Production of recombinant proteins by yeast plays a vital role in the biopharmaceutical industry. It is therefore desirable to develop yeast platform strains for over-production of various biopharmaceutical proteins, but this requires fundamental knowledge of the cellular machinery, especially the protein secretory pathway. Integrated analyses of multi-omics datasets can provide comprehensive understanding of cellular function, and can enable systems biology-driven and mathematical model-guided strain engineering. Rational engineering and introduction of trackable genetic modifications using synthetic biology tools, coupled with high-throughput screening are, however, also efficient approaches to relieve bottlenecks hindering high-level protein production. Here we review advances in systems biology and metabolic engineering of yeast for improving recombinant protein production.
Most of the time, when people talk about the cutting edge gene editing technology CRISPR, they are actually talking about CRISPR-Cas9. CRISPR, you see, is just one half of the genome editing tool, the programming that instructs where a DNA edit will actually be made. The other part consists of proteins that actually do the cutting. And one particular protein, called Cas9, has long been the snipping tool of choice. But now, there’s a new protein on the block—and it may open the door to curing a devastating genetic disease.
Scientists have long suspected that another protein, Cpf1, might actually be superior to Cas9 because it is a smaller, simpler enzyme. And now, for the first time, scientists have successfully used it to edit human cells.
In a new paper out Wednesday in Science Advances, researchers from the University of Texas detail using CRISPR-Cpf1 to correct mutations associated with Duchenne muscular dystrophy, a disease that results in muscular degeneration. In human heart muscle cells, the researchers were able to correct key mutations and prevent disease progression. And in mice with the disease, they were able to reverse symptoms like inflammation.
The authors note that CRISPR-Cpf1 may actually be more successful at targeting Duchenne muscular dystrophy, by accessing mutation sites the more unwieldy Cas9 can’t access. Cpf1, they said, could be a powerful new tool in the CRISPR arsenal. There are many different mutations associated with human disease, and not every mutation is compatible with Cas9. But some of those, as in the case of Duchenne, might be compatible with Cpf1.
In the midst of an ongoing legal battle over who owns the rights to CRISPR-Cas9, the new study highlights the fact that pace at which science moves may make today’s legal skirmishes far less relevant before they are ever settled. In 2015, the Broad Institute first suggested that CRISPR-Cpf1 might be a superior system. There are also a slew of other CRISPR alternatives in the works. In May, Chinese researchers published a controversial paper on NgAgo, an entirely new system that they said can also be used to edit mammalian DNA. In June, researchers from several universities announced the discovery of C2c2, a CRISPR enzyme that targets RNA, rather than DNA. And just before Christmas, researchers at Berkeley announced the discovery of two new CRISPR/Cas systems, CRISPR-CasX and CRISPR-CasY.
Most importantly, though, the study paves the way for more research into how Cpf1 might be used to cure diseases and conditions that even CRISPR-Cas9 has so far not yet been able to tackle.
The Synthetic Yeast Project (Sc2.0) aims to create the first synthetic eukaryotic genome. It is based on synthesizing, from scratch, a reworked Saccharomyces cerevisiae genome that is optimized for genomic stability and includes various design features to make it an easily engineerable chassis for future applications.
The increasing fossil fuel scarcity has led to an urgent need to develop alternative fuels. One of the most promising alternatives to petroleum for the production of fuels is microbial production. Yeasts are highly efficient producer of bioethanol with several superior traits over bacterial counterparts. Tools of synthetic biology has revolutionised the field of microbial cell factories especially in the case of ethanol and fatty acid production. Era of yeast synthetic biology began with the well-studied industrial work horse Saccharomyces cerevisiae. Despite many highly beneficial traits like ethanol tolerance, thermotolerance, inhibitor tolerance, genetic diversity, non-conventional yeast has for synthetic biology, it currently lags behind Sachharomyces cerevisiae in the number of synthetic networks that have been described. Currently synthetic biology is slowly widening to the non-conventional yeasts like Hansenula polymorpha, Kluyveromyces lactis, Pichia pastoris and Yarrowia lipolytica. Here we review basic synthetic biology tools that we can apply to non-conventional yeasts. Moreover we discuss how metabolic engineering and synthetic biology tools can be applied in nonconventional yeasts for improved biofuel production.
In order to deal with the complexity of biological systems and attempts to generate applicable results, current biomedical sciences are adopting concepts and methods from the engineering sciences. Philosophers of science have interpreted this as the emergence of an engineering paradigm, in particular in systems biology and synthetic biology. This article aims at the articulation of the supposed engineering paradigm by contrast with the physics paradigm that supported the rise of biochemistry and molecular biology. This articulation starts from Kuhn's notion of a disciplinary matrix, which indicates what constitutes a paradigm. It is argued that the core of the physics paradigm is its metaphysical and ontological presuppositions, whereas the core of the engineering paradigm is the epistemic aim of producing useful knowledge for solving problems external to the scientific practice. Therefore, the two paradigms involve distinct notions of knowledge. Whereas the physics paradigm entails a representational notion of knowledge, the engineering paradigm involves the notion of ‘knowledge as epistemic tool’.
The arms race between prokaryotes and their perpetually evolving predators has fueled the evolution of a defense arsenal. The so-called CRISPR-Cas systems—clustered regularly interspaced short palindromic repeats and associated proteins—are adaptive immune defense systems found in bacteria and archaea. The recent exponential growth of research in the CRISPR field has led to the discovery of a diverse range of CRISPR-Cas systems and insight into their defense functions. These systems are divided into two major classes and six types. Each system consists of two components: a locus for memory storage (the CRISPR array) and cas genes that encode the machinery driving immunity. Information stored within CRISPR arrays is used to direct the sequence-specific destruction of invading genetic elements, including viruses and plasmids. As such, all CRISPR-Cas immune systems are reliant on the formation of CRISPR memories, known as spacers, to facilitate future defense. To form these memories, small fragments of invader nucleic acids are added as spacers to the CRISPR memory banks in a process termed CRISPR adaptation. The genetic basis of immunity means that CRISPR adaptation provides heritable benefits, an attribute that is unparalleled in eukaryotic immune systems. There is widespread evidence of highly active CRISPR adaptation in nature, and it is clear that these systems play important roles in shaping microbial evolution and global ecological networks. ADVANCES CRISPR adaptation requires several processes, including selection and processing of spacer precursors and their subsequent localization to, and integration into, the CRISPR loci. Although our understanding of all facets of the CRISPR adaptation pathway is not yet complete, considerable progress has been made in the past few years. At the heart of CRISPR adaptation is a protein complex, the Cas1-Cas2 “workhorse,” which catalyzes the addition of new spacers to CRISPR memory banks. A combination of functional assays and high-resolution structures of Cas1-Cas2 complexes has recently led to major advances. There is now a sound understanding of how foreign DNA is converted to prespacer substrates and captured by the Cas1-Cas2 complex. After this, Cas1-Cas2 locates the genomic CRISPR locus and docks in the appropriate position for insertion of the new spacer into the CRISPR array, while duplicating a CRISPR repeat. The cues directing the docking of substrate-laden Cas1-Cas2 differ between systems, with some relying on intrinsic sequence specificity and others assisted by host proteins.
Before integration, accurate processing of the spacer precursors is required to ensure that the new spacers are compatible with the protein machinery in order to elicit CRISPR-Cas defense. For a given CRISPR-Cas system, spacers must typically be of a certain length and be inserted into the CRISPR in a specific orientation. It is becoming increasingly apparent that Cas1-Cas2 complexes from diverse systems are capable of ensuring that these system-specific factors are met with high fidelity.
New findings also account for the ordering of stored memories: Typically, the insertion of new spacers is directed to one end of CRISPR arrays, and it has been shown that this enhances immunity against recently encountered invaders. The chronological ordering of new spacers has enabled insights into the temporal dynamics of interactions between hosts and invaders that are constantly changing. Some CRISPR-Cas systems use existing spacers to recognize previously encountered elements and promote the formation of new CRISPR memories, a process known as primed CRISPR adaptation. Viruses and plasmids that have escaped previous CRISPR-Cas defenses through genetic mutations trigger primed CRISPR adaptation. Several recent studies have revealed that primed CRISPR adaptation is also strongly promoted by recurrent invaders, even in the absence of escape mutations. This has led to previously separate paradigms of invader destruction and primed CRISPR adaptation beginning to converge into a unified model. OUTLOOK CRISPR adaptation is crucial for ensuring both population-level protection through spacer diversity and protection of the host through invader clearance. Although many studies have explored CRISPR adaptation in a broad range of host-specific and metagenomic contexts, much of the mechanistic detail has been gleaned from studying a relatively small subset of systems. Thus, despite the relative wealth of mechanistic information about CRISPR adaptation in a few specific types, work in other systems continues to reveal distinct modes of operation for spacer acquisition. Therefore, studies of CRISPR adaptation in alternative systems are necessary to determine which processes are conserved and which are system-specific. An important remaining question is why the enhanced primed CRISPR adaptation commonly found in type I systems has not yet been observed in other types. Do other systems possess analogous mechanisms that have yet to be discovered, or does the absence of priming in these systems explain the prevalence of type I systems in nature? Future expansion of our understanding of how CRISPR adaptation is carried out in the diverse repertoire of CRISPR-Cas systems is vital for maximizing the potential for repurposing the spacer acquisition machinery in biotechnological applications. Commandeering CRISPR adaptation for on-demand memory formation will usher in a new era of biological information storage, with many applications that await discovery.
Jason Sheltzer, a cancer biologist at Cold Spring Harbor Laboratory in New York, was on the hunt for genes involved in tumour growth. He and his colleagues planned to disable genes using the popular gene-editing tool CRISPR–Cas9, then look for changes that reduced the rate at which cancer cells multiply. But they needed a control gene that would yield that same effect.
The literature suggested that the gene MELK was ideal: there was ample evidence that it is important in cancer-cell proliferation, and clinical trials are under way to test drugs that inhibit the MELK protein. But disabling the gene using CRISPR–Cas9 yielded no effect. “That threw a monkey wrench into our experiments,” says Sheltzer. “It brought everything to a halt.”
Related stories Enzyme tweak boosts precision of CRISPR genome edits RNA interference rebooted Cancer screen yields drug clues More related stories With that result, Sheltzer and his team joined an expanding club of laboratories that have been forced to re-evaluate and repeat experiments, as the spread of CRISPR–Cas9 uncovers potential errors in data collected using older techniques. On 3 April, Sheltzer's team presented the findings at the American Association for Cancer Research annual meeting in Washington DC. The results have also been published in the journal eLife1.
“There’s a whole lot of work to be done, just basically repeating the same screens that people had done” with other methods, says Michael Bassik, a molecular biologist at Stanford University in California. “And, I think it’s fair to say, to get much better data.”
Scale of the problem Nathan Lawson, a molecular biologist at the University of Massachusetts Medical School in Worcester, was one of the first to systematically characterize the problem. In 2015, he and his colleagues reported their efforts to compare results from two methods in zebrafish: knocking out genes using a gene-editing technique called zinc finger nucleases, and reducing gene expression using molecular tools called morpholinos. They found that half of the 20 genes they tested yielded different results2. An additional trawl through genetic databases and the morpholino literature revealed that 80% of results from published morpholino experiments were not reproducible in genetic mutants2.
Some zebrafish researchers said they welcomed the paper because it forced the community to confront a problem that had only been noted anecdotally. Others were not so happy. “I got some people who told me I ruined the field,” says Lawson.
Similar conflicts have cropped up in other organisms. In the model plant Arabidopsis thaliana, the use of CRISPR–Cas9 showed that a protein previously thought to mediate the effects of the plant hormone auxin does not have that function3. In fruit flies and human cells, large screening studies have turned up widespread discrepancies between results obtained using RNA interference (RNAi) — a technique that reduces gene expression — and those from genetic mutants4.
Both methods have their limitations, notes Lawson. RNAi occasionally alters the expression of genes other than its desired target. And meddling with the cell’s internal RNA-processing machinery can sometimes affect other cellular systems that involve RNA. CRISPR–Cas9 gene editing, meanwhile, requires breaking strands of DNA — which can trigger other responses in the cell, including cell suicide. And the technique can also sometimes cut DNA at unintended sites.
Back to basics Conflicting results from RNAi and genetic screens do not always mean that one approach was right and the other was wrong, cautions Bassik. Some cells might respond differently to a genetic change that wipes out expression of a gene, as is often the goal with CRISPR–Cas9, compared to how they respond to reducing the expression to very low levels with RNAi.
But often, he adds, the culprit behind the discrepancy can be tracked back to RNAi’s potential for off-target effects. And concerns about that have had researchers flocking to reproduce old results.
In the case of MELK, the CRISPR–Cas9 results are particularly concerning because they could undermine the scientific foundation for a clinical trial. But Sheltzer’s team showed only that MELK does not seem to have a role in cancer-cell division, notes Carlos Moreno, a cancer researcher at Emory University in Atlanta, Georgia. It is possible that other aspects of MELK, such as its purported role in making cancer cells more resistant to radiation[5], are still valid, he says.
And many successful drugs have been developed on the back of a faulty scientific hypothesis, he adds. The MELK inhibitors in clinical trials might work through some other mechanism, for instance. “That would be no reason to stop a trial if the trial is showing positive effects,” he says. “It’s important not to throw the baby out with the bathwater.”
We have developed an abiotic-biotic interface that allows engineered cells to control the material properties of a functionalized surface. This system is made by creating two modules: a synthetically engineered strain of E. coli cells and a functionalized material interface. Within this paper, we detail a protocol for genetically engineering selected behaviors within a strain of E. coli using molecular cloning strategies. Once developed, this strain produces elevated levels of biotin when exposed to a chemical inducer. Additionally, we detail protocols for creating two different functionalized surfaces, each of which is able to respond to cell-synthesized biotin. Taken together, we present a methodology for creating a linked, abiotic-biotic system that allows engineered cells to control material composition and assembly on nonliving substrates.
We are pleased to invite you to participate in the Fourth International Mammalian Synthetic Biology Workshop (mSBW 4.0) (Download flyer). This workshop will explore the latest trends and advances in the field, including recent foundational accomplishments and applications in addressing challenges to human health and beyond. This one-and-a-half day meeting brings together world’s leading researchers in synthetic biology, mammalian and cellular biology, and bioengineering from academic as well as industry partners. Our scientific program will include topics in many applications of Genome Engineering & Epigenome Biology, Systems & Genetic Circuits, Developmental & Regenerative Biology, Therapeutic Delivery Systems, and a panel on Synbio Regulatory: “Moving Synthetic Biology to Clinic”
We are also soliciting your contributions as SHORT TALKS and/or POSTERS as a means to disseminate the most up-to-date research and commercial applications which complement the presentations from the leaders in these fields. Submit your Abstract by March 31st.
–Please join us as we build the foundation for this exciting and promising new field
mSBW 4.0 will be held at Boston University on May 6-7, 2017 at CILSE
Developmental biology is mainly analytical: researchers study embryos, suggest hypotheses and test them through experimental perturbation. From the results of many experiments, the community distils the principles thought to underlie embryogenesis. Verifying these principles, however, is a challenge. One promising approach is to use synthetic biology techniques to engineer simple genetic or cellular systems that follow these principles and to see whether they perform as expected. As I review here, this approach has already been used to test ideas of patterning, differentiation and morphogenesis. It is also being applied to evo-devo studies to explore alternative mechanisms of development and ‘roads not taken’ by natural evolution.
Our planet is made up of 3.8-billion years of biodiversity, including five past mass extinctions brought about by climate change that wiped the slate clean, forcing organisms to start from scratch. Now, many scientists believe we could experience a sixth mass extinction in our lifetime, the Anthropocene – the human epoch. While we struggle to reverse and slow down the effects of global warming, a number of people have speculated on what Earth could look like after what's known as a “great dying”. One such project is Alexandra Daisy Ginsberg's Designing for the Sixth Extinction.
Rapid, inexpensive, and sensitive nucleic acid detection may aid point-of-care pathogen detection, genotyping, and disease monitoring. The RNA-guided, RNA-targeting CRISPR effector Cas13a (previously known as C2c2) exhibits a “collateral effect” of promiscuous RNAse activity upon target recognition. We combine the collateral effect of Cas13a with isothermal amplification to establish a CRISPR-based diagnostic (CRISPR-Dx), providing rapid DNA or RNA detection with attomolar sensitivity and single-base mismatch specificity. We use this Cas13a-based molecular detection platform, termed SHERLOCK (Specific High Sensitivity Enzymatic Reporter UnLOCKing), to detect specific strains of Zika and Dengue virus, distinguish pathogenic bacteria, genotype human DNA, and identify cell-free tumor DNA mutations. Furthermore, SHERLOCK reaction reagents can be lyophilized for cold-chain independence and long-term storage, and readily reconstituted on paper for field applications.
Synthetic biology is a recent scientific approach towards engineering biological systems from both pre-existing and novel parts. The aim is to introduce computational aided design approach in biology leading to rapid delivery of useful applications. Though the term reprogramming has been frequently used in the synthetic biology community, currently the technological sophistication only allows for a probabilistic approach instead of a precise engineering approach. Recently, several human health applications have emerged that suggest increased usage of synthetic biology approach in developing novel drugs. This mini review discusses recent translational developments in the field and tries to identify some of the upcoming future developments.
In his famous article “The Unreasonable Effectiveness of Mathematics in the Natural Sciences” Eugen Wigner argues for a unique tie between mathematics and physics, invoking even religious language: “The miracle of the appropriateness of the language of mathematics for the formulation of the laws of physics is a wonderful gift which we neither understand nor deserve” (Wigner 1960: 1). The possible existence of such a unique match between mathematics and physics has been extensively discussed by philosophers and historians of mathematics (Bangu 2012; Colyvan 2001; Humphreys 2004; Pincock 2012; Putman 1975; Steiner 1998). Whatever the merits of this claim are, a further question can be posed with regard to mathematization in science more generally: What happens when we leave the area of theories and laws of physics and move over to the realm of mathematical modeling in interdisciplinary contexts? Namely, in modeling the phenomena specific to biology or economics, for instance, scientists often use methods that have their origin in physics. How is this kind of mathematical modeling justified?
Swiss biomedical company regenHU has partnered with UK-based synthetic biomaterial producer PeptiGelDesign Technologies to release a series of synthetic bioinks for 3D bioprinting. The ready-to-print bioinks were developed for applications in tissue engineering and 3D cell biology.
Proteins are the workhorses of all living creatures, fulfilling the instructions of DNA. They occur in a wide variety of complex structures and carry out all the important functions in our body and in all living organisms—digesting food, building tissue, transporting oxygen through the bloodstream, dividing cells, firing neurons, and powering muscles. Remarkably, this versatility comes from different combinations, or sequences, of just 20 amino acid molecules. How these linear sequences fold up into complex structures is just now beginning to be well understood (see box).
Even more remarkably, nature seems to have made use of only a tiny fraction of the potential protein structures available—and there are many. Therein lies an amazing set of opportunities to design novel proteins with unique structures: synthetic proteins that do not occur in nature, but are made from the same set of naturally-occurring amino acids. These synthetic proteins can be “manufactured” by harnessing the genetic machinery of living things, such as in bacteria given appropriate DNA that specify the desired amino acid sequence. The ability to create and explore such synthetic proteins with atomic level accuracy—which we have demonstrated—has the potential to unlock new areas of basic research and to create practical applications in a wide range of fields.
The design process starts by envisioning a novel structure to solve a particular problem or accomplish a specific function, and then works backwards to identify possible amino acid sequences that can fold up to this structure. The Rosetta protein modelling and design software identifies the most likely candidates—those that fold to the lowest energy state for the desired structure. Those sequences then move from the computer to the lab, where the synthetic protein is created and tested—preferably in partnership with other research teams that bring domain expertise for the type of protein being created.
At present no other advanced technology can beat the remarkable precision with which proteins carry out their unique and beautiful functions. The methods of protein design expand the reach of protein technology, because the possibilities to create new synthetic proteins are essentially unlimited. We illustrate that claim with some of the new proteins we have already developed using this design process, and with examples of the fundamental research challenges and areas of practical application that they exemplify:
The ability to electronically interface living cells with electron accepting scaffolds is crucial for the development of next-generation biophotovoltaic technologies. Although recent studies have focused on engineering synthetic interfaces that can maximize electronic communication between the cell and scaffold, the efficiency of such devices is limited by the low conductivity of the cell membrane. This review provides a materials science perspective on applying a complementary, synthetic biology approach to engineering membrane-electrode interfaces. It focuses on the technical challenges behind the introduction of foreign extracellular electron transfer pathways in bacterial host cells and the past and future efforts to engineer photosynthetic organisms with artificial electron-export capabilities for biophotovoltaic applications. The article highlights advances in engineering protein-based, electron-exporting conduits in a model host organism, E. coli, before reviewing state-of-the-art biophotovoltaic technologies that use both unmodified and bioengineered photosynthetic bacteria with improved electron transport capabilities. A thermodynamic analysis is used to propose an energetically feasible pathway for extracellular electron transport in engineered cyanobacteria and identify metabolic bottlenecks amenable to protein engineering techniques. Based on this analysis, an engineered photosynthetic organism expressing a foreign, protein-based electron conduit yields a maximum theoretical solar conversion efficiency of 6-10% without accounting for additional bioengineering optimizations for light-harvesting.
Clustered regularly interspaced short palindromic repeats (CRISPR)–Cas systems provide protection against viral1 and plasmid2 infection by capturing short DNA sequences from these invaders and integrating them into the CRISPR locus of the prokaryotic host1. These sequences, known as spacers, are transcribed into short CRISPR RNA guides3, 4, 5 that specify the cleavage site of Cas nucleases in the genome of the invader6, 7, 8. It is not known when spacer sequences are acquired during viral infection. Here, to investigate this, we tracked spacer acquisition in Staphylococcus aureus cells harbouring a type II CRISPR–Cas9 system after infection with the staphylococcal bacteriophage ϕ12. We found that new spacers were acquired immediately after infection preferentially from the cos site, the viral free DNA end that is first injected into the cell. Analysis of spacer acquisition after infection with mutant phages demonstrated that most spacers are acquired during DNA injection, but not during other stages of the viral cycle that produce free DNA ends, such as DNA replication or packaging. Finally, we showed that spacers acquired from early-injected genomic regions, which direct Cas9 cleavage of the viral DNA immediately after infection, provide better immunity than spacers acquired from late-injected regions. Our results reveal that CRISPR–Cas systems exploit the phage life cycle to generate a pattern of spacer acquisition that ensures a successful CRISPR immune response.
Whole-genome engineering appears to be moving forward apace. The first synthetic biology effort to build a comprehensively re-designed eukaryotic genome
We have developed an abiotic-biotic interface that allows engineered cells to control the material properties of a functionalized surface. This system is made by creating two modules: a synthetically engineered strain of E. coli cells and a functionalized material interface. Within this paper, we detail a protocol for genetically engineering selected behaviors within a strain of E. coli using molecular cloning strategies. Once developed, this strain produces elevated levels of biotin when exposed to a chemical inducer. Additionally, we detail protocols for creating two different functionalized surfaces, each of which is able to respond to cell-synthesized biotin. Taken together, we present a methodology for creating a linked, abiotic-biotic system that allows engineered cells to control material composition and assembly on nonliving substrates.
Synthetic biologist Tal Danino manipulates microorganisms in his lab to create eye-catching, colorful patterns. Here’s a look at the process he uses to turn “Oh, yuck” into “Oh, wow.”
Synthetic biologist Tal Danino washes his hands constantly, one of the occupational hazards of working with bacteria all day at the Synthetic Biological Systems Lab, which he runs at New York City’s Columbia University. Danino, a TED Fellow, spends most of his time trying to harness bacteria’s unique properties — the same properties that can make them so dangerous for humans – and turn them into powerful cancer fighters. But when he’s not programming bacteria to fight cancer, he’s programming them to make art, in part to make difficult scientific principles more accessible. “It’s nice to use the visual arts to help communicate science,” he says, “and that’s because art really transcends the boundaries of language and also of knowledge.” Danino’s recent creative endeavors include a feminist installation of bacterial cultures taken from the bodies of 100 women (for which he collaborated with conceptual artist Anicka Yi), as well as a series of ceramic dishes inspired by naturally occurring bacterial patterns (a collaboration with artist and photographer Vik Muniz). For his latest project, Microuniverse, he produced a series of dazzling, abstract images created by different species of bacteria, each grown under different conditions for varying lengths of time. “The project is about getting to see this unseen universe that’s really small and all around us, every day,” he says. Here, he describes some of his strangely beautiful projects.
Synthetic biology was founded as a biophysical discipline that sought explanations for the origins of life from chemical and physical first principles. Modern synthetic biology has been reinvented as an engineering discipline to design new organisms as well as to better understand fundamental biological mechanisms. However, success is still largely limited to the laboratory and transformative applications of synthetic biology are still in their infancy. Here, we review six principles of living systems and how they compare and contrast with engineered systems. We cite specific examples from the synthetic biology literature that illustrate these principles and speculate on their implications for further study. To fully realize the promise of synthetic biology, we must be aware of life's unique properties.
In this work we consider Pareto optimality for automated design in synthetic biology. We present a generalized framework based on a mixed-integer dynamic optimization formulation that, given design specifications, allows the computation of Pareto optimal sets of designs, i.e. the set of best trade-offs for the metrics of interest. We show how this framework can be used for (i) forward design, i.e., fnding the Pareto optimal set of synthetic designs for implementation, and (ii) reverse design i.e. analyzing and inferring motifs and/or design principles of gene regulatory networks from the Pareto set of optimal circuits. Finally, we illustrate the capabilities and performance of this framework considering four case studies. In the first problem we consider the forward design of an oscillator. In the remaining problems, we illustrate how to apply the reverse design approach to find motifs for stripe formation, rapid adaption, and fold-change detection, respectively.
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