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 [1], immune system function and dysfunction [2], and even mental health [3]. 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 [4]. 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 [5]. 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 [6]. 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) [7]. 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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From the stethoscope to robotic surgery, the field of medical innovations has transformed to make disease diagnosis and prognosis fast, error-free, and widely accessible. A significant milestone in this endeavor involves the creation of point-of-care devices. The term “point of care” (hereby referred to as POC) was coined by Dr. Gerald J Kost, a University of California Davis doctor quantifying Calcium levels in blood samples using a biosensor1. Since then, POC devices have been used for a variety of diseases – from tuberculosis to infectious diseases such as HIV and syphilis, from diabetes to pregnancy. It is also remarkable that POC devices have been fabricated on a range of support material – from paper to microfluidic devices2-5.
In simple terms, POC refers to an examination/investigation of a disease that ensures instant availability of results determining whether the user is infected or not. The POC device/detection kit usually has an assembly of biochemical and immunological components that exhibit chemical reactivity with the disease-causing agent (antigen, receptor, specific surface proteins etc.) leading to a easy-to-interpret result that includes a colorimetric change, change in observed light intensity, fluorescence, etc. A POC device aims to accelerate the steps usually performed in a laboratory setting to give quick, instantaneous, and reliable disease diagnosis results.
Furthermore, a POC device should be easy to use and troubleshoot, accompanied with a clear set of instructions involving 1) type of sample required (e.g., clinical samples such as saliva, blood, urine; environmental samples, etc.), 2) quantity of sample, 3) any specific instructions involving operation of the POC (e.g., pressing a specific button, inserting the sample tube into a specific location, smartphone-based results interpretation etc.), 4) steps on how to observe and read the result generated by the POC diagnosis. Moreover, in most cases a POC device aims to provide results in a quick timeframe to enable the user (patient) to take the necessary next steps without delay, thereby leading to more informed healthcare.
Exhibit 1 (The Pregnancy home-test). POC pipeline for pregnancy testing using commonly available POC pregnancy kits, one of the most widely used POC devices today. Step #2 occurs via a process called Lateral Flow Chromatographic Immunoassay leading to either a positive or negative result as determined by one or both bands highlighted (in yellow, Step #3)
Exhibit 2 (Blood glucose monitoring). POC pipeline for blood glucose monitoring using the commonly available glucose strips and quantification meters (Image Credit on top: Accu-Chek). As opposed to the Pregnancy POC kit, biochemical reactions occur in the strip itself (Step #1A-B) leading to reaction end-products. These generate signals in the blood glucose testing device, leading to an instantaneous assessment of blood glucose levels (Step #3).
A summary of reports and peer-review studies on POC diagnosis and detection led to distilling the following as important for easy POC application and use.6-8
Exhibit 3: Operational, Quality, and Performance indicators for POC detection
1CLSI stands for Clinical and Laboratory Standards Institute
2CAP stands for The College of American Pathologists
3National Pathology Accreditation Advisory Council
Exhibit 4: Technology Trends are evolving rapidly to design POC devices that are efficient in terms of detection sensitivity, diversity of user samples, data availability and interpretation. A classification of 1st, 2nd, and Next-Gen POC technologies follows9 :
Note: ADR refers to Antibiotic Drug Resistance
A McKinsey study10 suggests a major shift in medical services from the clinic to the home to occur by 2025. Furthermore, the study provides a detailed insight into the extent by which capabilities are matured or still in development stage for various stages of medical services (primary, long term, acute, emergency etc.) – See Exhibit 4.
Exhibit 5: Market growth for medical services in clinics and how these services can shift to the home by 2025 (Source: McKinsey & Company)
The McKinsey thought article estimated up to $265 billion of care to shift from clinics (traditional setting) to in-house domestic care. Services such as primary care and patient consultations are expected to scale at home as point solutions. Furthermore, 15 – 40% of elaborate services from dialysis to infusions are expected to be increasingly delivered at home. Finally, acute conditions such as respiratory illnesses (asthma, pneumonia), cardiac failure, pulmonary diseases (COPD) etc. can be expected to be treated reliably in home settings. Clearly, there is ample opportunity to develop POC technologies for pre-disease assessments and informed next steps.
Moreover, integrating these POCs with developments such as telehealth and more connected health-information networks is expected to make disease diagnosis efficient, reliable, and fast at the domestic level. Well-connected and technologically sounds health ecosystems have the potential to deliver personalized and integrated diagnosis and assessment to users, enhancing productivity, and encouraging drive towards frugal solutions11. Technological developments (Exhibit 4) will help in this effort by providing more informed diagnosis platforms while enabling easier user experience. This would also assist in treatment of emerging diseases due to ADR strains, SARS-CoV-2, virus outbreaks etc.
Anirban Kundu is an Environmental Engineering PhD candidate and Sustainability ChangeMaker at McGill University. He's worked with superb teams at reputed universities & institutions across India, Canada, France; Fortune 500 companies; Governments; non-profit organizations. Demonstrated leadership excellence in Fine Arts and cultural activities, leading to being General Secretary of Students' Dramatics team, co-producing 4 theatre productions and annual cultural programs in India.
Over the past several years, I’ve had a growing affinity towards the science behind therapeutics. When it first began, I couldn’t necessarily explain what motivated it. However, over time I began to realize where my interest was tied to. This is a field where we are continuously learning about the correlation between anatomy, physiology, pathology, and pharmaceutic approaches. Yet, at the same time, the answers have been laying right in front of us waiting to be utilized. At least that’s how I view it. I see it as finding missing puzzle pieces and learning about the impact that can make towards seeing the whole picture. One puzzle piece I can’t seem to stop thinking about as of recent is pharmacogenomics. Although with the completion of the Human Genome Project has occurred almost two decades ago and most of the pertinent information from pharmacogenomics has already been attained, its impact is still only a potential. We are all waiting to see it in action.
Before defining the potential of pharmacogenomics, it would be ideal to thoroughly define the term. Pharmacogenomics is the study of how someone’s genes respond to medications. To put into context, Warfarin is a blood thinner commonly used for individuals with irregular heartbeats that can lead to clotting of the heart. This medication blocks protein complexes in our body to reduce our ability to form blood clots with the intention of prevent a serious clotting event from the irregular heartbeat. A side effect of this is an increased risk of bleeding which is ideal considering that the side effect is tolerable and worth for preventing a cardiac event in exchange.
However, we all know that drugs are not a one size fits all kind of therapy. Warfarin can cause more incidents of serious bleeding in some than others. It was through pharmacogenomics that proved that there is gene mutation that occurs frequently in African-Americans that impeded the body’s ability to get rid of the Warfarin in the body. Due to the body not being able to get rid of it as efficiently as it should, this led to a higher amount of Warfarin in the body and a much higher risk of bleeding. Here a race was experiencing a severe side effect due to a simple genetic alteration. This information was discovered from pharmacogenomics. This information now can allow health care providers to make adjustments to their strategic thinking in choosing therapy. Now other medications that aren’t affected by this mutation are may be chosen as there is evidence to support theses decisions. Pharmacogenomics has led us to discoveries similar to this for hundreds of drug-induced side effects including ones for over the counter meds and herbal supplements. That’s a pretty large puzzle piece.
What’s next? Taking this and implementing it into healthcare to personalize medicine. The one size fits all phenomenon can slowly be conquered with clinical trials demonstrating the impact this can have in health care and emphasize the need for pharmacogenomic testing of individuals to be more affordable. Tailoring a drug regimen to one’s ability to eliminate a drug from the body is trivial to the possibilities of pharmacogenomics. A world awaits us where affordable treatment targeted towards heart disease, asthma, Alzheimer’s, depression, cancer, HIV/AIDS, and more could all be greatly enhanced by having the patient’s genes mapped down precisely. At this point, it’s fair to say the potential of pharmacogenomics has been defined. Now it’s time to make everyone aware of it’s definition.
Pharm.D. Candidate Khallid Benson is a student of art as much as he is a student of medicinal sciences. Benson records, produces, and writes for other recording artists including his own group called “99%.” As far apart as creating music and practicing pharmacy may appear to be on the career spectrum, Khallid has manages to bridge the two fields through his work in graphic designing. This includes infographics, informational videos, and commercials that Conduit has utilized within their content.
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