Synthetic Biology in Medicine

WHAT IS SYNTHETIC BIOLOGY? Synthetic biology aims to redesign biological systems to perform novel functions in a predictable way and requires collaboration between specialists from multiple fields. In this infographic, we will explore some of the medical applications of synthetic biology across several key areas. Diagnostics approaches can be developed using synthetic biology. Cell therapies are the “most relevant” synthetic biology-inspired therapeutic. For example, they can use engineered cells, such as T cells, programming them to target and destroy cancer cells. Chimeric antigen receptor (CAR) T-cell therapy can be tailored to target specific cancer antigens and is customized for each patient – a type of personalized medicine. However, T-cell therapy can be highly toxic as it can lead to off-target interactions with other cells. Synthetic biology-inspired approaches may be able to enhance their safety and reduce toxic side effects. Engineered Escherichia coli bacteria can be used as whole-cell sensors to detect zinc deficiencies. These respond to zinc concentrations – an important mineral for health – to produce visible pigments. This works with minimal equipment and could provide the basis of a point-of-care, field-deployable test for zinc deficiency. Researchers are working on ways to program “safety switches” into cell therapies. If therapies cause toxicity, drug-controlled safety switches can enable the therapeutic cells to be eliminated in the presence of a specific drug. This successfully eliminated graft-versus-host disease – a potentially serious complication of cell therapy – in a clinical trial of patients with relapsed acute leukemia. Bacteria are great organisms to serve as a “chassis” for synthetic approaches due to their: EASE OF GENETIC ENGINEERING SIMPLICITY ROBUSTNESS They can be used to detect stimuli and produce a response. Synthetic biology may be able to advance existing treatments or precision medicines. Some synthetic biology-based approaches are being evaluated in clinical trials. Others, such as cell therapies, are already approved. It could even pave the way to treat “untreatable” conditions. Researchers have developed a synthetic live bacterial therapeutic for phenylketonuria. They engineered E. coli bacteria to produce the phenylalanine transporter (PheP) and enzyme phenylalanine ammonia lyase (PAL) when in the low-oxygen (hypoxic) environment of the digestive tract. This approach has shown promise in mice and healthy volunteers. An engineered fusion of two proteins – caspase 9 and an FKbinding protein – serves as a safety switch in the therapeutic cells. Two fusion proteins bind together, or dimerize, in the presence of a synthetic drug, given to a patient experiencing toxic side effects. Dimerization activates the caspase 9 protein, causing the cell to die by apoptosis, thus reducing toxicity. These methods show great promise, but most are still undergoing preclinical development. Sensors are selective and sensitive and are translated into an output such as fluorescence or a color change when the target cell, environmental cue or pathogen is detected. There are many different applications of synthetic biology: These can be used to monitor factors such as: DIAGNOSTICS CELL THERAPY AND PERSONALIZED MEDICINE SYNTHETIC BACTERIAL THERAPEUTICS THE FUTURE OF SYNTHETIC BIOLOGY IN MEDICINE 1 2 3 Example: zinc deficiency testing Example: cell therapy “safety switch” Example: phenylketonuria Synthetic circuitry and other engineered components are used to create novel molecular functions. The engineering approaches in synthetic biology have the potential to turn promising technologies into useful real-world tools to help diagnose, treat and prevent disease. Benefits of synthetic biology-based diagnostics approaches can include: • Earlier, more accurate diagnoses • Real-time monitoring • Enables personalized interventions/treatments • Relatively low-cost • Portability, for resource-limited settings CAR T-CELL THERAPY PRODUCTION T cells are isolated from the blood and genetically modified to express cancertargeting CARs. Engineered cells are then expanded and administered back to the patient. Phenylketonuria is an inherited metabolic disorder. It is caused by mutations in the phenylalanine hydrolase (PAH) gene that codes for an enzyme that converts the amino acid phenylalanine into tyrosine. Those affected cannot break down phenylalanine and it accumulates in the body, causing neurological symptoms. INTELLECTUAL DISABILITY PSYCHIATRIC DISORDERS SEIZURES PHENYLALANINE PHENYLALANINE TRANS-CINNAMATE HIPPURATE EXCRETED IN URINE PHENYLALANINE + HYPOXIA Synthetic biology efforts in diagnostics are typically focused on building molecular sensors that are linked to a measurable output. A key example is biosensors, synthetic systems that consist of three main components: SENSOR Detects signals from the environment, either in vivo or in vitro. LOW ZINC BORDERLINE ZINC NORMAL ZINC ISOLATION FROM BLOOD INFUSION EXPANSION FK-BINDING PROTEIN Casp9 DIMERIZING AGENT APOPTOSIS (PROGRAMMED CELL DEATH) DIMER T CELLS T-CELL ENGINEERING PROCESSOR A synthetic circuit that receives, processes and integrates the signal. REPORTER Produces an output, be it chemical, biological, electronic or a combination/ mixture. SYNTHETIC BIOLOGY IN MEDICINE SYNTHETIC BIOLOGY CHEMISTRY ENGINEERING BIOTECHNOLOGY MATHEMATICS BIOLOGY BIOINFORMATICS BIOFUELS CANCER CELLS MEDICINE DRUGS ENVIRONMENTAL ANALYSIS METABOLISM FARMING AND AGRICULTURE INFECTION