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Cancer, Gene regulation, Students, The immune system

Pinch by pinch

What does your genome have in common with a Michelin-starred chef? Find out in this article by Yale Michaels, a DPhil student in Tudor Fulga’s lab, written for the MRC Max Perutz Science Writing Award

You have always dreamt of becoming chef de cuisine at a Michelin-starred restaurant. You started sweeping floors and peeling potatoes and have worked your way up to apprentice. One day your world-renowned mentor is called away for an emergency mid-dinner-service. Amidst his hasty departure he turns to you and exclaims, “You must finish the soup, there is no time to waste.”

The moment to show off your skills has finally arrived. You know this recipe by heart and confidently add spices and garnish. You decide the soup tastes bland. It is in desperate need of salt, but how much should you add? Remembering the philosophical wisdom enshrined between the covers of Goldilocks and the Three Bears, you add the salt a pinch at a time until it tastes just right.

Genes are the ingredients for making life. Each gene allows cells to execute a specific function. Humans have about 20,000 of them listed in a recipe book called the genome. Our cells take great care to follow the instructions in the genome closely, ensuring that each gene is used at just the right quantity, at the right time and place. When this precision is lost, cells stop working properly. If an important ingredient is omitted, like one of several genes that tell cells when to stop growing and dividing, deadly diseases such as cancer can ensue. Genetic mistakes were responsible for the fourteen million new cancer cases diagnosed last year.

For decades, scientists and clinicians have worked hard to understand how we can manipulate genes to defeat cancer. Their approach has been one of extremes, not one of nuance. By either completely removing a gene from a group of affected cells, or alternatively, ramping up gene activity, I believe that scientists have often failed to find that exact level of salt needed to perfect the biological soup. In my PhD research I aim to develop a more subtle approach to gene manipulation, one that would allow us to control a gene until it is just right.

In complex organisms, each gene comes with instructions explaining when, where and how much that gene should be used. For months, I tried to re-write these genetic instructions, aiming to finely tune gene activity. Instead of an all or nothing comparison, I envisioned a tool that would allow scientists to carefully increase or decrease gene activity pinch-by-pinch.

To test this new tool, I added an artificial gene to cells to make them glow fluorescent green. Although scientists have been able to make cells ‘glow in the dark’ in the past, I wanted to precisely control the level of illumination. Into each batch of cells, I added the green gene along with different bits of genetic instruction. After meticulous trial and error and dozens of unsuccessful attempts, I was elated to see that, finally, each successive batch of cells glowed ever so slightly brighter than the last! We now had a tool to allow us to fine tune the amount of almost any of our cell’s 20,000 genes, many of which have important implications for treating cancer.

Often treatments that kill cancer cells have dangerous side effects that limit their clinical usefulness. Immunotherapies are a group of promising new cancer drugs, but even these cutting-edge medicines have side effects that seriously harm patients. But what if we could fine tune immunotherapy using my new pinch by pinch technique?

The immune system walks a fine line. It must simultaneously fight off foreign invaders such as bacteria and viruses, while carefully avoiding collateral damage to healthy cells. The immune system avoids healthy cells by using genes that behave like a brake pedal, slowing the immune system when it is not needed. But cancer cells perform a clever trick –they step on the immune cells’ brake pedal, allowing the cancer to escape detection. (Picture Obi-Wan waving his hand, proclaiming, “These aren’t the cells you’re looking for”).

Immunotherapy drugs treat cancer by cutting the brakes. They invigorate the immune system to fight tumours, but they activate immunity to such a high degree that healthy tissues like the skin and thyroid get caught in the crossfire. This poses a major risk to patients’ health and comfort.

We’re trying to finely control the immune brake pedal in the same manner that I was able to control the green fluorescent gene –pinch by pinch. We aim to identify a perfect balance between cancer killing and collateral damage, ultimately making immunotherapy safer. By tuning the brake genes on immune cells we could allow them to target cancer while simultaneously preventing them from assaulting patients’ organs, reducing pain and improving their quality of life. With 20, 000 genetic ingredients to work with, immunotherapy is but one of many opportunities to get our cells working just right.

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