This is written for all the non-scientists (i.e. most of the people I know!), and anyone who’s curious about what I’m actually doing over in NZ!

As you know, Tuberculosis (TB, or Consumption if you’re from Jane Austen’s period) is a horrible lung disease whose most famous symptom is coughing up blood. About a third of the worlds population is thought to have TB, but luckily for us only around 10% actually show any symptoms. The rest just have the bacteria living inside their lungs, waiting for a chance to strike (say if someone’s immune system becomes weak etc.), but more often than not it never does and will just sit there doing nothing until we die of old age.

When TB is in the dormant phase, a person is not contagious. It’s like the bacteria is in suspended animation inside our lungs, and is unable to attack the body or reproduce or do … well, anything. Once it wakes up, and a person has active TB they become highly infectious and pass it on through the air when they speak or cough or sneeze. They could pass it on to twenty or thirty people and whilst only 10% of those people will develop active TB, that still means that there will be 2 or 3 people coughing and sneezing and passing on more germs.

TB can be treated with a course of several different antibiotics (if you’re lucky enough to have access to them), but for those in the third world that do not, active TB will kill approximately 50 % of the people who have it. It’s the number one killer from infectious diseases world wide (more so than meningitis or HIV/AIDS for example).

Unfortunately for us, antibiotics are unlikely to be enough anymore. Because a lot of people have not been finishing their antibiotic courses (a pet hate of mine as this laziness is literally killing millions), a lot of TB varieties (or strains) have evolved that are resistant to certain antibiotics. In fact, in 2016 the World Health Organisation (WHO) had a consultation due to the emergence of a strain of TB that is totally drug-resistant. Yup, TB has now evolved to a point that there are strains of it that no drugs that we currently have can treat. Antibiotics are useless against it and this strain is only becoming more common.

And that’s where I come in! The idea behind my research is that the best time to treat and kill TB is before it comes active. If we can kill it whilst it’s dormant then the victim is not infectious and will not pass it on. We could cure millions of people before they ever displayed a symptom and (who knows?) maybe one day TB will be a disease of the past like Smallpox (a girl can dream, right?)!

But Annabelle, if our antibiotics are ineffective or even useless against a lot of TB, how can we possibly kill it? Well, that’s what’s so exciting and cool about this research (and a lot of the reason why I wanted to come here and study it) – this medicine follows a completely different path to antibiotics! When the TB bacteria are “asleep” and in their dormant state, they still have enzymes that perform processes to keep them alive (much like our body continues to breathe, even whilst we’re unconscious). So if we can find one of these enzymes and stop it from working, the bacteria will die before it ever wakes up.

Annoyingly, we share a lot of important enzymes with bacteria, so if we inhibit them to kill the bacteria we can also make ourselves very sick. The basics of making medicine that can kill bacteria or viruses is to try to make a molecule that will kill them without harming us which can be very difficult if the enzyme we are targeting exists in both of our systems! So here comes the really cool part! To survive in the dormant phase, TB rely on a pair of enzymes called ICL1 and ICL2 – if they stop working the bacteria die whilst still asleep and human beings do not have the ICL enzymes in their bodies. That means that we don’t have to worry about the drug switching off our own enzymes and hurting us, it can only target the bacteria! Awesome, right? 😀

So, I don’t know how much you know about designing an inhibitor (a drug that blocks (or inhibits) the action of an enzyme) so I’ll give you a quick explanation. Enzymes are like the machines in our bodies that make sure reactions happen and stuff gets done. There are literally millions of the things, each controlling a different process. For example, when our DNA is copied, there is an enzyme for unwinding the DNA, another for cutting it open, another enzyme that zooms along the length reading what it says etc.

ICL1 & 2 are enzymes that help the bacteria digest nutrients, so if we can stop them from working then the bacteria starve.

Enzymes always have a “pocket” and like locks, they require a “key” to open. So you know that thing where you try and open a locked door and you’re trying all the keys in the house and finally you force one in even though it isn’t really the right key? And then you try and turn it but the lock won’t turn and the door won’t open so then you try and take the key out but you realise you’ve jammed it in there and the door’s never opening again? That’s exactly what we want to do! We want to design a drug that is very similar to the correct key, similar enough to fit into the lock but different enough that it will not open the door. That way we have stopped the door from opening (i.e., stopped the enzyme from working) and if we design a specific key that will only fit that one lock, we don’t have to worry about it going into a different doors lock and breaking the wrong door.

Half the time when making medicines, people don’t actually know what the locks look like to begin with so rather than designing a key they just test a million other keys that they know exist and see if some of them sort-of fit the lock. Then, once they’ve found one that by pure coincidence fits, they go on to try improve it and eventually work out what sort of key they need.

I’m pretty lucky because for one of the ICL enzymes, the shape of the lock has already been discovered so now I need to try and design a key to fit. I like to think of this bit like lego – i.e. I know roughly what sort of structure I want to make and I add different building blocks in different positions to see if I can make it. Each time I make a key that doesn’t fit, it gets me a tiny bit closer as I now know at least one combination of building blocks that will not fit, and therefore I know a little bit more about the shape of the lock.

Unfortunately nothing is so simple and like everything in your body, enzymes are constantly moving and changing their position and arrangement. So the lock is often moving and shifting position whilst you’re trying to work out what shape it is – much like trying to solve a rubix cube that is moving on it’s own at the same time! This is partly why the chances of success when designing a medicine are so small. So now you know what I’ll be doing and if you ever hear me complaining about how nothing is working you’ll see how confusing it can sometimes be! But it’s awesome and amazing and fun at the same time and I would never change it for the world!

I hope that explains a little bit of what I’m doing, I’m not very good at explaining things without using a lot of scientific jargon so if that doesn’t make sense then feel free to ping me with any questions! As you know,  I love chemistry and want everyone else to love it too so it’d never be a bother! 😀