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Engineered Probiotics as Living Medicine

Posted January 16, 2017

Modern medicine has found many ways to use a pill of chemicals to improve human health for people around the world. Drugs are taken for infections, cancer treatment, metabolic disorders, and every other ailment. Despite the impact of chemical medicines, there are many problems that need a smarter solution with more targeted benefits. One smarter medicine to keep an eye on in 2017 and beyond is the use of engineered microbes to produce therapeutics or diagnostic signals within the human body. Living medicines designed to respond to cues in the human body can create new kinds of treatments or diagnostics that would be impossible with a traditional drug.

Our ability to reliably engineer microorganisms to do our bidding (synthetic biology) and our knowledge of the importance of balancing the vast community of bacteria in our gut (human gut microbiome) are both fairly new developments. Beyond just a combination of two buzzwords, synthetic biology applied to the microbes in our gut gives us a new treatment approach that uses a living product instead of a chemical.

Synthetic biologists put bits of DNA in the cells of an organism so that it does some new job in addition to all of its normal functions to survive. Meanwhile, studies of the human gut microbiome have lead to the realization that bacteria may be constantly influencing our health. While this microbiome knowledge has lead to fads in probiotic use, a more powerful application may be using probiotics engineered to address the specific problem for each patient.

Sense and destroy

A clear example of an engineered therapeutic was published in 2011 that created E. coli that could sense and destroy the pathogen Pseudomonas aeruginosa. The researchers from Nanyang Technological University in Singapore put the quorum sensing ability from Paeruginosa into E. coli and connected it to the production of the toxic proteins called pyocins. So when there’s a quorum of Paeruginosa, the engineered E. coli turn on pyocin production to kill Paeruginosa. Figure 1 below shows the overall system.

Engineer the good guys

Of course any living medicine would have new concerns about safety. Some synthetic biologists have worked on kill switches that could eliminate the microbes if something went wrong. But the major factor for safety is starting with an organism that is already safe to eat. The typical lab strains of E. coli are not helpful as probiotics, but there is a probiotic strain called E. coli Nissle. By using a bacteria deemed ‘good’ in our gut, we can give a boost to the good guys.

In late 2016 startup Synlogic, co-founded by Jim Collins and Tim Lu who are both at MIT now, got the patent for modifying E. coli Nissle to treat urea cycle disorders. The idea here is to give E. coli Nissle the ability to do the metabolic job that a patient’s body may not. This Nissle strain can have some beneficial effects but it must be replenished with repeated doses because it doesn’t colonize the gut.

Beyond just safety, another key factor to decide which organism to engineer, is the organism’s ability to survive in the part of your gut where you need it to do its job. Nissle doesn’t set up permanent residence in your gut so you have to keep replenishing it with new doses. An organism that colonizes your gut could be taken once or infrequently and provide continued benefits.

Tim Lu’s lab at MIT has created genetic parts that can be used in the gut bacterium Bacteroides thetaiotaomicron (B. theta). The B. theta bacteria are major players in our healthy gut microbiomes. Since its natural form is well adjusted to thriving in our guts, the engineered version should also be able to live in our guts for longer periods of time.

Living health monitors

Another job that could be given to engineered probiotics is diagnosis. By engineering the bacteria to sense an important molecule in our body and then produce some signal, our smart probiotics become a living medical test inside of us. For instance, researchers put DNA that codes for the LacZ protein that cuts a chemical substrate in two. Once cut, the substrate is able to pass through a mouse kidney give a luminescent (glowing) signal in the urine.

Similar probiotics could also be engineered to detect small molecules, quorum sensing signals, or growth states of the gut microbiome. These sensor-equipped probiotics could produce detectable signals in urine or stool; however the sensors could also be combined with therapeutic outputs to create probiotics that detect some signal and respond with a therapeutic response based on the specifics of the gut environment.

Expanding the engineered probiotic toolset

In addition to bacteria which are prokaryotes, a eukaryote like the probiotic yeast Saccharomyces boulardii could also be used. Using a eukaryote can help to make special changes to proteins, called post-translational modifications. Many potential therapeutic proteins need these modifications to be able to work in humans, so this yeast might be able to deliver therapies that a bacterium could not.

Other species will also be tamed and engineered for treating microbiome disorders. Different probiotics may survive better in different diseased guts, colonize different parts of the gut, or interact with the natural microbiome differently. Expect to see a ever increasing toolset of engineered probiotics to treat your gut microbiome.

Source: PLOS EveryONE

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