Synthetic Spider Silk & Morphogen Gradients (#12)

Plus: A biohacker, running experiments at home, decides to stop testing on himself (for now).

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Synthetic Spider Silk (Review)

Every once in awhile, a review comes along that makes me fall in love (again). I’ve always been intrigued by synthetic spider silk, but a review from Eriko Takano’s group, at the University of Manchester, has taken my obsession to new heights. This new review explores all the wondrous ways that living organisms—including, but not limited to, spiders—can be coaxed into producing synthetic silk. Takano and the other authors offer an exciting scientific journey through the challenges of producing, and harvesting, silk spidroin proteins from Salmonella bacteria, mammalian cells, rice (!), other plants (including Nicotiana tabacum) and even mice. I didn’t know that so many different critters could produce silk, nor did I understand just how big of a factor pH plays in the silk spinning process within a spider’s glands. This review, which is open access, was published in Trends in Biotechnology. Link

Source: Tumblr

Synthetic Morphogen Gradients Come of Age

Two back-to-back studies, published in the Oct. 16 issue of Science, have demonstrated tunable, synthetic morphogen gradients—one in an in vitro system, and the other in living fruit flies.

As a multicellular organism, such as the humble fruit fly (Drosophila melanogaster), develops, each cell needs to be directed, much like a player in a symphony. In many cases, a cell’s final role is assigned, during development, based on the local concentration of a small molecule. Many of these small molecules have fun or threatening names, like “sonic hedgehog” or the tongue-twisting “bone morphogenetic protein–transforming growth factor–b.

If a morphogen’s concentration is high near one cell, for example, that cell might become a wing. Cells located within a low morphogen gradient, on the other hand, might become, say, an antennae.

By building synthetic morphogen gradients that can be engineered and controlled, scientists are able to better understand how morphogen gradients work, how organisms develop, and how different, quantitative factors result in different developmental outcomes.

In the first study, by Toda et al., (Link) green fluorescent protein (GFP) was, itself, converted into a morphogen. The researchers designed three cells; a ‘sender’ cell that produces the GFP morphogen, ‘receiver’ cells that possess a synthetic Notch receptor that actually senses the GFP, and a so-called ‘anchor’ cell that captures GFP molecules and presents them to the receivers. When the synthetic Notch receptor on the ‘receiver’ cell is presented with a GFP molecule, it can turn genes within the cell ON or OFF. It’s quite a complicated experiment, I know, but bear with me.

By designing and building each of these cells, the researchers were able to tweak the morphogen gradient’s parameters to study how, say, the amount of GFP produced, or the affinity between GFP and the receiver cells, impacts the morphogen gradient’s pattern. In the first study, their synthetic morphogen system was tested in an “in vitro model of L929 fibroblast cells”. Using the three cell types, the team was able to create a “propagating wave of patterning” very similar to the morphogen gradient observed in a fruit fly’s eyeball during development. The team also implemented more complicated gradient patterns that involved the diffusion of two morphogens (GFP and a red fluorescent protein) simultaneously.

The second study, by Stapornwongkul, et al. (Link), took this work a bit further, and studied a synthetic morphogen gradient—again with GFP—directly in the “wing imaginal disc of D. melanogaster”. By studying a synthetic morphogen gradient, with tunable properties, in a living organism, the scientists were able to systematically explore the complex molecular dance that underpins multicellular development.

For a deeper dive on these studies, I highly recommend reading the Perspectives piece, also published in the Oct. 16 issue of Science. Link (none of these links are open access, unfortunately).

Source: Giphy

Mini Cannonballs, Grown & Tweaked Inside of Cells

Some organisms produce iron oxide nanoparticles, which are basically balls of magnetite (Fe3O4) that range in diameter from 1 to 100 nanometers. The applications for these “miniature cannonballs” (not a real scientific term, I assure you) are immense: they can be used as contrast agents for MRI, for example, or as gene carriers for genetic therapies. But, until now, it has been tough to coax cells—like M. magneticuminto producing iron oxide nanoparticles of a consistent size.

A new study, from Chris Voigt’s group at MIT, has developed a “genetically tunable” system for iron oxide nanoparticle production in M. magneticum cells. They developed a number of genetic parts—ribosome binding sites, promoters, and other components—that could be used to precisely tune those genes involved in producing these “mini cannonballs”. They were able to tune the size, morphology, and even surface coatings of the iron oxide nanoparticles. This study was published in Advanced Functional Materials.

The Mystery of Overlapping Genes in Phages

One of the wonders of viruses is that a lot of features can be packed into an itty-bitty genome. The sum total genetic information of SARS-CoV-2, the virus that causes COVID-19, for example, consists of a measly 30,000 base pairs. For context, that’s 1/100,000th of the size of the human genome. And yet, SARS-CoV-2 can wreak utter destruction on the human body.

Bacteria have their own set of viruses—or bacteriophages—to contend with. Bacteriophages, it turns out, also pack a massive punch in a small genome, and have a number of genes that overlap with one another (in other words, parts of genes are encoded inside of other genes). A new study has shown that, if you synthetically remove all of these overlapping regions in the φX174 genome, a type of phage that infects bacteria, the phages are not able to attach to bacterial cells as well and, even if they do infect a host, the number of new phages that they can create are drastically reduced. In other words, for some intriguing reason, overlapping genes increase the potency of a bacteriophage. This study was published in ACS Synthetic Biology.

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🧫 Rapid-Fire Highlights

More research & reviews worth your time

  • Fankang Meng and Tom Ellis wrote a review on “the second decade of synthetic biology”, spanning advancements from 2010 to the present. It’s a nice piece that covers the major milestones in this field. If you’re new to synthetic biology, or just want to relive the highlights, it’s a must read. Nature Communications (Open Access). Link

  • Even if a genetic cure were offered for sickle cell disease, would people expose themselves to genome editing? An important study takes a look at this issue. One fascinating result, that I noticed, was that “individuals with [sickle cell disease] demonstrated higher levels of genetic literacy than estimated by physicians.” AJOB Empirical Bioethics (Open Access). Link & Press Release

  • It’s exceedingly difficult to chemically synthesize long RNA sequences. Now, a new method enables “routine solid phase synthesis of long RNA strands”. The authors used this method to synthesize a 76-nt long tRNA and a 101-nt long sgRNA. bioRxiv (Open Access). Link

  • An online calculator can perform “techno-economic analysis” for scaling up a metabolic engineering project. Specifically, the calculator computes the “impact of fermentation level metrics on the commercial potential of a bioprocess for the production of a wide variety of organic molecules.” It is called the BioProcess TEA calculator, is freely available, and was developed by Michael Lynch at Duke University. bioRxiv (Open Access). Paper & Calculator

  • A wide-ranging perspective, from Ron Milo’s group at the Weizmann Institute, looks at carbon dioxide conversion in engineered organisms, especially algae, and how they can be used to feed a growing population. Cell Reports Physical Science (Open Access). Link

  • Even genetically identical cells behave differently, and so tools that probe metabolic flux, in single cells, are very desirable. A new study reports an RNA-based sensor for fructose-1,6-bisphosphate, an intermediate product in glycolysis, that “can be used to sense the glycolytic rate in single cells.” bioRxiv (Open Access). Link

  • Mikhail Shapiro’s group, at Caltech, has been at the forefront of synthetic biology and in vivo ultrasound technologies. Now, they’ve written a review that is very much worth your time; it covers the basic science behind ultrasound and discusses how engineered microbes can be used for in vivo imaging. Neuron (Open Access). Link

  • To determine a protein’s identity, within a cell, researchers often turn to an incredibly laborious method called mass spectrometry. A new study presents a method to fuse proteins to their mRNA transcript, enabling nucleic acid sequencing to be used for protein identification. This method could revolutionize proteomics. PNAS (Open Access). Link

  • Plants around the world produce thousands of different benzylisoquinoline alkaloids (yes, that’s a mouthful), chemical compounds that are widely used as antibacterial and anticancer drugs. Metabolic engineers have long been interested in producing these compounds in living yeast cells. Unfortunately, one of the enzymes that is required to produce these alkaloids—called norcoclaurine synthase—is toxic when present in the cytosol of yeast cells. A new study has found that, by targeting this enzyme to the peroxisome compartment, toxicity is reduced and titers for producing the alkaloids can be increased. Nature Chemical Biology. Link

  • I did not know this, but Vitamin E compounds can actually consist of eight different molecules; four tocotrienols and four tocopherols (which differ in their chemical structures). It turns out that tocotrienols can have really important health benefits, but are often left out of Vitamin E supplements. Now, a new study has engineered Baker’s yeast to produce tocotrienols by supplementing some native metabolic pathways in yeast with genes taken from photosynthetic organisms. Nature Communications (Open Access). Link

  • GFP is great to “light up” the insides of cells, but it has a problem: fluorescent proteins, in many cases, take several minutes to mature, or produce light, after they are produced in a cell. A new study has remedied this problem, reporting a “genetically encoded fluorescent biosensor” that, amazingly, enables the “detection of protein expression within seconds in live bacteria.” ACS Synthetic Biology. Link

  • A new study has, to some degree, standardized how genes can be expressed in cell-free systems. A paper from scientists at LanzaTech and Northwestern University reports a “modular vector system that allows for T7 expression of desired enzymes for cell-free expression and direct Golden Gate assembly into Clostridium expression vectors.” The new system enables scientists to quickly test genes in cell-free extracts, and then export those designs to living cells. Synthetic Biology (Open Access). Link

  • Plants, it turns out, are really good at producing antibodies against SARS-CoV-2. A new study has produced “milligram amounts of six different recombinant monoclonal antibodies against SARS-CoV-2 in Nicotiana benthamiana.” bioRxiv (Open Access). Link

📰 #SynBio in the News

  • The EBRC’s Student & Postdoc Association is looking for new members. Any trainees working in synthetic biology or adjacent fields are welcome to join. Membership is free and non-competitive, and members also get a few perks for professional networking: a mentorship program, an internship program, a Slack workspace, a LinkedIn page, and a few other things. Follow the link to join. Link

  • Mark Temple, at Western Sydney University, has “sonified" the coronavirus genome, turning its nucleotides into an hour-long musical composition. Mark has since written an article, for The Conversation, that explains the project’s inception, methods, and artistic merits. Link (To read the original study, click here).

  • A DIY “biohacker” made a COVID-19 vaccine in his house, tested it, and isn’t sure how to interpret the results. I am especially fond of this line from the article: “Zayner said his turn at vaccine testing has tempered his appetite for DIY human experimentation.” Hilarious. Link

  • Portable DNA sequencers enable researchers to collect genetic material and sequence it from (almost) anywhere in the world. Carlos de Rojas reports for Link

    If this is interesting to you, also check out Glen Gowers & co’s “off-grid” sequencing expedition in Vatnajökull, Iceland, which was published last year. Link

  • As ‘Chief of Staff’ roles become more common in biotech companies, an article in takes a look at what this role actually does. Link

  • Spectrum and Science ran a piece on gene therapy, and whether it’s ready to treat some forms of autism. Link

  • Synthetic proteins, engineered to target the coronavirus, have been made in a lab. Scientific American takes a closer look. Link

  • Making breast milk, “without the breast”. A deep piece of reporting, at least relative to articles that have previously been written on this topic, was published in Future Human. Link

🐦 Tweet of the Week

Before a synthetic biologist even touches a cell, it is often useful to first build models that predict, among other things, which genes should be altered to produce a given response, or chemical, or phenotype. And then, once those genes are identified, the researcher must carefully tune and tweak and prod and control the genes to get them at an expression level that is juuuuuuust right for his or her purpose.

Unfortunately, it is really challenging to predict gene expression. A new study from the Salis lab, at Penn State University, mixes a rich database with statistics and machine learning to better predict gene expression and alleviate this problem. Check it out. 👇

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