When I use the word “virus,” you may immediately think of COVID-19. The SARS-CoV-2 virus caused the largest pandemic in 100 years, but did you know there are nearly 10 quintillion (an impressive number of at least 30 zeros!) other viruses? Fortunately, most viruses do not infect humans, but bacteria do. We call this group of viruses (bacteria) phages. Phages destroy about half of the bacteria on Earth every day, ensuring natural balance. Through millions of years of co-evolution, the genetic material of these phages has fully adapted to its preferred bacterial host.
In synthetic microbiology, scientists use this genetic material to reprogram bacteria. Why? Well, bacteria produce chemicals to be able to survive in a certain environment. Man has found a way to deal with these chemicals. Consider, for example, antibiotics or some anti-cancer agents, all of which are beneficial molecules produced by bacteria. In this regard we can think of bacteria as mini factories. Unfortunately, these “factories” are not that efficient. They produce only a small amount of materials of interest to humans. This is why scientists are looking for ways to reprogram bacteria and increase the production of these chemicals for medical or industrial purposes.
Grandma’s recipe for producing chemicals
The way bacteria make these chemicals can be compared to following a recipe. The bacteria’s DNA serves as a guide for making the desired final product. This guide describes the ingredients we need to produce our final product as well as the quantities required. You can compare it a little to grandma’s recipe book. Moreover, bacteria have an additional advantage: they make all the ingredients themselves. Sustainable, right?!
As in a recipe, the mutual interaction between genetic components determines the characteristics of the final product. For example, if you adjust the quantities or add or remove certain ingredients, you will get a different chemical. By carefully balancing the amounts of each ingredient, we try to find the perfect combination for the best yield of our final product.
Unfortunately, it’s not as simple as it seems. After all, bacteria are not amateur chefs, but real professional chefs. Instead of preparing one dish, the bacteria try to prepare an entire seven-course meal. This means that we must take into account that the ingredients are sometimes used in different dishes. Furthermore, a higher quantity of each ingredient does not always guarantee a higher yield of the desired final product. For example, sometimes bacteria decide they would rather use this extra ingredient in another dish.
How can synthetic microbiologists decide for themselves which product to produce mainly? This is not a simple question because the bacteria simply do not follow our recipe and the prescribed amount of ingredients. That’s where phages come in again: these viruses will dominate the bacterial kitchen like a strict Gordon Ramsay. After all, phages are experts at changing the entire metabolism of bacteria. Gordon Ramsay may be the UK’s premier chef, but for our own Flemish food, most of us might prefer Jeroen Mius. This also applies to bacteria. They will better accept the instructions of phages occurring in their environment.
From grandma’s recipe to a bacteria factory
Today, scientists mainly use DNA from the T7 model phage to improve chemical production in… Escherichia coli bacteria. This is one of the best studied bacteria to date, and is often used in these applications. Scientists have shown this Escherichia coli Not always the best choice for chemical production. Hence, they tried to use the DNA of phage T7 in other bacteria. This had the opposite effect. Bacterial factories suddenly began producing less of the required substance. Some even stopped altogether. That’s why we’re looking for phages that are a good match for these bacterial factories.
We have currently identified more than 100 novel phage DNA switches and can integrate these phage components into bacterial genetic circuits to improve the production of our components. Today, DNA editing is mostly done by CRISPR-Cas editing. It is a technique developed by Jennifer Doudna and Emmanuelle Charpentier, winners of the 2020 Nobel Prize in Chemistry. This technique is used to introduce new DNA, remove pieces of DNA, or replace them with other DNA.
As for bacteria, we can use this technique to replace pieces of bacterial DNA with phage DNA. We then evaluate whether this reprogramming resulted in an increase in production of the desired final product. If not, we use the results for further adjustments. If it works, we now have a new, improved factory to produce the chemical we’re interested in, thanks to our phages.
