Powered by a chemical reaction controlled by microfluidics, the 3D-printed 'octobot' has no electronics
By Leah Burrows, SEAS Communications
(CAMBRIDGE, Massachusetts) — A team of Harvard University researchers with expertise in 3D printing, mechanical engineering, and microfluidics has demonstrated the first autonomous, untethered, entirely soft robot. This small, 3D-printed robot — nicknamed the octobot — could pave the way for a new generation of completely soft, autonomous machines.
Eventbrite - ThinkSTEAM presents Synthetic Biology Workshop with Columbia University's iGEM Team - Saturday, October 1, 2016 at Lasker Biomedical Research Building, New York, NY. Find event and ticket information.
Algae (a term used to group many photosynthetic organisms into a rather heterologous mash-up) do not have a kind place in the public imagination. Take for example the following passage from Stephen King’s Pet Semetary:
“Dead fields under a November sky, scattered rose petals brown and turning up at the edges, empty pools scummed with algae, rot, decomposition, dust… “
Leaving aside their use in a horror novel as a way to set an image of decay, algae attract significant scientific attention, and are even considered cool (well, at least by some). But when I tell people I work on algal Synbio, one question that eventually comes up (or is silently implied) is why do I bother, when there are more prominent and better-developed systems? In this blog I will try to partly address this point of view, as well as provide a small perspective on the subject.
The practical benefits of algae for humans date back to the days of early photosynthesis, when they produced the oxygenic atmosphere we currently breathe. Moreover, algal forms were the ancestors of chloroplasts and land plants. Today, algae are found in almost every environment, in having various forms and ecological roles. But what is their place in synthetic biology?
In terms of algal synthetic biology and biotechnology, there are two main research domains: eukaryotic microalgae and cyanobacteria.
The model for studying eukaryotic microalgae is Chlamydomonas reinhardtii—although the use of more species is being explored. C. reinhardtii can be transformed both via nuclear and chloroplast transformation, each having different potentials (e.g. random insertion vs. homologous recombination, eukaryotic vs. prokaryotic translation and protein maturation, etc.)
One of the goals of synthetic biology is to develop programmable artificial gene networks that can transduce multiple endogenous molecular cues to precisely control cell behavior. Realizing this vision requires interfacing natural molecular inputs with synthetic components that generate functional molecular outputs. Interfacing synthetic circuits with endogenous mammalian transcription factors has been particularly difficult. Here, we describe a systematic approach that enables integration and transduction of multiple mammalian transcription factor inputs by a synthetic network. The approach is facilitated by a proportional amplifier sensor based on synergistic positive autoregulation. The circuits efficiently transduce endogenous transcription factor levels into RNAi, transcriptional transactivation, and site-specific recombination. They also enable AND logic between pairs of arbitrary transcription factors. The results establish a framework for developing synthetic gene networks that interface with cellular processes through transcriptional regulators.
From individual cells deciding how to differentiate during development, to social insects intricately coordinating their actions when scavenging for food; the ability to perform complex computations and process information enables life. The Biocompute Lab explores biology from this perspective, focusing on the molecular-scale mechanisms that individual cells and groups of cells use to perform such tasks. We apply tools and methods from the field of synthetic biology to create new living systems from the ground-up. By studying these artificial systems using novel techniques we are developing that exploit next-generation sequencing, microfluidics and computational modelling, we aim to better understand the rules governing how biological parts are best pieced together to perform useful computations. Understanding the computational architecture of cells opens new ways of reprogramming cells to tackle problems spanning the sustainable production of materials to novel therapeutics. It also provides key insights into how biology controls the complex processes and structures that sustain life. The Biocompute Lab falls within BrisSynBio, a BBSRC/EPSRC Synthetic Biology Research Centre at the University of Bristol.
An MIT spinout, Synlogic, is aiming to create a new class of medicines, by re-programming bacteria found in the gut as “living therapeutics.”
Based on research by its co-founders, MIT professors Tim Lu and Jim Collins, Synlogic creates so-called synthetic biotics, which sense and correct metabolic abnormalities that underlie some major diseases and rare genetic disorders.
Human intestines are filled with trillions of bacteria, collectively called the microbiota, that carry out vital health functions. Synlogic’s synthetic biotics — capsules, liquid suspensions, or other dosage forms that can be taken regularly — augment the microbiota with new metabolic capabilities or complement lost functionality in organs such as the liver.
“Over the past decade or so, the intricate connections between microbes and our bodies have become clearer and clearer, and it’s well known now that the bacteria that live in our gut have a major influence on human health,” says Lu, an associate professor of electrical engineering and computer science and of biological engineering, and head of MIT’s Synthetic Biology Group, who serves as scientific advisor for Synlogic. “We leverage that interface as a way of treating human disease.”
Last month, Synlogic raised an additional $40 million in venture capital and secured its first industry partnership with pharmaceutical giant AbbVie. For the partnership, Synlogic will collaborate with AbbVie to develop synthetic biotics for the potential treatment of inflammatory bowel disease, which may include probiotic microbes programmed to detect intestinal inflammation, and produce anti-inflammatory molecules or break down pro-inflammatory effectors.
Two of Synlogic’s main candidate drugs, expected to enter clinical trials during the next 12 months, treat rare genetic metabolic disorders. One drug candidate is for treating urea cycle disorder (UCD), which is caused by an enzyme deficiency that leads to a buildup of toxic ammonia in the blood. The other is for treating phenylketonuria (PKU), which involves a dangerous excess of the amino acid phenylalanine due to a mutation in another metabolic enzyme. In both cases, Synlogic’s drugs process and flush out the toxic metabolites from the body.
Think of Synlogic’s drugs like biological thermostats, says Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Department of Biological Engineering and Institute for Medical Engineering and Science, who also chairs Synlogic’s scientific advisory board. Instead of identifying and regulating the temperature of a room, he says, “The synthetic biotics detect and regulate the amount of an enzyme or metabolic byproduct in a patient’s body.”
Programming E. coli
For more than a decade at Boston University and MIT, Collins and Lu (who is Collins’ former student) have been developing “genetic circuits” for bacteria, which include on/off switches made with synthetic DNA or RNA sequences that instruct the bacteria to count, store memory, and even perform logic.
Collins and Lu have used these genetic circuits to program bacteria to seek and cure infection. In 2011, this approach earned Collins funding from the Bill and Melinda Gates Foundation to engineer bacteria to detect cholera and produce targeted antimicrobial peptides to treat it.
A few years ago, Lu and Collins, along with several venture capitalists, launched Synlogic to focus on commercializing “a new class of therapeutics based on living cells,” Collins says. In 2014, Synlogic came out of stealth mode, securing $30 million in funding from venture firms and the Gates Foundation.
Since then, Synlogic has worked primarily on programming E. coli Nissle, a strain of bacteria derived from the gut that is also used widely and safely as a probiotic. The programmed E. coli Nissle, Lu says, provides greater precision, safety, and efficacy for disease treatment, compared with traditional methods.
For inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, for instance, current treatments include small-molecule drugs or antibodies with anti-inflammatory properties. But the challenge is getting the right dosage, Lu says. “If you apply too little, it’s not going to work. If you apply too much, you have a chance you may immunosuppress the patient and cause side effects,” he says.
Synlogic can “program microbes to detect inflammation and make anti-inflammation molecules at the site of inflammation, as well as produce molecules that positively impact immune system function,” Collins says.
Then there’s the more rare but debilitating urea cycle disorder, which affects 2,000 to 6,000 people in the United States and impairs their ability to processes ammonia. If ammonia builds up too much and reaches the brain, it can lead to brain damage, coma, and death. The best available treatment option for people with UCD today is a liver transplant.
Synlogic aims to treat UCD with a daily biotic that functions in a surprising way: “It can decrease the ammonia in the bloodstream, without even contacting the blood,” Lu says.
Ammonia levels in the bloodstream, he explains, are dependent on ammonia production in the large intestine. Synlogic’s biotic converts intestinal ammonia into an amino acid, which is flushed out of the body through the stool, thereby dramatically reducing the flow of ammonia to the blood and reducing ammonia levels in the bloodstream.
Synlogic’s biotic for PKU, which affects 13,000 people in the United States, functions in a similar way, to regulate the processing and extraction of phenylalanine. PKU patients must adhere to a lifelong, extremely low-protein diet that can result in serious developmental disorders, because they can’t eat normal foods that contain phenylalanine — including many meat, dairy, and seafood products. “If we can degrade phenylalanine with convenient administration of this probiotic, that will change the course of this disease,” Lu says.
Collins says Synlogic has potential to treat many other rare genetic metabolic disorders. But the recent AbbVie deal, he says, also “opens up possibilities of using these microbes to produce biologics or other small molecules to treat a range of conditions.” These include cardiovascular disease and autoimmune, oncology, and central nervous system disorders, which have been linked to metabolic dysregulation.
Reaching clinical efficacy
Part of the reason that probiotic treatments are not used for serious diseases is their lack of clinically validated efficacy. Synlogic, on the other hand, aims to overcome these efficacy issues with potent and precision-programmed synthetic biotics, Lu says.
For example, in engineering the safe and easily programmable E. coli Nissle, Synlogic engineers have designed the microbe to consume a massive amount of toxic metabolites. The E. coli Nissle strain that forms the basis of Synlogic’s UCD program, for instance, can consume orders of magnitude more ammonia than natural E. coli can, Lu says. “For this treatment to work for patients, you want the max performance you can squeeze out of any one of these biotics,” he says.
Based on their preclinical data, Synlogic’s treatments have the potential to reach “clinical levels” of efficacy not seen often in synthetic biology, says Collins: “Synlogic is programming these probiotic microbes to consume ammonia or phenylalanine for example, and they are reaching levels that are expected to be clinically meaningful, which is quite remarkable.”
RNA is involved in a wide-range of important molecular processes in the cell, serving diverse functions: regulatory, enzymatic, and structural. Together with its ease and predictability of design, these properties can lead RNA to become a useful handle for biological engineers with which to control the cellular machinery. By modifying the many RNA links in cellular processes, it is possible to reprogram cells toward specific design goals. We propose that RNA can be viewed as a molecular programming language that, together with protein-based execution platforms, can be used to rewrite wide ranging aspects of cellular function. In this review, we catalogue developments in the use of RNA parts, methods, and associated computational models that have contributed to the programmability of biology. We discuss how RNA part repertoires have been combined to build complex genetic circuits, and review recent applications of RNA-based parts and circuitry. We explore the future potential of RNA engineering and posit that RNA programmability is an important resource for firmly establishing an era of rationally designed synthetic biology.
Changing environments pose a challenge to living organisms. Cells need to gather and process incoming information, adapting to changes in predictable ways. This requires in particular the presence of memory, which allows different internal states to be stored. Biological memory can be stored by switches that retain information on past and present events. Synthetic biologists have implemented a number of memory devices for biological applications, mostly in single cells. It has been shown that the use of multicellular consortia provides interesting advantages to implement biological circuits. Here we show how to build a synthetic biological memory switch using an eukaryotic consortium. We engineered yeast cells that can communicate and retain memory of changes in the extracellular environment. These cells were able to produce and secrete a pheromone and sense a different pheromone following NOT logic. When the two strains were cocultured, they behaved as a double-negative-feedback motif with memory. In addition, we showed that memory can be effectively changed by the use of external inputs. Further optimization of these modules and addition of other cells could lead to new multicellular circuits that exhibit memory over a broad range of biological inputs.
Life on Earth is incredibly diverse. Yet, underneath that diversity, there are a number of constants and highly conserved processes: all life is based on DNA and RNA; the genetic code is universal; biology is limited to a small subset of potential chemistries. A vast amount of knowledge has been accrued through describing and characterizing enzymes, biological processes and organisms. Nevertheless, much remains to be understood about the natural world. One of the goals in Synthetic Biology is to recapitulate biological complexity from simple systems made from biological molecules–gaining a deeper understanding of life in the process. Directed evolution is a powerful tool in Synthetic Biology, able to bypass gaps in knowledge and capable of engineering even the most highly conserved biological processes. It encompasses a range of methodologies to create variation in a population and to select individual variants with the desired function–be it a ligand, enzyme, pathway or even whole organisms. Here, we present some of the basic frameworks that underpin all evolution platforms and review some of the recent contributions from directed evolution to synthetic biology, in particular methods that have been used to engineer the Central Dogma and the genetic code.
We define a new inversion-based machine called a permuton of n genetic elements, which allows the n elements to be rearranged in any of the n·(n – 1)·(n – 2)···2 = n! distinct orderings. We present two design algorithms for architecting such a machine. We define a notion of a feasible design and use the framework to discuss the feasibility of the permuton architectures. We have implemented our design algorithms in a freely usable web-accessible software for exploration of these machines. Permutation machines could be used as memory elements or state machines and explicitly illustrate a rational approach to designing biological systems.
About the Cover: The cover artwork shows an artist's rendition of programmable biology: a brittle star of the species Gorgonocephalus arcticus occupies the central processor slot on a motherboard. Artwork by Ana Vásquez based on an illustration by naturalist Ernst Haeckel.
The ability to record molecular events in vivo would enable monitoring of signaling dynamics within cellular niches and critical factors that orchestrate cellular behavior. We present a self-contained analog memory device for longitudinal recording of molecular stimuli into DNA mutations in human cells. This device consists of a self-targeting guide RNA (stgRNA) that repeatedly directs Streptococcus pyogenes Cas9 nuclease activity toward the DNA that encodes the stgRNA, thereby enabling localized, continuous DNA mutagenesis as a function of stgRNA expression. We demonstrate programmable and multiplexed memory storage in human cells triggered by exogenous inducers or inflammation, both in vitro and in vivo. This tool, Mammalian Synthetic Cellular Recorder Integrating Biological Events (mSCRIBE), provides a unique strategy for investigating cell biology in vivo and enables continuous evolution of targeted DNA sequences.
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