Designer Probiotics for Healthier Microbiomes
By: Logan Thrasher Collins
Though we often think of our bodies as composed of human cells, we contain a complex ecosystem of microorganisms which also represents an integral part of our inner workings. This human microbiome has been linked to obesity , immune system function and dysfunction , and even mental health . People who have lost much of their microbiome to broad-spectrum antibiotic treatments (intended to kill off harmful microorganisms) paradoxically possess susceptibility to future infections. Because the microbiome plays so many key roles within our bodies, there exists increasing scientific interest in technologies which improve human wellbeing through probiotic microbiome interventions. Here, I will provide a brief primer on the exciting world of designer probiotic biomedicines as well as some ways that researchers are learning more about the microbiome to guide the engineering of these probiotics.
In the future, we may apply probiotic technologies to improve our health by nudging our microbiomes towards equilibrium. Many of these interventions will show far greater precision than existing pharmaceutical methods and therefore have minimal or no side effects. Some of the most remarkable emerging probiotic technologies come from a field called synthetic biology, which takes a creative design approach to engineering new biological systems. Synthetic biologists like myself see biology as an enormous LEGO set in that it can be roughly thought of as comprised of a rich array of biological parts.
Smaller parts can be put together to create larger parts, different parts can be rearranged, and new groups of parts can be installed into existing biological systems (also called chasses) such as bacterial cells. By approaching bioengineering in this way, we can create probiotic microorganisms which respond to and communicate with their environments, allowing them to integrate elegantly into the rest of the natural world. Through synthetic biology, the probiotic biomedicines of the future may seek out and destroy infectious microorganisms, aid the human body in moving towards a healthy weight, strengthen the immune system, treat immunological disorders, and improve mental health.
Designer probiotics may soon offer a powerful alternative to traditional antibiotic medicines for treating infections. Though these technologies are not yet on the market, current proof-of-concept successes may propel them forward in coming years. One example of such an engineered probiotic for precisely targeting and eradicating pathogens comes from my own past research . I developed a way of using E. coli to transfer DNA encoding a new type of antimicrobial peptide (called OpaL) into other bacteria via a process known as bacterial conjugation. I designed this antimicrobial peptide to work by sticking together into globs which cause chaos in the target bacteria. When the DNA moved into these target bacteria, the gene turned on and produced the antimicrobial peptide, causing those bacteria to die. I used a genetic switch to ensure that the gene stays dormant in non-target bacteria and turns on in target bacteria, allowing for pathogen-specific pruning of bacterial populations.
In another example of a designer probiotic proof-of-concept, scientists at Nanyang Technological University genetically reprogrammed E. coli to seek out and attack a pathogen called Pseudomonas aeruginosa . They provided the E. coli with a genetic circuit which allowed them to sense molecules secreted by the Pseudomonas. The genetic circuit induced the E. coli to swim towards Pseudomonas and release an antimicrobial peptide, killing off the pathogen in a targeted fashion. Because Pseudomonas often protects itself by secreting a thick coating of slime, the scientists also provided their E. coli with the ability to produce an enzyme that breaks down this slimy layer. Such probiotic technologies for controlling infection represent an exciting first step into microbiome engineering.
The future may bring more complex types of microbiome interventions which address challenges like obesity, immunological function and dysfunction, and mental illness, yet many of these nudges will require an improved holistic understanding of how diverse microbial communities interact with each other and with their human hosts. To this end, researchers are developing new techniques to systematically decipher the complex molecular conversations of our microbial inhabitants. An example of such a technique is MaPS-seq (Metagenomic Plot Sampling by sequencing), a method for identifying the types of bacteria that cluster together as communities in a given microbiome sample . The method works by embedding a sample of gut microorganisms in a gel, breaking this gel into small chunks, encapsulating the chunks into oil droplets along with unique molecular barcodes, and performing DNA sequencing on the contents of each droplet.
With MaPS-seq, scientists can analyze the interactions of multispecies communities of bacteria. Another example of a new methodology for studying the microbiome is TRACE (Temporal recording in arrays by CRISPR expansion) . TRACE uses engineered bacteria which modify their own DNA whenever they are exposed to certain molecules. Scientists choose which molecules are recorded. So, the engineered TRACE bacteria can record molecular signals in their environment over time, providing a powerful tool for listening in on the biochemical conversations that occur among microbiome bacteria. As techniques like MaPS-seq and TRACE are implemented, we will gain a better picture of how the human microbial ecosystem works. By combining this systems-level knowledge of the microbiome with computational modeling, we will gain the ability to predict how the microbiome may respond to specific probiotic interventions, accelerating the design of more complex probiotic therapies for maximizing human health.
Technologies for reprogramming our microbiomes towards improved human wellbeing are beginning to emerge. Synthetic biology has matured as a discipline over the past 10 years and is now enabling designer probiotics. Some early-stage examples of such probiotics include bacteria carrying genetic circuits which allow them to seek and destroy pathogens as well as bacteria with equipped with gene transfer tools for spreading genes encoding selectively toxic antimicrobials through microbial communities. These early examples focus on pathogen eradication, which represents a relatively simple task, but future microbiome engineering may help address more complex types of dysfunction like obesity, immunological disease, and mental illness.
To reach the point at which we understand the microbiome well enough to accomplish this, scientists are designing new experimental techniques for holistically dissecting how the microbiome works and responds to change. Some of these techniques determine what types of bacteria consort with each other in the gut and others record molecular signals over time within microbial ecosystems. I believe that microbiome engineering will likely circumvent the need for many of the crude pharmaceutical interventions of today, making us healthier and improving quality of life.
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