SEED 2015: Designing a healthy world

Keynote: Pam Silver, Harvard University - Designing Biology for a Healthy World

Pamela Silver, scientist, chair of SEED 2015 and the namesake of a famous Israeli artist, gave an inspiring and exciting talk on how to apply synthetic biology to solve real world problems. She started off by telling how bacteria have become the candidate chassis for synthetic biologists to program new microbes to do their bidding. Essentially they sense something in their environment (as input), which elicits a response from them as output. These I/O blackboxes, as described by her, can be used for a wide range of applications, one of them being sensing.

So can we build cells that would interface with the environment – particularly the gut of mammals - such that they report back to us about what they were confronted with inside? Pam Silver’s lab has successfully demonstrated that “memory” can be built inside bacteria by creating stable on and off states in response to specific target chemicals that might be unwanted in the human guts. After taking care that this newly engineered microbe didn’t cause an antibiotic reaction in the host or attack the host cells, they selected lambda bacteriophage as the candidate carrier for the switch into bacteria which were subsequently introduced to cell cultures and mice. In both case, bacteria “remembered” they were exposed to certain antibiotics even after four generations in an antibiotic-free environment.

In the second part of her talk, Pam Silver shifted gears to circadian clocks. Bacteria have natural oscillators within them, albeit not 24-hour clocks. Synthetically, however, building bacteria that are tuned to our clocks would have huge therapeutic benefits in the controlled and timely release of drugs in not only humans (which is not likely to occur in the next 15 years) but in cattle and poultry as well. A lot of diseases are correlated to our body clocks – we feel certain symptoms more at certain times of the day than other. So impacting the administration of such drugs would increase their effectiveness.

To program 24-hour circadian rhythms in otherwise differently tuned bacteria, the group extracted cyanobacteria’s clock-associated proteins (KiaA, KiaB, KiaC), “plugged” them into E coli and observed a beautiful adoption of the bacteria to the new clock. This was amazing to see for a lot of reasons with respect to compatibility of the proteins in the new microbial system.

In the end Pam Silver gave us a peek into the season’s latest sustainable and solar harvesting fashion wear that is made of cool-looking plastic tubes full of cyanobacteria. These outfits can harvest sunlight and produce energy through the photosynthetic microbes growing inside them. Hopefully this will be at your nearest Old Navy in a few years!

 Links:

https://silver.med.harvard.edu/

http://blog.stratasys.com/2015/05/13/neri-oxman-ted-2015/

SEED 2015 - Microfludics for Synthetic Biology!

µsynth: A Versatile Microfluidic Device for Automating the Synthetic Biology Process

- by Steve Shih, JBEI

Steve Shih’s very well structured talk gave a concise and intriguing peek into the world of microfluidics and its promising potential in synthetic biology automation. In reference to his work he said that Synthetic Biology could be defined as the science to “design and build genetic circuits in living cells.” There is an inherent circular process in every synthetic biological experiment – design and selection of a particular target->build parts of the circuit or pathway as well as perform the actual microbial transformation to run the selected biological circuit->test the resultant engineered microbe using standard validation techniques->learn and repeat the step for optimization.

Microfluidics has been around for a long time and the technique has diversified into a wide range of types (microchannels, two-phase flow, paper fluidics, slip chips, to name a few), all allowing the controlled and regulated interaction of multiple fluids. In case of synthetic biology, microfluidics may hold the key to expediting and automating the experimental cycle described above. They will be able to integrate all chemicals and microbes onto one tiny handheld device, reminiscent of “lab-on-a-chip”.

Shih proposed a novel microfluidic device that controls the flow of liquids in various channels with the help of electrodes. The technique – called Digital Microfluidics (DMF) – harnesses the inherent ionic nature of different fluids and controls the motion of tiny droplets out of the device’s reservoirs and into the common mixing channels to prepare micro-solutions with extremely high efficiency and reproducibility.

The DMF is essentially a layer of alternating electrodes and insulators topped with a hydrophobic surface that contains the reservoirs and fluid channels. Each DMF device can be plugged to a computer and fed with a simple program that will sequentially mix different constituents of an experiment automatically. In his presentation, Shih also demonstrated a successful proof of concept using a bicistronic design. Looking forward to more widespread use of DMF devices in the future!

Their lab website: http://www.jbei.org/research/divisions/technology/microfluidic-assays/

SEED 2015 - Jeff Way, Wyss Institute - Spatial and Quantitative Optimization of Engineered Multi-Element Therapeutic Proteins

Dr. Jeffrey Way started off session 2 on biomedical applications at the SEED (Synthetic Biology: Engineering, Evolution and Design) conference by talking about the application of synthetic biology in protein drug design and production.  Protein drugs are essentially drugs that either target proteins thereby blocking their activity or replace a missing protein (as in case of diabetes or anemia).

Dr. Way discussed how nature uses highly complex systems to achieve immune responses – multiple proteins interact with multiple ligands and this complex network is constantly edited by evolution.

At its core, Synthetic Biology is about learning from Nature and improving our methods of producing organic compounds. Borrowing a leaf from redundant and complex mammalian pathways Dr. Way proposed to improve specificity of protein drugs in two ways – first, by introducing minor mutations in the proteins such that their affinity to bind to non-targets reduces, albeit at the cost of 40x-200x reduction in target-specific activity and second, by physically linking the protein to another protein that will bind to a spatially nearby cell-surface receptor.

Dr. Way and others in the Dr. Pamela Silver lab have demonstrated the aforementioned strategies using two protein drug systems – the IFNα and Erythropoietin (EPO). This technology holds promise in the billion-dollar field of EPO production – the key drug for anemia - but work needs to be done in making this suitable for scenarios such as “solid” tumors that are rendered inaccessible due to lack of proper exchange of fluids with lymph nodes and are impervious to diffusion.

To address the current challenges in protein drug design, Dr. Way urged the need for computational tools that would allow spatial optimization of protein-protein complexes and increase the throughput of the current method of experimental trial and error.

For more information, visit their lab site: https://silver.med.harvard.edu/

DNA nanobot for medicine

It sounds very very crazy at first, but as I take your hand and we venture deeper into the physics and chemistry behind it your eyes will slowly grow larger (because your eyelids will open, of course) and you'll look like a crazy awestruck scientist (even if you're a banker). The simplicity will grip you like you just heard the answer to everything and you'll realize it truly isn't rocket science, so to speak.

That's how I imagine, with proof to back up, a conversation about my project with a stranger. My boss and I have been nurturing this brainchild of his for four years now. It looks nothing like the rough sketch he had conjured when the idea was first born, because I came along and made it wackier yet closer to what I like to call the benevolent mutant XI of DNA nanomachines (Xmen, anyone?).

It's a small machine packed with opportunities to detect any molecule that can be detected. It's like a color-gun that is limited by how many colors you have. So this machine, let's call it the Slider, is made using DNA as the building material, which makes it extremely cheap. DNA is also quite robust; its insane desperation to exist on this planet gives it very high shelf-life - throw a tube of dried DNA in the desert, come back after 6 months, rehydrate and use it! My boss, in one of his coffee breaks, calculated the cost of 1 one these bad boys to be $0.000000000000000001...that's 17 zeros in case you aren't counting.

DNA is a very fascinating molecule. Everyone knows it as the instruction manual of living organisms on Earth. If we, the products of our genomes, were fictions, then evolution would blow Tolkein, Rowling and Martin and every bestselling author out of the water. It codes genes and those genes pretty much run the world by expressing proteins and RNA molecules. Another facet of DNA is its extreme inclination to form double helices - two DNA strands wrap up around each other based on their very specific sequence - like two spies meeting in a shady ally, "did John send you?" "No, John's my middle name". Right, I'm not the spy-type.

Using this highly specific sequence, different DNA strands can be synthetically designed and if allowed to mingle in a match.com cocktail event for DNA strands, lo and behold you have a DNA nanostructure! Now imagine these DNA nanostructures to look like, for simplicity, the big rectangle lego boards that we build skyscrapers on (though DNA nanostructures can be pretty much of any shape). The way one can plug other lego pieces on the board, scientists can chemically and very precisely attach different molecules onto DNA nanostructures - you want protein A 5.5nanometers away from protein B on the top left corner of this DNA nanostructure? Done and done! And then done again! In less then a week.

This nanomachine, the Slider, works the same way. It has been plugged with a molecule capture site and a light-emitting site to tell us humans of the diagnosis. It's a pregnancy-test stick, only extremely small and tailored to diagnose other diseases.

We believe in our DNA and in synthetic DNA, and we have dedicated our time to creating a very inexpensive, easy to implement diagnostic tool. The Slider, can be coded to have signals that indicate the presence of certain disease-related molecules. For instance, Ebola is causing massive havoc. It's not affordable to provide every make-shift clinic around the world with state-of-the-art testing machines. If we can program the Slider to detect the presence of Ebola associated molecules, diagnosis can hopefully become a $1-1day-every-person affair.

Traditionally, scientific research has been considered a thing for geeks. But, did you know you have been part of it all this time? The money that goes into universities and research labs is yours! Crowd funding is a very exciting strategy to bring you closer to the product of your money. So please consider making a difference by funding us!