Why 2018 Was the Year of Living Medicines

How Engineered Organisms are Being Programmed to Fight Disease

E. coli cells magnified 10,000x. Original image by Eric Erbe and Christopher Pooley, USDA.

Leeches, those blood-sucking, slimy animals that are too often the stuff of nightmares and B-movies (for a great B movie example, see Leeches!, a movie from 2003, with the actual plot line of: “Mutated leeches terrorize a college campus after feeding on blood tainted by steroids”), are actually amazing healers. The word ‘leech’ even derives its name from the Anglo-Saxon loece, meaning ‘to heal’. These oozing creatures have been used in medicine for thousands of years, with medical documentations dating back to at least the time of Themison of Laodicea, a Greek physician that lived between 80–40 BC and is credited as the founder of the Methodic School of Medicine.

Leeches are placed on the skin of the patient for about 30 minutes. They pierce the skin with sharp rows of teeth and inject anticoagulants and other bioactive compounds into the bloodstream. Leeches are still used in certain medical applications today, including for osteoarthritis and some inflammatory diseases. But the future of ‘organismal-based’ therapies is far more extreme than just leeches. Research published in 2018 has changed everything, ushering in a new era of ‘living’ medicines.

Leeches. Photo by Stones Pixabay

Bacteria inhabit almost every part of the human body, covering our skin, lining our digestive tracts and even living in our eyes. Significant research efforts in the last decade have uncovered the important effects that the gut microbiome plays in human health, with new reports emerging every month. Recently, a study published in Nature found that changes to the gut microbiome alter immune cell activity in mice with multiple sclerosis. Fluctuations in the gut microbiome also have implications in type 2 diabetes, obesity, certain cancers and Alzheimer’s. If microbial communities play such an important role in disease, it stands to reason that we must look more broadly than just the engineering of our genomes to resolve life-threatening conditions — we must also study our symbiotic relationships with microorganisms and, in the near future, begin to engineer these human:bacterial interfaces.

But the gut microbiome is really complicated. It contains at least 1,000 unique species of bacteria. Though varied, most of these bacteria belong to only 4 phyla: Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. The relative populations of microorganisms in the gut can fluctuate based on a person’s diet, use of antibiotics, genetics and their environment. Researchers even found that microbiome fluctuations could happen after only 3 or 4 days on a new diet.

These rapid fluctuations have caused no shortage of headaches in the scientific community. Recent studies, though employing powerful, high-throughput approaches, often do not show causality between the gut microbiome and a specific disease.

A study published in October 2017 in Scientific Reports, for example, found that Alzheimer’s patients had less microbial diversity, namely decreased Firmicutes and increased Bacteroidetes. The authors stated that gut bacterial communities could potentially be therapeutically targeted to treat Alzheimer’s, but it is still extremely uncertain whether the changes observed in the gut microbiome in these patients are a contributing cause of Alzheimer’s or a side-effect. Unless a clear pathological mechanism for a given disease is fully understood, it seems highly unlikely that engineering bacteria in the gut microbiome will work as a therapy. But that has not stopped scientists from trying to develop diagnostics and therapeutics for diseases.

This year, entrepreneurial scientists developed new approaches, and created start-up companies, to begin targeting the gut microbiome for diagnostic purposes. Pamela Silver’s laboratory at the Wyss Institute for Biologically-Inspired Engineering at Harvard has published perhaps some of the most exciting papers in gut microbiome engineering. One study, led by David Riglar from the Silver lab, demonstrated that engineered bacteria could be used as ‘live diagnostics of inflammation’. To do this, Riglar and colleagues engineered a strain of Escherichia coli to detect tetrathionate, a small chemical with four sulfur atoms, in the guts of mice. Though tetrathionate is just one of many compounds produced during inflammation, the authors were still able to detect inflammation after 6 months of feeding the mice the engineered E. coli. Microorganisms can be engineered to detect a wide range of molecules in the human gut and then produce a detectable output in response, so this approach is likely not limited to just measuring gut inflammation.

This year, Timothy Lu’s laboratory at MIT also released a study in Science, led by Mark Mimee and Phillip Nadeau, that demonstrated how engineered bacteria and electronics could be interfaced in an ingestible system to monitor gastrointestinal conditions in real-time. The device, which was tested in pigs, contains bacteria that produce a small amount of light after detecting a desired signal. This light output then interfaces with nearby electronics, which relays the results to a phone or computer.

These research efforts attest to the idea that engineered bacteria could be useful as powerful diagnostic tools for treating symptoms in the gut, but could similarly-engineered bacteria actually treat disease?

One Cambridge, Massachusetts spin-out company, called SynLogic, is betting that they can. The company has been working to develop living therapeutics to tackle diseases associated with the gut microbiome for over a decade. Using synthetic biology, the company engineers probiotic microorganisms to function as living therapeutics within the gut or gastrointestinal tract.

SynLogic is currently developing therapies for two specific conditions — hyperammonemia, which is associated with cirrhosis (scarring of the liver), and phenylketonuria, or PKU, which is an inherited genetic condition that causes a dangerous accumulation of phenylalanine, an amino acid, in the blood and brain because patients are unable to break down the molecule. Those with PKU typically avoid foods that contain phenylalanine and may take medicines to help break it down.

In the last year, the company started phase I clinical trials targeting these conditions in healthy volunteers. The probiotic medicine for PKU was even granted fast-track status by the US FDA. In August of this year, the company reported in the journal Nature Biotechnology that they had successfully engineered a particular strain of Escherichia coli bacteria, called ‘Nissle’, to treat PKU in both mice and monkeys.

Cell Design Labs, a spin-out company from UC San Francisco, USA, was also sold to Gilead for up to $567 million (£408 million). Cell Design Labs was working on a new type of cancer therapy known as CAR T-cell therapy, a process in which T-cells are removed from a patient, genetically engineered to produce chimeric antigen receptors (CARs) on their surface and then reintroduced into the patient. These engineered T-cells then act as a smart therapeutic, hunting down specific types of cancer cells and targeting them for destruction by the immune system. The US Food & Drug Administration has already approved two different types of these CAR T-cell therapies, which will be used increasingly in the clinic in 2018 for certain types of cancer.

‘Living therapies’ for many conditions are looking exceedingly promising for improved clinical outcomes. Medicines are getting smarter, as scientists program bacteria to behave and process information in new and exciting ways. It is even possible that, in the next 10 years, scientists could develop improved, personalized probiotic therapies for patients. I, for one, am looking forward to the next year of research.