What if Microbes Were Smarter than we Thought?

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Bacteria’s age-old tool could combat difficult cancers and “incurable” genetic diseases

Soon after sequencing the human genome, scientists were faced with a new challenge — making sense of it all. It’s one thing to identify all of our genes, and quite another to understand what each of them is doing: which ones are essential for survival and which are dispensable. Until recently, we didn’t have a reliable way to “turn off” specific genes in a cell, to see how the cell would fare without them.

But in 2012, scientists caught on to a technique that’s been used by bacteria for millions of years called CRISPR-Cas9. Essentially this is a bacterial death squad. The bacteria store genetic clippings from invading viruses within their own DNA. In subsequent viral attacks, bacteria recognize their assailant and send proteins to slice out the offending viral DNA at the precise locations identified by those clippings.

Researchers are harnessing this system to selectively delete specific genes in a cell and monitor the results. Molecular Genetics Professor Jason Moffat, a scientist at U of T’s Donnelly Centre for Cellular and Biomolecular Research, uses the technique to examine human cancer cell lines — in brain, retinal, ovarian and two types of colorectal cancers.

By turning genes off one by one, he is mapping genetic vulnerabilities — showing which genes could be targeted to wipe out each type of cancer, without also damaging healthy cells. He identified distinct sets of genes that could prove good targets for each of the cancers analyzed. In fact, based on these, he predicted that some of the cancer cells would be susceptible to treatment with metformin, a common diabetes drug, and others to certain antibiotics. He was right in both cases, in the lab. As it turns out, a tool refined by bacteria in their age-old battle against viruses could prove vital in outwitting difficult human cancers.

It could also provide a treatment for “incurable” genetic diseases like muscular dystrophy. Molecular Genetics Professor and Paediatrics Department Chair Ronald Cohn used CRISPR-Cas9 to successfully snip out a DNA duplication in the cells of a patient with muscular dystrophy. The cells were then able to produce a key protein that had been blocked by the genetic disorder. The next step will be finding out how to deliver the gene therapy to the patient’s muscle cells.

Antimicrobial resistance: Humanity’s next great challenge

Alongside climate change and economic upheaval, antimicrobial resistance is a major societal threat. With an alphabetic army of superbugs like MRSA, VRE, CRE and C. difficile pushing past our last defences — we risk returning to an era where minor infections, especially those of children, frequently prove deadly. Did we become complacent with our seemingly all-powerful antibiotics? As we turned to them ever-more frequently, we shot ourselves in the foot with our prized silver bullet.

Microbiologists and molecular genetics researchers are now racing against time to devise new alternatives, based on extensive research of the microbial world. As one example, Molecular Genetics Professor Alan R. Davidson investigates how we might use bacteria-killing viruses — called bacteriophages — to combat resistant bacteria. Like fighting fire with fire, could these infectious agents quell life-threatening infections?

And Biochemistry Professor and Department Chair Justin Nodwell examines the idiosyncrasies of microbes — trying to understand how they can produce anti­bacterial compounds without killing themselves. He sets out to uncover hidden reservoirs of antibiotics and antibiotic targets in nature. By tapping into these secrets, we might find a way to turn the tide on antimicrobial resistance.

If we can’t obliterate killer bacteria, can we neutralize them?

C. difficile is an unnerving reminder of our vulnerability in the face of anti­microbial resistance. This bacterium thrives in the aftermath of an antibiotic assault, and often survives subsequent attacks. But what if we’re taking too blunt an approach for such a tenacious rival? What if we don’t need to obliterate C. difficile at all, but instead could neutralize it by muzzling the toxins it secretes? After all, it’s the toxins that do the damage.

Biochemistry Professor and SickKids Scientist Roman Melnyk investigates the role that small molecules could play in blocking these toxic agents. He studies how small envoys could be employed to disarm harmful pathogens, as an alternative to our reliance on all-too-often ineffective use of brute force. He also studies the toxins’ unique ability to deliver their poison directly into our cells. A shortcoming of many drugs is their inability to get inside our cells to reach their targets. By borrowing techniques from bacterial toxins, Melnyk hopes to bring help to where it’s needed most.

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