SynBio Newsreel, July 2017

A day may come when I break these into several smaller posts. But it is not this day!

Biohacking is coming to Chicago!

• Excited to announce the launch of ChiTownBio, a community biohacking/DIYbio organization. Our mission is to put the knowledge, skills, and tools of biotechnology into the hands of all Chicagoans who want to explore the living world and use it to benefit our community. Our kickoff event will be hosted at the Empirical Brewery on Wednesday August 9th at 7 pm. We will, among other things, make a DNAquiri, a cocktail that extracts and makes visible the DNA in strawberries.

Podcasts

• The GeneMods podcast has new episodes! This month, we had a fascinating conversation with professor Julius Lucks about engineering RNA, and learned about lots of new synbio developments in the news quiz. We also recorded an extra episode about synthetic biology in science fiction.
• GeneMods isn’t the only group talking about synbio on SoundCloud! I’ve reposted a bunch of synbio-related podcast episodes onto the GeneMods channel. Two of my favorites: an interview with NASA astrobiologist/bioengineer/badass Lynn Rothschild, and a conversation with CoderDojo founder and SOSV partner Bill Liao about a tech investor’s perspective on biohacking.

Videos

• All the talks from SB7.0 are now freely available online! Three of my favorites: Omar Akbari’s talk about how gene drives might be used for conservation; Linda Kahl’s talk about open sharing in biology, which ends with the announcement of the 10,000 free genes initiative; and David Kong’s talk about DIYbio, Metafluidics, and connecting the  hip hop/DJing world to synbio.

Books

• Synthetic: How Life Got Made, by Sophia Roosth, is a first-person account of the birth of synthetic biology, as well as an anthropological analysis and critique of the field. The chapter on biohacking and DIYbio is particularly good. Great read.
• Last month, before I had the chance to read it, I recommended A Crack in Creation, by Jennifer Doudna and her former student Samuel Sternberg. Now I’ve read it, and I recommend it even more. The context it provides on the history of genetic modification, gene therapy, and the discovery of CRISPR is very useful, but my favorite parts are the last few chapters, where Doudna talks about the future, and how her own views have evolved on germline gene editing.

Blogs and Community News

• Favorite new magazine: Neo.life. A Medium-based publication started by Jane Metcalfe (one of the founders of Wired!), it focuses on engineering biology, mainly from a health and human augmentation perspective. Their book reviews and recommendations in particular are outstanding.
• My favorite science writer, Ed Yong, covered a lot of synthetic biology this month. He wrote about yeast biosensors to quickly and cheaply detect cholera; Kevin Esvelt’s efforts to employ gene drives to improve human health, protect endangered species, and change the way science is done; and on how Seth Shipman wrote a digital image and a GIF into the DNA of living bacteria by repurposing the memory part of the CRISPR immune system.
• Newsweek ran a cover story about synthetic biology in academia and industry. A good one to send to your friends and family members who wonder what synthetic biology is all about.

Policy and Bioethics

• The MIT Technology Review is reporting that human embryos have been edited with CRISPR in the US for the first time, by the lab of Shoukrat Mitalipov in Oregon. Moreover, it sounds like the new work has overcome technical hurdles related to editing efficiency and off-target cleavage. Rubicon, crossed.
• An editorial in the Baltimore Sun by Gigi Gronvall argues that the US must redouble its investment in synthetic biology and biotechnology, in order to maintain its edge in the 21st century world economy.
• This thought-provoking essay on Biopunk and Subverting Biopolitics from Heather Dewey-Hagborg, Simone Brown and Joerg Blumtritt is definitely worth reading.
• The convergence of conservation and synthetic biology continues. The Audubon Society published an in-depth article exploring the potential of gene drives for protecting endangered bird species.

Biosecurity

• Since FBI special agent Scott Mahloch is coming to talk to GeneMods, here’s a profile of his boss Ed You by the always-excellent Antonio Regalado.
• The Pentagon has partnered with the National Academy of Sciences to review the threat posed and policy around synthetic biology research. What are they worried about? Among other things, stuff happening in Canada:
• Not cool, Canada. A team at the University of Alberta lead by David Evans synthesized a horsepox virus (a relative of smallpox) from scratch for about $100,000 and 6 months of work. The purpose of this research was to learn to synthesize poxviruses as a possible way to kill cancer tumors, but it has prompted concern and discussion of dual-use in synthetic biology.
• Not new news, but worth reading: this decade-old Technology Review article about the Soviet Union’s bioweapons development program, and the way the biosecurity community grapples with its implications. Particularly poignant given how precipitously the price, time and skill required for the molbio techniques described continue to fall.
• DARPA just awarded grants from its Safe Genes program to seven teams. The awardees will attempt to develop technologies to make gene editing ‘safer’ by reducing, stopping, or reversing unwanted/dangerous edits. Particularly excited to see Kevin Esvelt’s team get funding to study self-limiting gene drives.

Industry and Funding

• DuPont Pioneer has secured exclusive rights to agricultural use of Emmanuel Charpentier’s CRISPR IP, via a license from ERS genomics. However, it’s not clear how ‘exclusive’ these exclusive rights are, since Monsanto has already non-exclusively licensed CRISPR for agriculture from the Broad institute. Perhaps DuPont now owns all rights in Europe, while it will need to share with Monsanto in the US?
• Google is getting into the engineered mosquito business. Alphabet subsidiary Verily has announced plans to grow and release (in California!) 20 million male mosquitos infected and sterilized with Wolbachia, a bacterium which prevents the bugs from producing viable offspring.
• Speaking of mosquitoes, Oxitec has just signed a contract to release its genetically sterilized ‘Friendly Aedes’ mosquitoes in Brazil.
• Maxx Chatsko writes that at current prices, it would cost ~$2 billion to make a 1 terabyte DNA-powered data server. Microsoft and others are betting on massive cost reductions in the next decade or two.
• Gene therapy may get a lot cheaper and more mobile, thanks to Jennifer Adair.
• Baker lab spinout company Arzeda just raised $12 million to grow its de-novo enzyme design business.

Now, on to the research papers!

Building Life From the Bottom Up

• Life runs on proton gradients across cell membranes. Now, Ritzmann et al. have built a minimal system for generating these gradients, by fusing GFP to a light-driven proton pump, so that the pumps insert directionally into vesicles and can then pump protons into them.
• Adding new letters to the code of life has unexpected applications. Kimoto and Hirao show that two hydrophobic, unnatural DNA bases, Ds and Px, can be copied and read with high fidelity, and that primers with Ds bases can sensitively detect single base mismatches in DNA sequences in a qPCR assay.

Biomolecule Engineering

• Baker lab is getting even better at building proteins from scratch. This month, Rocklin et al. take advantage of high throughput DNA synthesis and a clever stability assay to synthesize and characterize the stability of thousands of small de novo designed proteins. With this giant dataset, they are able to iteratively improve their protein design algorithms. Where before fewer than 1 in 10 designs folded properly, by the end of this study almost half of all their new proteins fold as designed. Tour de force. Summary in phys.org.
• Baker lab aren’t the only ones designing useful proteins! Terada et al. have built a three-lobed protein (and named it ‘Mitsuba’) which binds tightly and specifically to cancer cells expressing a sugar molecule called globotriose.
• Folliard et al. have made better, more modular riboswitches that display consistent performance even when the gene they’re regulating is swapped out.

Genetic Circuits

• Zong et al. are getting really good at programming genetic circuits. By developing libraries of insulated minimal promoter and operator sequences, they were able to reliably and rapidly build bacterial genetic circuits that performed almost exactly as modeled in the computer. Biology has rarely looked more like an engineering discipline than it does in this paper.
• Gene circuits based on…chewing up plasmids? Baumgart et al. show that you can build a stable genetic oscillator based on two plasmids, where one drives expression from the second, and the second expresses a nuclease that destroys most copies of the first plasmid. DNA copy number is now (at least in E. coli) a dial you can use to dynamically tune genetic circuit performance.
• Genetic circuits that function in multiple species can be very difficult to build. Xiao et al. have achieved that for a nitrogen sensor, demonstrating ammonium detection and response in three species of bacteria.
• Super cool supercoiling. Yeung et al. show that the supercoiling of DNA at one gene’s promoter can significantly affect the expression levels of a nearby gene. They then take advantage of this property to build a better genetic toggle switch.
• Computational biology? No, this is biological computation. Chatterjee et al. have built spatially localized DNA-based logic gates using DNA origami and hairpins. Turns out DNA compuation run on a scaffold works 35 times faster at 50 times lower concentration than equivalent systems with freely diffusing components. Summary on the Microsoft Research Blog.

Computational Biology

• Levin et al. use genomic databases to propose a genetic toolkit for modifying Symbiodinium, photosynthetic dinoflagellates that live in coral cells. No wet lab work here, but maybe the basis for some in the future.
• Amazon wrote a blog series about how to use their AWS cloud computing platform to analyze genomes. They claim that if you bid on secondhand/spare compute capacity, you can analyze an entire genome for as little as $1.
• In this era of big biological data, how can you efficiently find the right enzyme from the right organism to catalyze the right reaction to make the molecule you want? Swainston et al. are here to help: they’ve built biochem4j, a searchable meta-database that combines information on small molecules, reactions that make them, predicted enzyme function and enzyme taxonomy from the UniProt, KEGG and NCBI Taxonomy repositories.

CRISPR and Gene Editing

• CRISPR isn’t all gene editing! Shipman et al. from George Church’s lab show that you can use the DNA acquisition parts of this bacterial immune system to write digital data, including a picture of a hand and a GIF of a horse, into the genomes of live bacterial populations.
• Doudna lab found an anti-CRISPR protein called AcrIIA4 that is a natural phage inhibitor of CRISPR. It binds to the sgRNA-Cas9 complex at the region of Cas9 that normally engages the DNA protospacer adjacent motif, blocking DNA recognition. They also found that timed delivery of the protein into human cells reduced off-target effects!
• Jung et al. are CHAMPs at analyzing CRISPR complexes! They’ve shown you can take a used Illumina flow cell and perform massively parallel analyses of the binding propensities of fluorescently labeled CRISPR machinery. This technique should easily generalize to analyzing other DNA-binding proteins as well.

Therapeutic SynBio

• Researchers are slowly solving the delivery problem for in vivo genetic modification and therapeutics. For instance, Smith et al. report the design of a stable polymer nanoparticle which efficiently delivers genes into white blood cells in the bloodstream and reprograms them to attack leukemia cells and cure blood cancer (in mice).

The Strains, They Are A-Changin’

• Hashimoto et al. have isolated a gene from a notoriously hardy tardigrade (water bear), and shown that it makes human cells more resistant to DNA damage from X-rays and hydrogen peroxide. If you wanted to engineer microbes, algae or humans to thrive in a high-radiation environment (like space, or Mars), this might be a good gene to splice in. News summary here. (This is from 2016?)
• It can be hard to make lots of human proteins in bacteria, because the human proteins will misfold. Reyes et al. have made it a little easier now, demonstrating that adding lots sucrose to the culture and inducing osmotic shock enhanced the folding and expression of a human protein in E. coli.

Plant Engineering

• Want a quick, cheap and easy way to make a plant resist drought? Douse it with vinegar. Kim et al. tried modeling and engineering the drought response pathway in Arabidopsis, and found out that acetic acid alone can induce a protective drought response in unmodified plants. This trick works in wheat, maize and rice, too. Who needs gene editing, anyway?
• Reed et al. show that you can (relatively) rapidly make gram-scale quantities of previously uncharacterized molecules by transiently expressing the biosynthesis enzymes in tobacco plants.

SynBio Newsreel, June 2017

GeneMods has a podcast now!

• For the first episode, we interviewed Professor Danielle Tullman-Ercek about synthetic biology in space. We also run through some of the May newsreel, gameshow-style!

Other Podcasts

• In Our Time, the BBC’s history podcast, devotes a whole episode to enzymes: how they were discovered, why they’re amazing, and what we use them for. Well worth a listen.

Videos

• Josiah Zayner, biohacker extraordinaire, gave a riveting opening presentation at the Festival of Genomics in San Diego. Three thoughts after watching it: I want to know how he built a fully furnished lab for only $5000; I want to see the data confirming that he’s been able to genetically modify his skin cells; and I really felt iffy about the part where he implied that he was helping a guy treat his wife’s cancer.

Books

• I just read (well, listened to) Change Agent, a new thriller by Daniel Suarez set in a biotech dystopia. An interpol officer in charge of hunting black market embryo editors in Southeast Asia gets dosed with a Change Agent, and finds his appearance and DNA fingerprint transformed into that of the very kingpin he has been chasing. It’s a richly imagined world and a fun read for anyone interested in synbio. The ‘mirror man’ assassin is my favorite character–you’ll have to read it to find out why!
• Haven’t read the whole thing yet, but the first chapter of Cory Doctorow’s new scifi/spec-fic novel Walkaway opens with a party serving genemod fluorescent beer (which is already a thing, thanks to Josiah Zayner). On my reading list!
• John Cumbers of SynBioBeta is teaming up with Karl Schmieder to write What’s Your Bio Strategy, a book about the massive advances in bioengineering and the synthetic biology entrepreneurs these advances are enabling. The book isn’t available yet but the site linked above contains numerous excerpts, comprising interviews with leaders in the synbio industry. One to watch for!

Big Conferences

• SB7.0, the 7th iteration of the largest meeting in the field, took place in Singapore. There haven’t been a lot of recaps posted online, but I’m sure there will be more in July. The most exciting announcement I saw came from bionet, the organization Drew Endy helped start to facilitate the open sharing and modification of biological molecules, tools and protocols. The Biobricks Foundation is partnering with Twist Bioscience to synthesize and share, free of charge, 10,000 genes with the entire synthetic biology community. This unprecedented biotechnological commons will be available to anyone to use, modify, share and sell through the bionet license. Which 10,000 genes? You decide! Bionet will create a forum through which the whole synbio community can advocate for parts to go into the commons (perhaps through this subreddit). You can bet that GeneMods will do what it can to help build this new resource. I can’t wait to get started.
• Busy month for synbio conferences! The week after SB7.0 in Singapore, Vancouver hosted the Synthetic Biology: Engineering Evolution and Design (SEED) conference. Many GeneMods members attended, and this month’s meeting includes a recap of their favorite SEED talks.
• CRISPR 2017 happened in Big Sky, Montana. Michael Chao wrote a good overview in Nature Microbiology. The conference apparently featured positive mouse data from Locus and Eligo Biosciences, two companies trying to redirect CRISPR to kill antibiotic-resistant bacteria.

Blogs and Community News

• The always-excellent Daniela Quagliela over at PLOS Synbio interviewed Julie Legault, the founder and CEO of bioengineering-in-a-box company Amino Labs.

Industry and Funding

• CRISPR counter-punch! China sides with Europe, and grants foundational CRISPR patents to Jennifer Doudna and Emmanuelle Charpentier’s team. The US PTO’s decision granting the patent to Feng Zhang and the Broad is starting to look more like an outlier.
• Microsoft is doubling down on DNA data storage, purchasing 10 million more long oligonucleotides from Twist Bioscience.
• DNA synthesis company IDT has announced a new competitive grant for synthetic biology start-ups, the winners of which receive 100,000 base pairs of free DNA (and the runners-up 50,000). Get that DNA!
• Speaking of competitions: the X-Prize Foundation (of private spaceflight fame) is considering launching an X-prize for the first team to build a microbe that can survive, reproduce and make useful products under Martian conditions.
• Bolt Threads got $50 million in funding and a partnership with Patagonia. Recombinant spider silk jackets aren’t far off!
• Ecovocative, the company that makes packaging and furniture out of mushroom mycelium, just won a $9 million DARPA grant to develop living building materials!
• Nature Jobs published five rules for building a synthetic biology startup.

Now, on to the research papers!

Small, Cheap, and Open

• Microfluidics are going open-source. Kong et al. debut Metafluidics, a site for sharing and modding designs and synthesis protocols for microfluidic devices, such as the controller/mixer part they use to assemble genetic elements at much smaller scale than pipetting would allow. It’s halfway between Github and Thingiverse, and aimed specifically at shrinking and democratizing the hardware required for synthetic biology. Summary in MIT News.

Build More Biohackers!

• An article in Nature Biotech argues for increased high school participation in iGEM, and tracks the growth of and lessons learned from Canadian high school iGEM teams. and similar competitions (BIOMOD? BioTreks? News to me).

Who Needs Cells?

• It’s been a good month for cell-free protein synthesis. Nieß et al. published a predictive model of cell-free protein synthesis which points the way towards increasing protein production rates. Also, Schoborg et al. from Jewett lab that figured out how to screen for transmembrane sugar-transferring enzymes in a cell-free context.

Biomolecule Engineering

• Another tour-de-force Baker lab collaboration: Strauch et al. designed a protein inhibitor of influenza that matches both the geometry and the binding pockets in hemagglutinin, and which can protect mice from influenza the day before or after exposure. Summary in Science.
• Northwestern alert! Alam et al. design a split fluorescent RNA aptamer that lights up in cells expressing both halves of the aptamer, and can be tagged onto other RNA sequences.

Genetic Circuits

• Riglar et al. in Pam Silver’s lab have built E. coli that can live and persist in mouse guts for long periods, and can switch on a stable reporter circuit in the presence of an inflammatory signaling molecule. Living gut diagnostics aren’t far away!
• That’s…much easier. Borkowski, Endy and Subsoontorn build a simple recombinase-based circuit that turns on protein expression when E. coli reach a certain density. No IPTG, quorum sensing, or autoinduction media needed!
• Bacterial vision gets an upgrade, courtesy of (who else) Voigt lab! Fernandez-Rodriguez et al. build a circuit that can sense and respond to red, green, and blue light independently. Summary on the PLOS SynBio blog.
• Maier et al. build an epigenetic memory circuit in bacteria (not eukaryotes! What?!). I bet the metabolic load for epigenetic memory is quite low.
• Gander et al. use dCas9 repression build the most complex genetic logic gates yet in a eukaryote.

Computational Biology

• Want to build genomes from scratch, but not a programmer? Then Genome Partitioner, a new web tool from Christen et al. for breaking huge DNA constructs into synthesizable chunks, might be right for you.
• Want to massively engineer existing genomes? Try Millstone, a web-based toolset from Goodman et al. for designing MAGE experiments in any microbe with a reference genome.
• Design and build (highly symmetric) biomolecules from scratch with ISAMBARD! Nice open source tool from Wood et al.

CRISPR and Gene Editing

• Pineda et al. have a very useful review of the challenges facing CRISPR gene editing therapies, and the approaches to solve them.

The Strains, They Are A-Changin’

• Dalia et al. efficiently transform DNA into Vibrio natriegens, and do multiplex genome engineering for desired traits. It’s similar to last month’s Church lab recombineering preprint, but requires a co-selection marker.

Metabolic Engineering

• Yeast can now make waxy, very long chain fatty acids, courtesy of Yongjin and colleagues.
• From fat yeast to fat algae! After over a decade of work, a group from Synthetic Genomics have built a macroalgae strain which grows about as well as wild type and accumulates twice as much fat. Summary in Ars Technica.

Useful Parts Galore

• Rapidly explore vast genetic design spaces with Woodruff et al.’s new Registry in a Tube: a strategy to make giant pools of standard, barcoded genetic parts, which can then be rapidly extracted and combinatorially assembled into an enormous number of composite devices.
• What if you want to assemble all your parts-in-a-tube, but don’t want to buy restriction enzymes or Gibson master mix? Liang et al. have a solution: a twin-primer assembly method that requires only DNA primers (with overhangs) and polymerase for PCR.
• Did you know gut fungi digest lignocellulose using massive complexes of carbohydrate binding and degrading enzymes called cellulosomes? I didn’t. But now Haitjema et al. have figured out a minimal set of genes for scaffolding and assembling fungal cellulosome enzymes. Watch out, cellulosic biomass!

GeneMods has a podcast now!

Excited to announce that the first episode of the GeneMods podcast, Synbio in Spaaaace!, is now live! Jordan Harrison and I interviewed Professor Danielle Tullman-Ercek about synthetic biology in space. We also run through some of the May newsreel, gameshow-style. Hope you all like it!

We’re just starting this thing so we’d love to know what you liked, things you’d change, or topics you want us to explore in future episodes. If you have feedback, you can reach us here or on the GeneMods Twitter account. Looking forward to hearing from you!

SynBio Newsreel, May 2017

 Want to write about synbio?

• There are three online publications (that I know of) that cater specifically to essays/articles about synthetic biology/biohacking: BioCoder, the PLOS Synthetic Biology blog, and the GeneMods blog. BioCoder has an open call for submissions to its June newsletter, while PLOS SynBio and GeneMods welcome guest writers.

The Means of Production

• How do you turn more people into scientists? Make it cheaper to do science. How do you make it cheaper to do science? Teach people to build their own equipment. An excellent essay on The Conversation analyzes the intersection of citizen science and the Open Hardware movement, which seeks to develop free manuals for cheaply building all sorts of useful (often scientific) equipment. I particularly liked how the essay argued that making instruments cheaper changes the kinds of experiments people can conduct—science becomes something that can be performed by and for the specific benefit of small, local communities.

Blogs and Community News

• Fastco Design reviews the latest work from artist Robert Zhao Renhui, a book about the animals humans have modified or changed throughout history.
• Daniela Quagliela over at PLOS Synbio interviews chemist, protein engineer and directed evolution wizard Frances Arnold.
• Aaron Dy at PLOS Synbio looks at crowdfunding in synthetic biology, from the failure of Glowing Plant to the success of smaller iGEM crowdfunding campaigns, and proposes guidelines that might make crowdfunded synbio projects more likely to succeed.
• Is cell-free synthetic biology about to take off? Steven Burgess highlights some of the advances, advantages and challenges of engineering biology without cell membranes.
• Antonio Regalado at Technology Review summarizes the recent advances and ambitions surrounding DNA data storage. Most exciting part for me: Church lab is working on enzymatic DNA synthesis, and plans to have an announcement about it later this year!

Policy and Bioethics

• GP-Write organized its second annual meeting. They’ve shifted away from immediately synthesizing a human genome, broadening the focus to large genomes generally. Funding remains a challenge, but one pilot project to synthesize a prototrophic human cell has received a $500,000 DARPA grant.
• The FDA is seeking advice on how to regulate genome editing technologies, and has extended the public comment period through June 19. So if you have any valuable input (when, if ever, might genome edited plants/animals be riskier than those bred or engineered with older techniques? At what point does a small-time bioentrepreneur hacking a new plant/animal need to seek regulatory approval? Can they avoid oversight by using certain biosafety precautions or accepted model organisms?), let the FDA know!

Industry and Funding

• I think this extended 2012 article about the rise and fall of Amyris is essential reading for anyone interested in the synbio industry. Many things to learn from the successes and mistakes of the first generation of synbio companies.
• Hey, Open Hardware again! The open source liquid handler OpenTrons gets an upgrade: it can now do everything two times faster. Gotta get one of these for Northwestern!
• The Economist publishes an enthusiastic essay about cell-free bioengineering. Worth a read to get a sense of all the companies operating in this space!
• RebelBio, Ireland’s biotech accelerator, has launched its fourth class of startups, including an STD biosensor, a cell-free synbio kit, and microbial fuel cell that runs on wastewater.
• DNA sequencing is coming to the classroom, courtesy of PlayDNA, a new startup that uses Oxford Nanopore’s MinION sequencer to teach middle schoolers about biology.

Books, Videos, Podcasts

• Jennifer Doudna is (co-) writing a CRISPR book! Actually, she already wrote it, and it’s coming out in a month or so. The Curious Wavefunction offers an enthusiastic review and synopsis of the book, A Crack in Creation.
• I just read (well, listened to) Life at the Speed of Light, by J. Craig Venter. It’s a short book packed with Venter’s thought-provoking perspectives about the nature of biology, the history of the life sciences, the Human Genome Project and his transition to synthetic genomics. It also provides entertaining insights into Venter’s personality—namely, that he’s a little obsessed with Nobel prizes, and isn’t above using his book to settle decades-old scores with doubters, competitors and the press.

 

Now, on to the research papers!

The Digital to Biological Converter

• It’s finally happened: a team led by J. Craig Venter and Dan Gibson have built a digital to biological converter (DBC): a machine which, when fed a digital gene sequence (up to 6000 bases), will print, assemble, and express that gene sequence, all without a human touching it. They use their DBC to make GFP, antibody fragments, and influenza proteins for potential use in vaccine development. This is the first prototype and it’s bulky and expensive, but expect smaller, cheaper DBCs to start showing up in the coming years. This may be the beginning of the end for cloning DNA by hand.

Biomolecule Engineering

• High throughput measurement of engineered protein-protein interactions using…sexual agglutination?
• Savage lab uses recombineering to make protein engineering easier/faster/cheaper.
• Measure that protein! Kawasaki et al built RNA sensors to quantify protein concentrations in mammalian cells.
• Build those cassettes! Andreou and Nakayama design a new (better?) Golden Gate cloning system.

Genetic Circuits

• ‘Essentializer’ and ‘Cryodeath:’ Silver lab’s either building genetic kill switches or starting several metal bands.
• Voigt lab pulls a Voigt lab, and refactors+simplifies the entire Salmonella Type III secretion system.
• Weenink et al. rationally design 5’UTRs of yeast genes to fine-tune expression.
• Modular is better! Orthogonal ribosome subunits decouple gene circuits from normal cell processes.

Computational Biology

• Buzzword bingo! Cuperus et al. apply deep learning to synbio, to predict and design the expression regulation of yeast 5’UTRs.

CRISPR and Gene Editing

• NgAgo? Uh oh. Nature Biotechnology notes that no one can replicate 2016’s DNA-guided gene editing paper.
• Harrington et al. in Doudna lab report a thermostable Cas9 with increased stability in human serum.

Therapeutic SynBio

• Where would YOU stick your subcutaneous capsule of therapeutic cells to treat insulin insensitivity? I vote under the clavicle.

The Strains, They Are A-Changin’

• Watch out, E. coli! Church lab reports recombineering in Vibrio natriegens.
• Recombineering is everywhere this month! Silver lab reports that it works in Salmonella, with massive recoding (1557 Leu->Leu)!

Not synbio, but cool

• Olivia Judson developed an eloquent model of how life got better at exploiting energy over time. This is not technically synbio, but it’s very useful for thinking about how efficiently different organisms can grow/exploit energy.

Pore’s Law

• Oxford Nanopore’s annual DNA sequencing conference, London Calling, was amazing. Nanopore sequencing is getting faster, cheaper, smaller, larger, more accurate, and higher throughput all at once. Other sequencing companies had better look out. If you want to quickly catch up on everything presented, James Hadfield of Enseqlopedia covered both Day 1 and Day 2 of the conference extensively. Keith Robison over at OmicsOmics had probably the most comprehensive summary and perspective on Clive Brown’s keynote about Oxford Nanopore’s progress and future plans.
• My favorite nanopore sequencing preprint thus far: Jain et al. report the sequencing and de novo assembly of a human reference genome using only MinION nanopore sequencers. Best part: they tried sequencing extra-long DNA fragments and out popped an 885 kb single read—~1000 times longer than the best read you could get from Sanger sequencing.
• If you want to really get in the weeds and understand how Oxford’s Nanopore sequencer works, this review on BioRxiv is worth a read.

SynBio Newsreel, April 2017

Blogs and community news

• Startup incubator YCombinator publishes an enthusiastic essay on CRISPR, and gene drives. Worth reading to see how the field is viewed by entrepreneurial software engineers.
• Slate is running a whole series of articles on synthetic biology and its intersection with business, culture and ethics this month.
• Appropriately for this month, Make magazine features an article detailing how to cheaply obtain the equipment for a DIYbio lab.

Policy and Bioethics

• In an about-face, the FDA has approved 23andMe to supply users with information about their risks for various diseases. Previously, 23andMe was only allowed to provide information on diseases the users might be carriers for.
• Researchers are taking more seriously the idea that humans will need to be genetically modified in order to colonize Mars and the rest of the solar system.
• In the future, will some forms of gene editing be required? Intriguing article in The Atlantic draws comparisons between the prosecution of Christian Scientist parents for the avoidable deaths of their children, and a potential future in which parents are held accountable for not editing deadly diseases out of their children’s genomes.

Industry and Funding

• At their London conference, SynBioBeta founder John Cumbers announces a new synthetic biology venture fund in partnership with Data Collective. If you need money for your synbio startup, now there’s one more place to apply.
• The biohacking project to build a glowing plant has run out of money and had to stop. They’re still working on making a fragrant moss, however.

Books, Videos, Podcasts

• Drew Endy’s keynote at SynBioBeta London was something else. No one can accuse him of not dreaming big.
• The Naked Scientists (perhaps my favorite general science podcast) devote an episode to organs-on-chips. And if you don’t like listening, you can read the transcript.

Biosecurity

• The SB7.0 conference is offering a Biosecurity Fellowship. Only a 1 page application, but it’s due on April 28th, so apply fast!
• Labs are trying to use CRISPR as an antibiotic, delivered via bacteriophage to chop up the pathogenic bacteria’s DNA. It’s an interesting idea, but I wonder: if you’ve found a phage to deliver CRISPR into target bacteria, why not just use the phage to kill the bacteria?

Now, on to the research papers! Fewer than most months; I’ll try to find more in May.

Detection and Genetic circuits

• Belkin et al. can find landmines from a distance with E. coli, in a field trial. Summary in The Guardian (though the paper is really short, so a summary is almost unnecessary).
• Gottenberg et al. reveal SHERLOCK, a CRISPR/C2c2-dependent strategy to detect minuscule concentrations of specific RNA and DNA sequences. Summary in MIT News.

Therapeutic synbio

• Birey et al. have used human stem cells to grow ‘human forebrain spheroids’ and study brain disease in them. Impressive work that strongly reminds me of last month’s bioethics paper on the implications of synthetic human entities with embryo-like features.
• Phage therapy FTW! Green et al. report that commonly isolated bacteriophages can kill multidrug-resistant pathogenic E. coli, and can alleviate infections in mice. Summary in GEN.
• Zhang et al. use CRISPR-Cpf1 to correct muscular dystrophy disease genes in human stem cells and mice.

SynBio Newsreel, March 2017

Lots of things happened in March!

Blogs and community news

• Aaron Dy discusses how the bionic leaves being developed in Pam Silver’s lab could aid in the colonization of Mars.
• Daniela Quagliela interviews the founders of UK synbio company Synthace about Antha, the high-level programming language they developed to speed up and simplify automated bioengineering protocols.
• Indiebio’s blog now has interviews with most of their portfolio companies. A great place to find synbio companies doing cool work!

• Policy and Bioethics
• Induced pluripotent human stem cells can now be patterned to generate structures that look a lot like early embryos. These synthetic human entities with embryo-like features (SHEEFs) will force us to rethink the decades-old rules surrounding human embryo research.
• In ever greater numbers, parents are starting foundations and companies to develop gene therapies for the rare diseases that afflict their children.

Industry and Funding

• Forbes profiles Craig Venter—what he’s done, what he’s doing, and what he hopes to do in the future.
• eGenesis raises $38 million to engineer pigs that can serve as organ donors to humans.
• Wired profiles two startups—Venomyx and VenomAB—that are trying to make cheap, recombinant snake antivenom. But will their approach be able to tackle antivenom’s distribution challenges?
• Twist raises an extra $33 million to expand its gene synthesis, and DNA data storage and pharmaceutical discovery strategies.
• If February was a great month for Broad in the CRISPR patent fight, March looks a bit tougher. The European Patent Office granted a broad (not Broad) CRISPR patent to University of California and University of Vienna (Doudna and Charpentier’s institutions), for developing the single guide RNA to guide Cas9.

Books, Videos, Podcasts

• Radiolab devotes an entire episode to an update about CRISPR and gene drives, including interviews with Jennifer Doudna, Kevin Esvelt and the best (well, only) audio representation of a bacterial CRISPR repeat I’ve ever heard.
• George Church gave an hour-long talk to the Innovative Genomics Institute. Worth watching!

Biosecurity

• Bill Gates publishes an op-ed arguing that bioterrorism is a serious threat to global security, and that to counter this threat we must strengthen public health infrastructure in the developing world, increase our ability to rapidly generate new vaccines, openly share health/epidemiological data between countries, and ‘prepare for pandemics the way the military prepares for war.’ Interestingly, these steps are very similar to the global health goals his foundation has been pursuing for a while, just repackaged to emphasize the economic and security arguments for them. Perhaps this reframing will persuade the current US government to maintain or increase spending on global health?

Now, on to the research papers!

Genetic circuits

• If most synbio takes steps toward making biology easier to engineer, Weinberg et al. just took a giant leap. They use recombinase-based genetic circuits to reliably build over 100 complex logic gates in mammalian cells, including a 6-input AND gate, and even adder and subtracter modules. It’s like Endy lab’s reliable, stable genetic programs in E. coli—but bigger, and in mammals! Summary in Wired.

Biomolecule engineering

• Running out of colors to paint your cells for fluorescent imaging? Frances Arnold’s lab has your back. Herwig and Rice et al. engineered an opsin protein to accept a synthetic chromophore, so that it now fluoresces brightly in the infrared. Works in both bacteria and mammalian cells, too.
• Bedbrook and Rice et al. from Arnold lab also take aim at engineering new light-activated ion channels for optogenetics, using recombination of diverse channelrhodopsin sequences to generate new proteins with distinct expression, localization, and light-induced activation patterns.
• Praetorius and Dietz report DNA origami, with TAL effector staples!

Computational biology

• Data storage in DNA just got much more feasible. Erlich and Zielinski combine fountain codes (a robust encoding strategy from mobile video streaming applications) and automated, iterative oligo sequence optimization to store 72 MB of data in easily sequenced DNA. They achieve unprecedented retrieval fidelity (100%), lossless copying capacity (a quadrillion replications), and storage density (250 petabytes per gram), approaching the theoretical limit for data storage in DNA.

Gene Drives and CRISPR (also, preprints are cool)

• One of the primary ethical challenges confronting gene drives is that, even if the population of one region supports drive use, the drive could easily spread to areas where people don’t want it. In a new preprint, Min et al. from Kevin Esvelt’s lab propose a technical solution to this problem of universal consent: a daisy quorum gene drive. This system combines the limited spread of a daisy chain gene drive with a genetic ‘quorum sensing’ capability, so that after the daisy drive runs out of gas, the drive modifications are only stable in regions where most of the target organisms have already been modified. This architecture also enables a second gene drive to revert a modified population to the wild genotype, increasing the potential reversibility of gene drives.
• Efficient editing with CRISPR is a challenge, so it would be great if you could just select for the cells that have been edited. Well, now you can! Agudelo et al. report on Biorxiv a method to select for edited cells by co-delivering guide RNAs which generate toxin-resistant mutations in a sodium/potassium pump gene.

The strains, they are a changin’

• Saccaromyces cerevisiae 2.0, the yeast with a synthetic genome, is more than halfway complete. 7 articles detailing Boeke and company’s progress appeared simultaneously in Science. Pretty frickin’ cool.

SynBio Newsreel, February 2017

I’ll put the videos up here as well once they upload. Enjoy!

Blogs and community news

• PLOS Synbio has an excellent interview with Christina Agapakis, creative director at Ginkgo.
• STAT profiles Jeantine Lunshof, the bioethicist embedded in George Church’s lab who makes sure they don’t rush too quickly into ethically questionable research.
• SynBioBeta highlights five women CEOs of synbio companies.
• Keith Robison of OmicsOmics has an excellent perspective piece on Gen9’s acquisition by Ginkgo and the challenges of the high throughput DNA synthesis business, with a bonus appearance by Gen9 CEO Kevin Munnelly in the comments section.
• Bioscentric argues that synthetic biology can bridge the coming ‘protein gap’ (disparity between available supply of protein and demand for it by global middle class) by engineering plant-based meat substitutes to taste and feel more like the real thing.

Policy and Bioethics

• The National Academy of Science’s report on the ethics of human embryo editing, a year in the making, argues for cautious use of germline editing, for diseases which have no “reasonable” therapeutic alternatives, and following much more research into safety and efficacy. Notably, while the report advocated against genome editing to enhance embryos ‘at this time,’ it rejected the argument that genetic enhancement would be likely to significantly increase societal inequality. This comes after the American College of Medical Genetics urged against clinical editing of embryo genomes, at least until further ethical and technical issues are addressed. NAS’s report seems to be running a little ahead of public sentiment, according to a recent Pew poll which showed a majority of Americans are more worried than enthusiastic about genome-edited babies.
• The FDA curbs a biohacker’s plans to use CRISPR correct a genetic disease carried by purebred dalmatians. He may just do it anyway, though.
• India doesn’t have an official government policy on synthetic biology, but that’s about to change.

Industry and Funding

• The patent for using CRISPR in eukaryotes belongs to the Broad institute, according to the Patent and Trademark Office. Expect UC Berkeley to appeal, but this is a major blow to their legal claim that gene editing with CRISPR in eukaryotes is an obvious extension of Doudna and Charpentier’s work in vitro and in bacteria. Berkeley professor and soon-to-be Senate candidate Michael Eisen wrote a scathing critique of the decision, and of University patent rights generally.
• Meanwhile, the Innovative Genomics Institute (run by UC Berkeley and UCSF) intends to invest $125 million into gene editing research on crops and microbiomes. That’s a lot of CRISPR!
• IndieBio graduates its fourth class of startups (full demo day video here). Among them are companies specializing in DNA data storage, enzyme engineering, high-throughput embryo editing, and microfluidic cell culture devices.
• A year later, Twist Bioscience responds to Agilent’s lawsuit alleging IP theft.
• You can now buy CRISPR-Cpf1 for gene editing from IDT.

Books, Longreads, Podcasts

• Society needs to prepare for The End of Sex (for reproductive purposes), according to the book of the same name written by Stanford Law professor Hank Greely. Greely predicts this shift will be causes by the convergence of two technologies, in vitro generation of gametes from induced pluripotent stem cells and pre-implantation genetic diagnosis (PGD). These technologies will soon combine into a simple procedure called Easy PGD that enables parents to generate thousands of zygotes in vitro, implanting only those which have been sequenced, screened and edited to prevent genetic disorders (and, potentially, select for non-disease traits). The book provides a good overview of the scientific progress on both technologies, and extensively explores the legal, ethical and social implications of Easy PGD. I highly recommend it.

Biosecurity

• Devang Mehta argues in an excellent PLOS Synbio post that biosecurity threats from DIY biohackers are overblown (for now), while threats from state actors are potentially more serious.
• Former Ventria Biosciences employee Weiqiang Zhang is convicted of attempting to steal a genetically modified rice strain.

Now, on to the research papers!

Biomolecule engineering

• Pu et al. use continuous, directed evolution to build a split RNA polymerase whose activity is dependent on the dimerization of modular protein-protein and small molecule binding domains. Basically, constructing a genetic sensing/actuation circuit from two interacting or molecule-binding protein domains just got a lot easier. Really cool.
• Does Baker lab just publish a Science paper every month at this point? Marcos et al. have figured out how to build proteins from scratch with surface cavities structured around distorted beta sheets.
• The last restriction enzyme you’ll ever buy? Enghiad and Zhao use a thermostable, DNA-guided nuclease called PfAgo to generate artificial restriction enzymes which can cleave any sequence while leaving sticky ends of any sequence at the cut sites. Summary in GEN.
• Quagliela et al. use Golden Gate cloning to combine multiple different mutagenesis strategies in a single protein engineering library.

Genetic circuits and Metabolic Engineering

• Gupta et al. apply quorum sensing to metabolic engineering, constructing strains of E. coli that switch off essential glycolytic enzymes when they reach a high enough density, thereby increasing the output of chosen metabolites derived from central carbon metabolism. Summary in MIT News.
• Engelen et al. augment the field of DNA-based computing by debuting antibody-templated strand exchange, a process by which antibodies initiate the strand displacement reactions of peptide-functionalized DNA strands. They show how antibodies and their cognate antigens can now be used as inputs for DNA computing circuits.
• Wearable computing is cool, but how about wearable, living computing? Liu et al. use a printed silicone/hydrogel combination material to construct simple wearable devices into which engineered E. coli can be embedded and subsequently sense small molecules on the surface of the skin.
• Want to learn more about optogenetic control of gene expression in budding yeast? Then this review by Salinas et al. is for you.

Photosynthetic Synbio

• Higo et al. build RNA-based, small molecule-inducible genetic circuits in cyanobacteria, thereby adding a modular and portable tool to the sparse cyanobacterias toolbox.
• Song et al. show that new, fast-growing cyanobacterium UTEX 2793 can be engineered to produce more sucrose and glycogen than any strain before it. This is actually a paper from last year that got caught in my NCBI crawler, but it was relevant to Quentin’s November presentation so I thought it was worth adding.

Computational biology

• Model and build biology to understand it! Moreno-Fenoll et al. explore how microbial communities that rely on commonly produced resources can survive the emergence of ‘cheaters,’ which consume the common resource without producing it. The show through mathematical modeling and engineering a synthetic microbial community with ‘cheater’ and ‘cooperator’ strains of E. coli that spatial division of the community into many random sub-populations promotes recovery of the cooperators after a cheater-induced population crash.

The strains, they are a changin’

• Agmon et al. generate biocontained yeast by placing several essential genes under small molecule-inducible promoters, such that the strains won’t grow in the absence of, for instance, estradiol. They also demonstrate a strategy to dope in ‘decoy’ small molecules which don’t affect cell viability but make it harder for biopirates to figure out which small molecules are required to make the strains grow.
• Two papers on improving the expansion of the genetic code, both from UT Austin labs! First, Monk et al. showcase a dual fluorescent protein reporter which can rapidly quantify the activity and specificity of non-standard amino acid (nsAA) incorporation by orthogonal tRNAs, and also an evolved, faster growing variant of the amber-codon-lacking recoded E. coli strain developed in Church lab. Maranhao and Ellington simultaneously debuted a new positive/negative selection strategy to develop more active and specific orthogonal tRNAs. They also show that non-recoded E. coli expressing their improved tRNAs grow faster than strains expressing the original tRNAs (recoded E. coli grows the same either way).

Therapeutic synbio

• Qasim et al. report that they have cured two infants of aggressive leukemia using universal, off-the-shelf CAR-T cells edited with TALENs. New Scientist has the summary.

The CRISPR Patent Battle

For this month’s main presentation, Albert Xue gave a comprehensive and entertaining overview of the patent interference proceedings between UC Berkeley and the Broad Institute over the patents for using CRISPR to edit eukaryotic genomes. Watch below, and feel free to comment if you have additional insights/opinions about this patent battle.

SynBio Newsreel, January 2017

Happy new year, synbio community! And also happy first anniversary of this blog, approximately. Joe Muldoon gave an excellent summary of the newsreel at today’s meeting; watch below, and then continue to the full linkstorm!

Synbio community news

• The United Nations biodiversity conference rejects calls for a moratorium on gene drives.
• A man attempts gene therapy on himself, with plans to commercialize his technique. Anyone interested in self-electroporation?
• David Baker’s lab shows up in The Atlantic, for their recent, jaw-dropping prediction of the structures for 614 uncharacterized protein families.
• Twist Bioscience summarizes some of the most important developments in synbio from the past year.

Synbio profiles

• Ginkgo Bioworks co-founder Tom Knight appears in Forbes. Main takeaway: it’s never too late to go back to school and learn a new field.

Industry news

• Editas licenses CRISPR-Cpf1 exclusively from the Broad institute for therapeutic applications, and non-exclusively to Monsanto for agricultural applications. Meanwhile the Doudna-Charpentier CRISPR teams have pooled their resources, with Intellia, Caribou, CRISPR Therapeutics and ERS Genomics all signing a mutual patent sharing and protection agreement.
• Oh snap! Ginkgo Bioworks acquires Gen9. This insightful Boston Globe commentary explains that the acquisition happened in large part because Gen9 ran out of funding in the cutthroat DNA synthesis market. Meanwhile, it looks like Ginkgo is trying to become the first vertically integrated synbio company. What will this mean for Twist Bioscience, now that their largest customer has bought its own DNA synthesis company?

Books, Longreads, Podcasts

• Nick Lane’s The Vital Question, which tackles the origins of both life and eukaryotes, is excellent. Fun fact from the book: multicellularity has independently evolved over 30 times, but endosymbiosis between prokaryotes (the origin of eukaryotes) has only given rise to complex cells once, as far as we know.
• Clarkesworld Magazine’s podcast is just what any sci-fi fan could want—a new short story (~20-90 minutes), read into your ears, every week. Lots of synbio speculative fiction here; I particularly enjoyed a recent episode (text version here) about two friends who make counterfeit steaks in China using high-end cell culture.

And now onto the research articles!

The strains, they are a-changin’

• Zhang et al. report the first organism to stably integrate and replicate unnatural DNA base pairs into its genome. If they can get to transcription and translation, the genetic code may be massively expanded. Summary in The Guardian.

Biomolecule engineering

• Brödel et al. turn one transcription factor into several, using directed evolution to engineer orthogonal cI variants and construct multiple genetic circuits from it.
• Northwestern alert! Schwarz et al. from Leonard lab design modular, synthetic extracellular signal transduction proteins to program Jurkat T Cells to produce an immunostimulatory response (IL-2) to an immunosuppressive signal (VEGF).
• Qudrat and Truong construct synthetic transmembrane proteins from minimal component domains that traffic efficiently to the plasma membrane in mammalian cells.
• How do you build your genes so they’re less expensive for cells to express? Frumkin et al. investigate, and find slower translation, more stable mRNA, and small hydrophilic amino acids are all important.
• Portela et al. develop a library of synthetic core promoters of different strengths for yeast cells. However, expression from a promoter differs significantly even between different yeast species. Universal synbio parts are hard to come by!

Genetic circuits and Metabolic Engineering

• To increase bioplastic production, He et al. engineer a genetic circuit that turns on only when high density (measured by quorum sensing) and stationary phase are reached.
• Crocker et al. use TALE protein fused to activator and repressor domains to develop a fully synthetic transcriptional regulation system in fruit flies. They then use this platform to explore the function of the pioneer/transcriptional enhancer Zelda, and to determine the best genetic architecture for generating sharp boundaries at the intersection of two developmental signaling factor gradients.
• Maurer et al. compare lab yeast with industrial yeast using quantitative trait loci (QTL) mapping, figure out the alleles which matter most for the industrial yeast’s productivity, and use CRISPR to put those alleles into lab yeast. The result is a lab yeast strain which outperforms the original industrial strain!

Plant Synbio

• Researchers improve the efficiency of photosynthesis in C3 plants by increasing the speed with which the plant’s photoprotective mechanisms kick in during high light intensity, and turn off during low light intensity. Legume Laboratory has a detailed summary.

CRISPR/gene editing

• Anti-CRISPR proteins discovered by Rauche et al. inhibit spCas9 activity, and may facilitate biocontainment and reduce off-target effects of CRISPR applications. GenomeWeb has the summary.
• Two new, compact CRISPR systems, dubbed CasX and CasY, discovered in uncultured archaea by a team including Jennifer Doudna. Their biochemistry and potential for genome editing applications should follow shortly, so watch this space! GenomeWeb has the summary.
• This is genetics on CRISPR. Peters et al. use an inducible CRISPRi library to produce a powerhouse study of essential gene knockdown and function in B. subtilis. One of those fun papers where the new results barely fit even in a Cell paper.

Computational biology

• Obertorner et al. from the Joint Genome Institute debut BOOST, a web design program for genetic parts that can modify sequences to make them easier/cheaper for for DNA synthesis companies to build.
• Gumulya and Gilliam present a really cool review of how sequence data from diverse evolutionary branches of life can be used to reconstruct approximate ‘ancestral’ enzymes, which are useful both for evolutionary biology and as starting points for protein engineering studies.

Engineering mammals

• Xie et al. efficiently treat diabetes in mice, using a capsule of human cells programmed to measure high glucose levels and release insulin in response. Classic Fussenegger lab work.
• YACs into HACs! Brown et al. develop an efficient method for transferring artificial chromosomes from yeast into human cell lines.
• Müller et al. reprogram mammalian fragrance receptors to generate a multi-cell analog-digital converter which can sense and perform digital logic operations in response to multiple odor molecules. Another powerhouse Fussenegger lab project.

Cyanobacteria: the Green E. coli

The November meeting’s main event was a presentation and discussion led by Quentin Dudley about the merits of photosynthetic cyanobacteria as a platform for synthetic biology applications. Watch the video below!