Bacteria armed to seek and destroy disease

Katrina Megget

International study could open up a new approach to disease management using engineered bacteria.

The promise of targeted cellular medicine using bacteria as a one-stop shop to not only detect and diagnose, but also treat disease, is a step closer after a landmark study looking at colorectal cancer.

This proof-of-concept study expands on the goals of cellular medicine and bacteria-based therapies (Science, doi: 10.1126/science.adf3974).

A form of cellular medicine in the same group as CAR-T cell therapies, bacteria-based therapies are a new and developing field that could use bacteria to deliver anti-cancer therapies or treat infectious diseases.

In this study, researchers in the US and Australia engineered the bacteria Acinetobacter baylyi and demonstrated, in mice, the feasibility of also using bacteria as a biosensor in the gut to detect colorectal cancer. Should both detection and therapy be combined in one entity, it could open up a whole new approach to disease management.

The premise behind the research is based on two facts – that tumours are known to shed their DNA into the environments surrounding them; and that many bacteria are known to take up DNA from their environment (a skill called natural competence) and integrate this newly acquired DNA into their genome.

The technique of moving genetic material between bacteria that doesn’t involve parent-to-offspring inheritance is known as horizontal gene transfer and has been well studied. The researchers aimed to apply this concept to move genetic material from a mammalian tumour into bacteria.

To do this, the team used CRISPR technology to engineer Acinetobacter baylyi as a biosensor to identify DNA from a mutated KRAS gene, which is present in many cancers including colorectal cancer. The modified genome sequences in the bacteria meant tumour DNA was more likely to integrate into the bacterial genome. This integration activates an antibiotic resistance gene, which is used as a signal that cancer has been detected when the bacteria with integrated tumour DNA are successfully grown on antibiotic-impregnated culture plates.

The researchers have called the technology CATCH (cellular assay for targeted, CRISPR-discriminated horizontal gene transfer), and believe it holds great promise for the detection and treatment of disease.

The team believed that while plausible, this completely new concept was ‘far-fetched’, says Dan Worthley, a gastroenterologist and cancer scientist at Australia’s Colonoscopy Clinic. Yet they found that when the biosensor was delivered into live mice, it was able to discriminate between the mice with colorectal tumours and those without. ‘This was a moment of great surprise, great relief, and, to be honest, not a little delight,’ he says.

The researchers have called the technology CATCH (cellular assay for targeted, CRISPR-discriminated horizontal gene transfer), and believe it holds great promise for the detection and treatment of disease.

Not only can the technology detect any arbitrary DNA sequence, Worthley says the team has essentially engineered the laboratory to exist within the bacterial cell, meaning the traditional complexity of sample collection, processing and analysis for disease diagnosis is vastly reduced. This would be a boon for resource-poor settings, such as developing countries.

But the real triumph of this cellular detection approach is that the bacteria can be engineered to respond directly at the time and place where the disease is detected. ‘The bacteria [could be programmed to] both seek and destroy disease at its very origin. A remote laboratory cannot and can never achieve such a thing,’ Worthley says.

The potential for targeted genotype-specific therapies to be designed and engineered into the disease-detecting bacteria to diagnose and treat in one move would be great and could have fewer off-target effects by being more targeted, says Catherine Pickworth, Research Impact Manager at Cancer Research UK.

‘Finding new ways to detect and treat cancer early, when it’s less difficult to treat, is vital to improving survival,’ she says. But she also cautions that the research is a long way off showing a two-in-one approach using bacteria is viable, and notes that ‘even if shown to be effective, the complex and evolving nature of cancer means it’s unlikely to be a holy grail solution for all cases’.

Next steps in development include increasing sensitivity, formulating for oral delivery, exploring alternate species as biosensors, exploring therapeutic responses and studying the approach’s application as a rapid diagnostic for infectious diseases.