Probiotics Worthy of The Name: Biosensors and Living Therapies

We have all heard of probiotic drinks containing just the right number of beneficial bacteria to help us build muscle, lose weight, be smarter and live longer. These claims rest on wobbly, inconclusive evidence (the fact they are classed as foods rather than medicines is quite revealing). It is hard to muster any enthusiasm for these probiotics despite celebrity endorsements galore. However, some probiotics worthy of the name are on the horizon. Synthetic biology is a discipline aiming, amongst other things, to engineer bacteria capable of diagnosing and responding to human disease.

Overheating? Start sweating. Increased blood pressure? Widen blood vessels. Hungry? Eat. Using more oxygen? Breathe faster. Examples of the body’s exquisite systems for controlling the details of our physiology are well known and absolutely crucial for survival.  When these systems malfunction, the consequences are often dire, think of hypothermia or a cytokine storm.

Decades and millions of pounds have been spent unravelling the genetic circuits that underpin the sensors and mechanisms exerting such a tight grip on our physiology. Understanding reached a point where gene circuits could be devised and the technology for inserting genetic changes into living cells soon caught up.  By introducing these so-called synthetic gene circuits into cells, scientists can choose what signal the cell responds to, what the response is – what genes will be turned on – and the response threshold – how much of a signal the cell has to perceive before the response occurs.

What does this mean? It’s now possible to create living sensors and therapies. I thought I’d detail some of the most promising studies I came across in this brilliant review article published this month.

US Army 2016.
(Yep, you read that right).

Biosensors inside a living body would be able to monitor changes in molecules associated with a particular disease as they happen and display these changes for us to see. This would be a radical improvement on current diagnostics…

As I’ve outlined before, there is no shortage of microbial job applicants jostling for positions in our intestines.  One study used genetically modified E. coli which detected tetrathionate, an indicator of gut inflammation. For 6 months, these reliable bacteria turned on β-galactoxidase in response to tetrathionate so when they were taken from faeces and plated on agar plates containing X-gal they stained blue. Tracking the results gave a glimpse into the guts of these mice and if translated to humans, provides a non-invasive way to monitor patients with irritable bowel syndrome (IBS) over extended periods.

It may be that the intestines are the low-hanging fruit in this endeavour with enviable masses of microbes and easily accessible faecal samples. Detecting cancer in the liver would be considerably higher-hanging fruit yet this has already been achieved in mice. The nutrients and refuge from the immune system that tumours provide enables some bacteria strains to grow preferentially in and around tumours. Researchers made use of this fact by genetically engineering E. coli which selectively colonised liver tumours to release a coloured substrate into the urine. The E. coli were able to detect tumours just 1 millimetre in size that are notoriously difficult to detect on conventional scans. They were also able to distinguish between healthy liver tissue, fibrotic (or damaged) liver tissue and liver tumours. Interestingly, some bacteria are being designed to recognise cell-type specific receptors.

Danino et al (2015) Programmable Probiotics for Detection of Cancer in Urine. Science Translational Medicine 7 (289).
Danino et al (2015) Programmable Probiotics for Detection of Cancer in Urine. Science Translational Medicine 7 (289).

Getting this to work in humans is a challenge as it isn’t clear genetically modified E. coli would get a clear run at the tumours in humans due to the vastly different bacterial populations between mice and humans. Plus, many cancer patients have weakened immune systems making them especially vulnerable to infections and dangerous changes in the microbiome. Despite these hurdles, clinical trials are underway.

If we can design bacteria that get to the right places and ‘tell us’ when they get there, why don’t we design them to release a drug when they arrive?

Engineered S. typhimurium were able to selectively colonise liver tumours (similarly to the engineered E.coli) but these bacteria had an additional gene circuit which caused them to burst open and release an antitumor drug (haemolysin) when the number of bacteria present reached a certain threshold. By synchronising the release of haemolysin between the bacteria this living therapy pulses when the bacteria are administered at regular intervals to prevent tumour growth. Using a mice model, the investigators were able to show that using this probiotic therapy alongside chemotherapy was more effective than chemotherapy alone.

Din et al (2016) Synchronized cycles of bacterial lysis for in vivo delivery. Nature 536 (7614) p81-85.

I should add, as an avowed eukaryote and mammal, that it isn’t just bacteria that are making all the progress. Human white blood cells are being genetically engineered to selectively target tumours and kill them by releasing cytotoxic compounds and some designer CAR T-Cell therapies are  already approved for leukaemia. Designer mammalian cells are also being developed to fight drug resistant infections, an ever more pressing need with antimicrobial resistance (AMR) claiming more and more lives worldwide.

I hope I managed to convey some of the progress that synthetic biology is making possible. I also hope that next time you hear some suspicious sounding claims about probiotics, you will roll your eyes and think of the genetically engineered microbes too busy fighting disease to make their way into flavoured milks.

Jack Gordon

Biomedical science undergraduate interested in genetics, neuroscience, cancer research and the pharmaceutical industry.