Question: How do you fix broken cells?

David Foley answered on 18 Nov 2014:

Hi Molly.

First, we need to understand what is going wrong in our bodies that results in us getting ill. If you imagine the London Underground – it is a complex network of trains, signals and stations – and most of the time it works well. But when it breaks, there is chaos until the cause is understood and repaired.

Each cell in your body is similar – only the network is much more complicated and, (since we didn’t build it ourselves) when it goes wrong we often don’t know why. Biologists spend years trying to tease apart and understand the network, so they can trace the fault that is causing the disease. This “fault” is often an protein (an enzyme or receptor) or sometimes a piece of DNA or RNA that has gone wrong. We call this a “target” – and if we “hit” our “target” we cure the disease.

It is the job of chemists like me to find a molecule that hits our target. We do this by screening vast libraries of up to a million known compounds that we keep in stock to identify starting points. We can also be inspired by natural products (like morphine for pain) or natural ligands (Ventolin inhalers contain a drug based on adrenaline and works on adrenaline receptors in the lung)

We then refine these molecules, adding and subtracting functional groups (such as amines, acids, esters, alcohols) to improve our compound. It’s a bit like playing with Lego (only we don’t have picture to go on). Of course, there are a lot of parameters that need to be refined to make a drug. For example, there is no point being able to hit your target really well if your compound won’t dissolve in water or is toxic. We therefore work with biologists and pharmacologists to test our compounds for many parameters. Once we’ve found a compound with the right balance of properties we move forward to animal testing.

Animal testing is, of course, controversial. Whilst we do our very best to minimise the use of animals, the sad reality is that we can only prove our molecules might work and are reasonably safe for people by performing animal tests. Indeed, there are some diseases – for example HIV, Alzheimer’s and most mental illness – that can never be properly reproduced “in a test tube”. Tragedies like thalidomide would not have happened if today’s standard of animal testing had been performed, and chemists remember this painful lesson very well. We were and are responsible for every “thalidomide baby” and we cannot allow that to happen again. Animal testing is one of the most tightly regulated aspects of our work, second only to human trails themselves in terms of the amount of oversight and documentation we have to provide to show they are critical for project progression.

If our molecule is safe and works in animals, we then move to human testing. This takes up to 10 years to complete and is by far the most expensive part of the process. It is also the point where we often fail! In fact, drug discovery has a 95% failure rate and most medicinal chemists will go their entire careers without every getting a new drug into patients on a global scale. The reasons for failure are the subject of much debate amongst my industry – it comes back to our incomplete understanding of how our bodies really work.