecedented resolution, moving beyond the whole (single-)cell to the subcellular level of an individual copy of the gene. This resolution will allow us to ask how the transcriptional activity of the gene is affected by the presence of additional copies of the same gene within the same cell, and how the activity changes during the cell cycle. The ultimate goal is to measure all the relevant cellular parameters such that we can describe gene activity precisely and remove as much as possible the role of “noise” (stochasticity) from the process.
Dr. Leonard: My research group engineers novel biological systems that perform customized, sophisticated functions for a variety of applications in biotechnology and medicine. Using the tools of synthetic biology, protein engineering, and computational systems biology, we develop technologies such as mammalian and microbial cell-based “devices,” immune therapies for cancer and chronic disease, novel gene-delivery platforms, smart vaccines, biosensors for global health applications, and adaptable metabolic engineering platforms.
Dr. McMillen: We pursue several parallel research themes: 1) developing systematic design principles for biological regulatory systems, drawing on mathematical approaches from control theory and elsewhere; 2) building systems exploiting new modes of biological regulation, like activating RNA and targeted activation using modified T7 polymerases; and 3) cheap, cell-based solutions to health and other problems.
We’re working on a cellular biosensor that can detect disease antibodies in a low-cost, low-infrastructure way that makes it appealing for low-resource applications. Partnerships in the Philippines and the Caribbean are helping us target the system to local needs.
We’re also collaborating with a team of medical researchers and engineers to develop a bacterial system to sense and regulate molecular concentrations in the intestine, with applications in treating inflammatory bowel diseases.
Mr. Munnelly: Synthetic DNA is a foundational tool used in the field. Our focus is the further scaling of our platform to continue providing game-changing economics and quality for scientists using DNA. With sophisticated design algorithms, chip-based oligo synthesis, and error-correction technologies, our BioFab® platform builds 100% clonal sequence-verified synthetic DNA constructs up to 10,000 base pairs in length in a massively-parallel fashion.
This year, we’ve demonstrated the ability to multiplex 50 DNA synthesis reactions in a single well, enabling us to build 50 gene-length constructs simultaneously. Gene-synthesis demand is approximately 1 billion base pairs per year. A 50× increase in capacity could represent synthesis of multibillion base pairs in our small facility and will drive costs to subpennies per base pair when fully implemented.
Dr. Rosser: We have a wide array of projects in synthetic biology relevant to industrial biotechnology, medicine, and healthcare. In industrial biology, we are reconstructing the metabolic pathways for useful chemicals such as terpenes from plants and transferring these into yeast, and we are engineering bacteria to produce electricity. In mammalian systems, we are developing tools for making the engineering of mammalian cells easier. We are using these tools to re-engineer cells to enhance production of biologic drugs, and creating novel biosensors for diagnostics and drug testing.
More broadly, in SynthSys at the University of Edinburgh, synthetic biology approaches are being explored for extracting copper nanoparticles from distillery byproducts, thereby reducing environmental impacts. In medicine, we are engineering bacteriophage to work as selective antimicrobials, and creating synthetic controllers of cell morphology to make tissue engineering a reality.
GEN: How would you describe the current state of synthetic biology both from a research perspective and from a funding standpoint? In other words, is the field in a good spot right now scientifically and in terms of financial support?
Dr. Collins: The field of synthetic biology is still quite young and taking baby steps toward being able to engineer biology in a predictive, efficient manner. The field is relatively well funded with strong support coming from DARPA, ONR, DTRA, USAF, NIH, NSF, and a variety of private foundations including the Paul Allen Foundation and the Gates Foundation.
Dr. Gibson: From a research perspective, there has never been a more exciting time in the field of synthetic biology. A major outcome of the minimal genome project has been the development of new gene-assembly tools and the automation of gene construction and cloning through the BioXp instrument. These tools and the BioXp instrument are commercially available through SGI-DNA. As far as funding goes, this is not unique to synthetic biology, but is true for life sciences research in general—because of the scarcity of government funding, private money is a huge driving force behind new discovery.
Dr. Golding: We’re in very exciting times. The capability for precise genetic manipulation is being combined with the capability for high-throughput synthesis and measurements, dramatically advancing our ability to create and characterize synthetic biology elements. An important lesson regarding funding is that new techniques still come from doing basic science: Without curiosity-driven research into the lives of simple bacteria, we would never have CRISPR or recombineering. Nor, of course, any of the earlier tools of molecular biology.
Dr. Leonard: Both research activity and financial support for synthetic biology have broadened as the field matures, which is an encouraging sign that applications are increasingly being pursued and realized. In large part, application-driven research can be supported by mechanisms that have traditionally supported those goals. Therefore, support for truly interdisciplinary investigations, which fall between the missions of major funding mechanisms, remains just as vital today as it was when some relatively moderate investments initially helped to launch the field.
Dr. McMillen: In Canada, synthetic biology has not yet received anything like the level of federal funding attention it has enjoyed elsewhere (the U.S. and the U.K. have made substantial investments, for example). Canada has a strong base of expertise in both biology and biological engineering, and I think we’re in a good position to lead a variety of synthetic biology efforts.
It is fair to say that the funding agencies have not yet embraced it as a vital research area to support. Globally, synthetic biology is thriving: great work is being done, and new capabilities are continually being developed.
Mr. Munnelly: The field of synthetic biology is stronger than ever in terms of research and investment. For example, 2015 was a huge year for synthetic biology with both the private sector and governments making giant investments. It was reported that over $500 million was invested in synthetic biology startups last year. This is becoming the trend—the U.K. alone has invested over $300 million in the last few years.
This year’s upcoming International Genetically Engineered Machine (iGEM) competition just surpassed the 300-team threshold—the most in the competition’s history. Students are getting more involved in synbio research earlier, which means more talent in synbio in the years to come. Pair this with technological breakthroughs and the scaling of gene synthesis, and breakthroughs are inevitable.
Dr. Rosser: The U.K. government has invested over £300M in delivering a synthetic biology roadmap over the past three years helping to put the U.K. at the forefront in this rapidly emerging technology space. Edinburgh has benefited from this and now has a new £13.4 center for mammalian synthetic biology research and a fully automated DNA assembly capability.
We also benefit from funding to stimulate research collaboration with industry and will be able to tap into the U.K.’s dedicated seed venture fund and industrial support for product development. With a newly published “roadmap 2.0” we hope that this commitment to synthetic biology will continue as we need further investment in underpinning research if we are to stay ahead.
GEN: Looking toward the future, say 10 years from now, what types of innovative and revolutionary synthetic biology products or processes might we expect to see?
Dr. Collins: In the coming decade, we will see a number of innovative synthetic biology products, including: 1) engineered therapeutic microbes for treating rare genetic metabolic disorders and other complex disease conditions; 2) paper-based diagnostics for a variety of bacterial infections, viral infections, and complex disease conditions such as cancer; and 3) rapid synthesis protocols for creating synthetic gene networks and other biomolecular constructs.
Dr. Gibson: I believe synthetic biology could one day solve many of the global sustainability challenges we face. As a society it’s not just about bringing novel solutions to market, but having solutions that enable a healthier planet. Synthetic biology, and programs we currently have at Synthetic Genomics, can tackle challenges across industries, from biofuels to textiles to medicines. As an example, we’ve already shown that synthetic biology can be harnessed for an improved influenza vaccine.
Over the next decade, we’ll start seeing vaccines produced that are much more efficacious, much more rapidly. Pharmaceuticals produced using synthetic biology could be constructed on an individual basis (personalized medicine), rather than produced en masse, resulting in more precise targeting of disease. The possibilities are boundless: wearing clothes constructed from renewable, bio-based sources; driving a car that runs on biofuel; drinking from biodegradable plastic containers; “printing” therapies at the bedside. These applications would be monumental.
Dr. Golding: We are still far from fulfilling the vision of synthetic biology, where (in analogy to electronic circuits) we can assemble discrete elements and successfully predict how the resulting system will behave. This is because (unlike electronics) we still lack quantitative understanding of the most fundamental cellular processes (e.g., transcription) in even the simplest model systems.
Thus, a prerequisite to meaningful synthetic biology is progress towards the formation of a quantitative, experiment-based description of cellular processes, at the level of individual molecules in the single cell. I’m hoping that the technological advancements described above, when combined with theoretical modeling of the experimental data, will allow us to move forward towards obtaining this description.
Dr. Leonard: Although prediction is difficult (especially regarding the future), there are several areas in which substantial progress is expected. The total number of small molecule products manufactured via metabolic processes is likely to continue to grow. Whether this growth will be disruptive over the next 10 years remains to be seen, but it is within the realm of possibility.
Given the remarkable promise of cell-based immunotherapy of cancer, this area is likely to expand substantially beyond the treatments for B-cell malignancies that established the first toehold in the area of engineered cell-based therapies. Other, more speculative, possibilities include the use of engineered human cells as well as engineered microbiota to treat chronic conditions including autoimmune diseases, inflammation, and even obesity. Another compelling possibility is technology for meeting emerging public health needs, including therapeutics tailored to protect against infections that arise along with travel by both vectors and humans.
Dr. McMillen: The low-hanging fruit is in applications like biosensing and the industrial production of biological molecules: things that don’t need to operate inside a human body. Synthetic biology’s most significant industrial success, artemisinin precursor production, is an example of the kind of thing that we can expect to see a lot more in the coming decade: cells are efficient producers of complex molecules, and the cost advantages of these approaches are increasingly being recognized industrially.
Using cells as low-cost solutions for detection, whether of disease states or environmental toxins or other targets, is another front on which I expect to see significant progress in the next 10 years. Longer term, there’s a lot of exciting potential for synthetic biology to make an impact on medical treatments, but it’s worth keeping in mind how lengthy the process of development and clinical testing tends to be.
Mr. Munnelly: In 10 years, we will see the eradication of mosquito-borne diseases. Waiting lists for organs will be eliminated as immune-compatible organs are created via animals or 3D printers. We will synthesize a treasure trove of new therapeutic agents, treatments aided by better production of induced pluripotent stem cells made from donors themselves.
Materials and data storage industries will also greatly advance as synthetic biology enables both archival storage and retrieval. It will be possible to replace costly tape backups. Today, we use thousands of warehouses of servers. In 10 years, we will store all of that data in an amount of DNA that fits in a small closet in one of those warehouses.
New biomaterials will be made in bioreactors from engineered microorganisms for industrial applications and new clothing. Finally, food shortages will be addressed with better agriculture or cultured foods. Basically, synthetic biology will be addressing gaping needs in human health, planetary sustainability, and energy.
Dr. Rosser: We are already benefiting from some of the industrial applications of synthetic biology, and over the next decade, we anticipate that even more everyday products will be bio-derived. However, we believe that the truly innovative “game changing” applications for synthetic biology will be for human medicine to help generate better clinical outcomes and reduce healthcare costs.
Personalized medicine will become a reality when we can recapitulate an individual’s pathophysiology “in a dish” using synthetically modified adult cells and identify effective therapies in vitro. We see the successful implementation of theranostics: cells engineered to incorporate genetics circuits that can sense hallmarks of disease or dysfunction and activate a therapeutic response.
Integrating stem cell and synthetic biology approaches will generate new routes for reliable and cost-effective sources of transplantable cells for restoring tissue functions lost through trauma or disease.
