Concern over the reports of antibiotic-resistant bacterial infections in hospitals and in the community has been publicized in the media, accompanied by comments on the risk that we may soon run out of antibiotics as a way to control infectious disease. Infections caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Clostridium difficile, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and other Enterobacteriaceae species represent a major public health burden. Despite the pharmaceutical sector's lack of interest in the topic in the last decade, microbial natural products continue to represent one of the most interesting sources for discovering and developing novel antibacterials. Research in microbial natural product screening and development is currently benefiting from progress that has been made in other related fields (microbial ecology, analytical chemistry, genomics, molecular biology, and synthetic biology). In this paper, we review how novel and classical approaches can be integrated in the current processes for microbial product screening, fermentation, and strain improvement.
University of California, Berkeley, researchers have discovered a much cheaper and easier way to target a hot new gene editing tool, CRISPR-Cas9, to cut or label DNA.
The CRISPR-Cas9 technique, invented three years ago at UC Berkeley, has taken genomics by storm, with its ability to latch on to a very specific sequence of DNA and cut it, inactivating genes with ease. This has great promise for targeted gene therapy to cure genetic diseases, and for discovering the causes of disease.
The technology can also be tweaked to latch on without cutting, labeling DNA with a fluorescent probe that allows researchers to locate and track a gene among thousands in the nucleus of a living, dividing cell.
The newly developed technique now makes it easier to create the RNA guides that allow CRISPR-Cas9 to target DNA so precisely. In fact, for less than $100 in supplies, anyone can make tens of thousands of such precisely guided probes covering an organism’s entire genome.
The process, which they refer to as CRISPR-EATING – for “Everything Available Turned Into New Guides” – is reported in a paper to appear in the August 10 issue of the journal Developmental Cell.
Accurately reconstructing gene regulatory network (GRN) from gene expression data is a challenging task in systems biology. Although some progresses have been made, the performance of GRN reconstruction still has much room for improvement. Because many regulatory events are asynchronous, learning gene interactions with multiple time delays is an effective way to improve the accuracy of GRN reconstruction. Here we propose a new approach, called Max-Min high-order dynamic Bayesian network (MMHO-DBN) by extending the Max-Min hill-climbing Bayesian network technique originally devised for learning a Bayesian network's structure from static data. Our MMHO-DBN can explicitly model the time lags between regulators and targets in an efficient manner. It first uses constraint-based ideas to limit the space of potential structures, and then applies search-and-score ideas to search for an optimal HO-DBN structure. The performance of MMHO-DBN to GRN reconstruction was evaluated using both synthetic and real gene expression time-series data. Results show that MMHO-DBN is more accurate than current time-delayed GRN learning methods, and has an intermediate computing performance. Furthermore, it is able to learn long time-delayed relationships between genes. We applied sensitivity analysis on our model to study the performance variation along different parameter settings. The result provides hints on the setting of parameters of MMHO-DBN.
For thousands of years, yeast has been used for making beer, bread, and wine. In modern times, it has become a commercial workhorse for producing fuels, chemicals, and pharmaceuticals such as insulin, human serum albumin, and vaccines against hepatitis virus and human papillomavirus. Yeast has also been engineered to make chemicals at industrial scale (e.g., succinic acid, lactic acid, resveratrol) and advanced biofuels (e.g., isobutanol) (1). On page 1095 of this issue, Galanie et al. (2) demonstrate that yeast can now be engineered to produce opioids (2), a major class of compounds used for treating severe pain. Their study represents a tour de force in the metabolic engineering of yeast, as it involved the expression of genes for more than 20 enzymatic activities from plants, mammals, bacteria, and yeast itself. It clearly represents a breakthrough advance for making complex natural products in a controlled and sustainable way.
DNA origami is a robust assembly technique that folds a single-stranded DNA template into a target structure by annealing it with hundreds of short ‘staple’ strands1, 2, 3, 4. Its guiding design principle is that the target structure is the single most stable configuration5. The folding transition is cooperative4, 6, 7 and, as in the case of proteins, is governed by information encoded in the polymer sequence8, 9, 10, 11. A typical origami folds primarily into the desired shape, but misfolded structures can kinetically trap the system and reduce the yield2. Although adjusting assembly conditions2, 12 or following empirical design rules12, 13 can improve yield, well-folded origami often need to be separated from misfolded structures2, 3, 14, 15, 16. The problem could in principle be avoided if assembly pathway and kinetics were fully understood and then rationally optimized. To this end, here we present a DNA origami system with the unusual property of being able to form a small set of distinguishable and well-folded shapes that represent discrete and approximately degenerate energy minima in a vast folding landscape, thus allowing us to probe the assembly process. The obtained high yield of well-folded origami structures confirms the existence of efficient folding pathways, while the shape distribution provides information about individual trajectories through the folding landscape. We find that, similarly to protein folding, the assembly of DNA origami is highly cooperative; that reversible bond formation is important in recovering from transient misfoldings; and that the early formation of long-range connections can very effectively enforce particular folds. We use these insights to inform the design of the system so as to steer assembly towards desired structures. Expanding the rational design process to include the assembly pathway should thus enable more reproducible synthesis, particularly when targeting more complex structures. We anticipate that this expansion will be essential if DNA origami is to continue its rapid development1, 2, 3, 17, 18, 19 and become a reliable manufacturing technology20.
You are a bodyhacker. Yes, you. Bodyhackers come in all shapes, sizes, and colors. Even “normal” ones. That’s because bodyhacking isn’t just about appearances. It can relate to inward reflection, chemical adjustment, or even a fancy new watch that connects to a smartphone. The body is a vehicle to be tuned, modified, added to, taken away from, painted, tweaked, and customized. Maybe your preferred method is listed here. Maybe it isn’t. Either way, you belong at BDYHAX
The cells in this microscope image were arranged in three dimensions using a new DNA-based technique. The cells stained green were meant to mimic cells that lead outgrowth during natural organ formation.
Before scientists can build human organs in the lab, they need to figure out how to build tissues that work like those in the body. A new method, in which DNA acts like Velcro that makes cells stick to each other, could help pave the way toward building functional tissues that might one day comprise organs.
In nature, cells self-assemble into the complex three-dimensional architectures that comprise tissues. Biological function follows from this structure, and depends on the specific arrangement of cells, often of different types, in relation to one another. An individual cell’s behavior depends on signals from neighboring cells, and the collective behavior of the cells and tissues in an organ emerges from these 3-D relationships.
The new method employs DNA strands, attached to the outside of individual cells, to cause them to stick to surfaces—or other cells—that feature complementary strands, and assemble into prescribed arrangements. The researchers use it to programmatically build tissues, layer by layer.
Other groups are taking a range of approaches toward building functional tissues (see “A Manufacturing Tool Builds 3-D Heart Tissue”). But compared to existing 3-D culture methods, the new one provides a greater level of control over “the ultimate tissue architecture,” argue its creators in a recent paper describing the research.
3-D printing of cells has become a popular way to arrange them for tissue engineering. But this method is hampered by the fact that it’s hard to keep cells alive and healthy throughout the printing process, and it can’t place cells with the precision that is needed, says Zev Gartner, a professor of pharmaceutical chemistry at the University of California, San Francisco, who led the research. Achieving “single cell resolution” is important, and the new method is able to do that, he says. Indeed, “high degrees of control and versatility” give this technique advantages over previously reported tissue assembly techniques, says Lisa Freed, a senior scientist at Draper Laboratory.
At this point the new method can be used to make structures—composed of tissue as well as a gel that surrounds it and simulates the environment in which the tissue lives in the body—that are a few hundred micrometers thick and several centimeters wide. Making thicker tissues will require clearing a huge hurdle facing all of tissue engineering: giving cells oxygen and nutrients, like blood vessels do in the body. Gartner says this could potentially be accomplished by combining tissues made using this new method with microfluidic devices like those used in so-called organ-on-a-chip technologies (see “Building an Organ on a Chip”). The long-term goal, he says, is to use cells and other tissue components as “building materials” that could be induced to assemble themselves into functional organs or organ-like structures.
Higher multi-cellular organisms have evolved sophisticated intra- and inter-cellular biological networks that enable cell growth and survival to fulfil an organism's needs. Although such networks allow the assembly of complex tissues and even provide healing and protective capabilities, malfunctioning cells can have severe consequences for an organism's survival. In humans, such events can result in severe disorders and diseases, including metabolic and immunological disorders [1, 2], as well as cancer . Dominating the therapeutic frontier for these potentially lethal disorders, cell and gene therapies aim to relieve or eliminate patient suffering by restoring the function of damaged, diseased, and aging cells and tissues via the introduction of healthy cells or alternative genes. However, despite recent success, these efforts have yet to achieve sufficient therapeutic effects, and further work is needed to ensure the safe and precise control of transgene expression and cellular processes. In this review, we describe the biological tools and devices that are at the forefront of synthetic biology and discuss their potential to advance the specificity, efficiency, and safety of the current generation of cell and gene therapies, including how they can be used to confer curative effects that far surpass those of conventional therapeutics. We also highlight the current therapeutic delivery tools and the current limitations that hamper their use in human applications.
Opioids are the primary drugs used in Western medicine for pain management and palliative care. Farming of opium poppies remains the sole source of these essential medicines, despite diverse market demands and uncertainty in crop yields due to weather, climate change, and pests. We engineered yeast to produce the selected opioid compounds thebaine and hydrocodone starting from sugar. All work was conducted in a laboratory that is permitted and secured for work with controlled substances. We combined enzyme discovery, enzyme engineering, and pathway and strain optimization to realize full opiate biosynthesis in yeast. The resulting opioid biosynthesis strains required the expression of 21 (thebaine) and 23 (hydrocodone) enzyme activities from plants, mammals, bacteria, and yeast itself. This is a proof of principle, and major hurdles remain before optimization and scale-up could be achieved. Open discussions of options for governing this technology are also needed in order to responsibly realize alternative supplies for these medically relevant compounds.
Biohacking and transhumanist advances (including nootropics, extended longevity, cybernetic implants, better behavioral and genetic self-understanding) will materially advance our quality of life and productivity in the coming decade, but we need to be thoughtful about the potential social and ethical pitfalls as we transform. Google Trends shows a marked uptick in searches for “nootropics” and related biohacking fields, so now is the time to have the conversation about the direction we’re headed.
this essay was co-written with Michael Brandt
Digital products and companies are not just changing the way we live our lives, but also playing larger and more influential roles in public policy and governance. This trend of the technology industry driving broader social policy will perhaps be even greater with biohacking companies as their product innovations begin to alter and transform what it means to be human.
Biohacking is simply the next frontier in the drive to better ourselves. People will enhance themselves physically to have better bones, better eyes and better resilience to disease, as well as attain an overall better standard of living. More people will have access to their full potential. However from an ethics perspective, there’s already worrying concerns about the widening socio-economic gap around the world today; there’s an argument that when only the wealthy have access, it further separates the haves from the have-nots.
What is life and how could it originate? This question lies at the core of understanding the cell as the smallest living unit. Although we are witnessing a golden era of the life sciences, we are ironically still far from giving a convincing answer to this question. In this short article, I argue why synthetic biology in conjunction with the quantitative sciences may provide us with new concepts and tools to address it.
“What is cell biology?” asks the Journal of Cell Biology on the occasion of its 60th anniversary. Raising this simple, yet fundamental question at a time when new data on cells are being collected by the minute is an excellent idea. Information is a necessary, but unfortunately by no means sufficient, requirement for understanding, and the vast amount of data we are now producing may help understand the details but obscure our vision of the cell as a whole. Living systems are inherently complex; this is one of their most distinctive features after billions of years on earth. Complexity is key for their adaptability and resilience, and is both the playground, and the result, of evolution. Unfortunately, the tolerable level of complexity in a connection of thoughts that our brain accepts as an “understanding” is usually rather low, and the most powerful scientific insights, derived by abstraction, have been formulated on the basis of only a few parameters. So either we give up on a systems-level understanding of a cell, and leave it to computers to compile, or we try a theoretical and experimental abstraction of the living cell from its manifold of actual representations. I would like to argue that the latter is possible and will help further our quest to understand the origins of life itself.
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