Engineering an “Invisible Cloak” for Bacteria to Deliver Cancer Drugs

Scientists exploring a novel but highly promising avenue of cancer treatment have developed a type of “invisibility cloak” that helps engineered bacteria sneak through the body’s immune defenses. The result is more powerful delivery of anti-cancer drugs and shrinking of tumors in mice, with the scientists hopeful the approach can overcome toxicity issues that have plagued these techniques so far.

Traditional forms of cancer treatment – radiotherapy, chemotherapy and immunotherapy – each have their own strengths when it comes to combating tumors, and what’s known as therapeutic bacteria could bring its own set of skills into the mix. Bacteria itself can have powerful anti-tumor effects, but genetic engineering could allow it to take on entirely new capabilities, including releasing specific compounds or carrying potent anti-cancer drugs. There are a number of challenges in using bacteria for this purpose, however, with the issue of toxicity chief among them. Living bacteria can grow rapidly in the body, and because the body’s immune system sees them as a threat, too many can trigger an extreme inflammatory response.

In clinical trials, these toxicities have been shown to be the critical problem, limiting the amount we can dose bacteria and compromising efficacy,” said Columbia University‘s Jaeseung Hahn, who co-led the research. “Some trials had to be terminated due to severe toxicity.

Addressing this toxicity problem would mean finding (or engineering) bacteria that can evade the body’s immune system and safely make it to a tumor to fulfill their anti-cancer potential. Hahn’s team has made new inroads in this space by turning to sugar polymers called capsular polysaccharides (CAP), which naturally coat bacterial surfaces and protect them from immune attacks.

We hijacked the CAP system of a probiotic E. coli strain Nissle 1917,” said Tetsuhiro Harimoto, the study’s co-lead author. “With CAP, these bacteria can temporarily evade immune attack; without CAP, they lose their encapsulation protection and can be cleared out in the body. So we decided to try to build an effective on/off switch.”

Source: https://www.engineering.columbia.edu/

3D-Printed Chicken

Who hasn’t dreamt of coming home after a long day and simply pressing a few buttons to get a hot, home-cooked 3D-printed meal, courtesy of one’s digital personal chef? It might make microwaves and conventional frozen TV dinners obsolete. Engineers at Columbia University are trying to make that fantasy a reality, and they’ve now figured out how to simultaneously 3D-print and cook layers of pureed chicken, according to a recent paper published in the journal npj Science of Food. Sure, it’s not on the same level as the Star Trek Replicator, which could synthesize complete meals on demand, but it’s a start.

Coauthor Hob Lipson runs the Creative Machines Lab at Columbia University, where the research was conducted. His team first introduced 3D printing of food items back in 2007, using the Fab@Home personal fabrication system to create multi-material edible 3D objects with cake frosting, chocolate, processed cheese, and peanut butter. However, commercial appliances capable of simultaneously printing and cooking food layers don’t exist yet. There have been some studies investigating how to cook food using lasers, and Lipson’s team thought this might be a promising avenue to explore further.

We noted that, while printers can produce ingredients to millimeter precision, there is no heating method with this same degree of resolution,” said coauthor Jonathan Blutinger. “Cooking is essential for nutrition, flavor, and texture development in many foods, and we wondered if we could develop a method with lasers to precisely control these attributes.” They used a blue diode laser (5-10 watts) as the primary heating source but also experimented with lasers in the near- and mid-infrared for comparison, as well as a conventional toaster oven.

The scientists purchased raw chicken breast from a local convenience store and then pureed it in a food processor to get a smooth, uniform consistency. They removed any tendons and refrigerated the samples before repackaging them into 3D-printing syringe barrels to avoid clogging. The cooking apparatus used a high-powered diode laser, a set of mirror galvanometers (devices that detect electrical current by deflecting light beams), a fixture for custom 3D printing, laser shielding, and a removable tray on which to cook the 3D-printed chicken.

During initial laser cooking, our laser diode was mounted in the 3D-printed fixture, but as the experiments progressed, we transitioned to a setup where the laser was vertically mounted to the head of the extrusion mechanism,” the authors wrote. “This setup allowed us to print and cook ingredients on the same machine.” They also experimented with cooking the printed chicken after sealing it in plastic packaging.

The results? The laser-cooked chicken retained twice as much moisture as conventionally cooked chicken, and it shrank half as much while still retaining similar flavors. But different types of lasers produced different results. The blue laser proved ideal for cooking the chicken internally, beneath the surface, while the infrared lasers were better at surface level browning and broiling. As for the chicken in plastic packaging, the blue laser did achieve slight browning, but the near-infrared laser was more efficient at browning the chicken through the packaging. The team was even able to brown the surface of the packaged chicken in a pattern reminiscent of grill marks.

Millimeter-scale precision allows printing and cooking a burger that has a level of doneness varying from rare to well-done in a lace, checkerboard, gradient, or other custom pattern,” the authors explained. “Heat from a laser can also cook and brown foods within a sealed package … [which] could significantly increase their shelf life by reducing their microbial contamination, and has great commercial applications for packaged to-go meals at the grocery store, for example.” To make sure the 3D-printed chicken still appealed to the human palate, the team served samples of both 3D-printed laser cooked and conventionally cooked chicken to two taste testers. It’s not a significant sample size, but both taste testers preferred the laser-cooked chicken over the conventionally cooked chicken, mainly because it was less dry and rubbery and had a more pleasing texture.

Source: https://www.wired.com/

New Crispr Fixes 89% Of The Mutations That Cause Heritable Diseases

Andrew Anzalone was restless. It was late autumn of 2017. The year was winding down, and so was his MD/PhD program at Columbia. Trying to figure out what was next in his life, he’d taken to long walks in New York’s leaf-strewn West Village. One night as he paced up Hudson Street, his stomach filled with La Colombe coffee and his mind with Crispr gene editing papers, an idea began to bubble through the caffeine brume inside his brainCrispr, for all its DNA-snipping precision, has always been best at breaking things. But if you want to replace a faulty gene with a healthy one, things get more complicated. In addition to programming a piece of guide RNA to tell Crispr where to cut, you have to provide a copy of the new DNA and then hope the cell’s repair machinery installs it correctly. Which, spoiler alert, it often doesn’t. Anzalone wondered if instead there was a way to combine those two pieces, so that one molecule told Crispr both where to make its changes and what edits to make. Inspired, he cinched his coat tighter and hurried home to his apartment in Chelsea, sketching and Googling late into the night to see how it might be done. A few months later, his idea found a home in the lab of David Liu, the Broad Institute chemist who’d recently developed a host of more surgical Crispr systems, known as base editors. Anzalone joined Liu’s lab in 2018, and together they began to engineer the Crispr creation glimpsed in the young post-doc’s imagination. After much trial and error, they wound up with something even more powerful. The system, which Liu’s lab has dubbed “prime editing,” can for the first time make virtually any alterationadditions, deletions, swapping any single letter for any other—without severing the DNA double helix.

“If Crispr-Cas9 is like scissors and base editors are like pencils, then you can think of prime editors to be like word processors,” Liu told reporters in a press briefing. Why is that a big deal? Because with such fine-tuned command of the genetic code, prime editing could, according to Liu’s calculations, correct around 89 per cent of the mutations that cause heritable human diseases. Working in human cell cultures, his lab has already used prime editors to fix the genetic glitches that cause sickle cell anemia, cystic fibrosis, and Tay-Sachs disease. Those are just three of more than 175 edits the group unveiled in a scientific article published in the journal Nature.

The work “has a strong potential to change the way we edit cells and be transformative,” says Gaétan Burgio, a geneticist at the Australian National University who was not involved in the work, in an email. He was especially impressed at the range of changes prime editing makes possible, including adding up to 44 DNA letters and deleting up to 80. “Overall, the editing efficiency and the versatility shown in this paper are remarkable.”

Source: https://www.broadinstitute.org/
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Long-term memory forming mechanism discovered

Your brain has its own box of memories. If you were to hold it in your hand, brush off the dust and open it up, you’d be able to pull out Polaroid snaps of your most treasured memories. Your graduation ceremony perhaps, your wedding day, your daughter’s first words – all things you wouldn’t want to forget. But how does your brain keep these memories in their crystal-clear clarity? The strength of a memory lies in its formation and upkeep. When we create a memory, thin connections, called axons, form between nerve cells in our brain. The point at which two axons connect is called a synapse, and it is the strength of the synapse that determines if the memory is kept or allowed to fade away.

Now, a study in mice carried out by Nobel Prize-winning researchers at Columbia University has shown that a protein called CPEB3 plays an important role in the formation of memories. The team discovered how this protein is stored and used in the brain and hope it could lead to new methods of slowing memory loss in humans.

The science of how synapses form and are strengthened over time is important for deciphering any disorder in which synapses – and the memories associated with them – degrade and die, such as Alzheimer’s disease,” said Dr Luana Fioriti. CPEB3 is created by the brain’s memory centre, the Hyppocampus. Once produced, it is stored in chamber-like structures called P bodies that protect it from other parts of the cell. It then travels to the synapse between nerve cells where required and is gradually released to help create a specific memory.

The findings suggest that the more CPEB3 released at a synapse, the stronger the connection and thus, the more concrete the resulting memory is. When the protein was removed, the mice could create new memories but were unable to keep them.

Source: https://www.sciencefocus.com/