Of all the information shared to me by my microbiology lectures in undergrad, one analogy stood out the most: “if alien’s visited the planet and said ‘We come in peace. Take us to your leader.’ I would point to a random space occupied by any number and variety of bacteria” Dr. Bouwer. Of all the taxa on earth, bacteria consist of the greatest population, even occupying some of the most inhabitable spaces on Earth. It’s therefore only wise to try get to know these organisms as best as we can. It is also of know surprise that bacteria both pose some of our greatest global problems and yet have birthed some incredible solutions. Our best-friends among bacteria are a lot more close to home than as far as the eye can see: the bacteria living in your gut. The gut microbiome and the role of probiotics in human immunity, for example, is hotly contested area of research among molecular biologists. Another gift of the bacterial kingdom is the diabetes therapeutic, insulin. Engineering bacteria to mass produce this life-saving protein was partly brought about through studying the genetic machinery of bacteria: how do they produce proteins efficiently and effectively? So if the exciting prospect of “killing 99.9% of germs” seemed smart before, this may not be to our advantage. But not all bacteria are worth saving and if the proverbial 0.1% which survive take lives themselves, we still have a problem.
In South Africa, the leading cause of death is caused by the germ, Mycobacterium tuberculosis. If there is one bacterial disease that convinces us that not one size fits all it is TB. I argue this as TB is curable if both the patient and the bacteria respond to the first-line treatment. It is when the first line regimen doesn’t fit the patient and/or the bacteria they are infected with that the risk of death increases frighteningly at the onset and progression of multiple-drug resistant (MDR) and Extremely drug resistant (XDR) TB. Some die of TB before these questions are even raised because of lack of diagnosis or a test that did not fit. For diagnosis and treatment, TB eradication needs a multiplicity of strategies. It would certainly help to understand the genetic machinery (the genome) that keeps TB bacteria alive, causing disease, resisting treatment and the human immune system. The genome of TB is largely uncharacterised. That is, if TB was a person, researchers are hard at work to locate his eyes, his nose, his circulation system, etc. We are noticing more and more that TB is startlingly different to some our best-known bacteria like Escherichia coli. Where do we start? The genome of TB was sequenced 21 years ago, earmarking just under 4000 genes. Since we don’t know what most of these genes do and therefore what they are called, most of them are just a number between 0001 and 3959.
That is where gene characterisation starts: with just a number thrown at you after some thorough comparitive analyses: basically, borrowing the sequence of a gene for which the function is known in other bacteria and asking “is there something like this in TB?” And the software hands you a number. The more you study this “number” you learn it’s not just a number: it’s a sequence that leads to a protein with a special shape and architecture. That structure gives you clues to function that you can test by measuring the “number”: how much of this gene does the bacterium need? When does it need it the most? – highly insightful questions answered using what’s called gene expression analysis. You can study it via reverse genetics where you “delete” the number and see how much the bacterium can live without it or if it falls apart completely? What does it do without it? Does it heartlessly replace it with another number? Does it only miss having this number when it is stressed out or when it is trying to survive in a host? You can “re-save” the number, and if it all goes back to normal then you know you’ve found something that is not just a number. If you find the “numbers” TB needs to grow, cause disease, avert stress, or helps it resist, you can design drugs against that number. If successful, you can pass these drugs through clinical trials and eventually find a new way of treating TB. What started out as just a number can become a life-saving intervention.
Written by: Ms Andrea Papadopoulos
Postgraduate level: PhD (Medicine) at University of the Witwatersand (Wits) node of the DST/NRF Centre of Excellence for Biomedical Tuberculosis Research