Producing new blood cells – why reading the recipe matters

If you want to be like Nancy and win the Great British Bake Off, or the #sciencecakes competition that ran earlier this week, you need a close eye for detail and an encyclopaedic knowledge of baking tricks and techniques.

Surprisingly, these criteria aren’t a million miles away from what’s needed to crack cancer’s secrets – only instead of knowing how cakes are made, scientists need to understand fully how cells grow.

And by figuring this out, scientists will be able to develop kinder, better treatments that will save more lives in the future.

One way we can learn more about the disease is by understanding how different processes work in healthy cells. When we know how things should be working, we can spot when they go wrong – as they do in cancer.

A new study from scientists in Cambridge, led by Augusto Rendon and published in the journal Science, does just this. They found that small changes in how the genetic ‘recipe’ is read when new blood cells are made are key to deciding which type of blood cell is produced and making sure only healthy, functioning cells are made.

They also went a step further, identifying how mistakes in this process can trigger the development of blood cancers (leukaemias), pointing to new ideas for ways to treat these diseases.

Where does it all stem from?

Mistakes made when our bodies produce white blood cells can lead to cancers of the blood, such as chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML).

To better understand how such mistakes cause our bodies to make abnormal, cancerous cells, Dr. Rendon and his team started by looking at how healthy cells are made.

Specifically, they looked at the changes that happen in specialised cells called blood stem cells and progenitor cells as they transform into more mature types of blood cells, including white blood cells, red blood cells and platelets. Here’s a handy diagram showing the process:

Diagram showing how blood cells are made

On your marks…..Get set…..MAKE!

While it may seem unlikely, making different types of blood cells is a bit like the technical challenge on The Great British Bake Off.

Each week on the show, the bakers are given the same batch of ingredients and the same recipe. But each contestant reads the recipe differently and makes their own modifications and adjustments. Some prove their dough for longer; others bake at a higher temperature.

In our bodies, DNA is the ‘master cookbook’ that holds all the information we need to make us who we are. This cookbook contains lots of different recipes that are copied – or transcribed – into RNA, which make proteins inside our cells. In the case of blood cell production, our bodies follow specific RNA recipes that ensure we make all the different types of blood cells we need.

And, as on Bake Off where tweaks in the recipe makes the difference between winning and leaving the competition, small changes in these RNA recipes, or how they’re read, can have a big impact in determining which type of cell is made and if it works properly.

The important thing is to follow the recipe to the letter. Changing it even slightly could lead to bad or faulty cells which, in turn, could lead to cancer.

Reading the recipe

Structure of RNA

Over the last few years scientists have learned that while it’s vital to study how mistakes in DNA cause cancer, it’s also very important to look at how RNA errors can cause the disease too. And they’ve developed a new technology called RNA-Seq to do this.

RNA-Seq helps researchers identify very small changes in the RNA code between different types of cell – for example between healthy cells and cancer cells. It also allows them to find changes in the RNA recipe that can cause cells to become cancerous.

In this study researchers studied the RNA code in healthy blood stem cells and progenitor cells.

Using RNA-Seq, the researchers examined the RNA code of eight types of blood stem and progenitor cells. They found that each cell type makes its own small modifications and adjustments to the RNA recipe – adding their own particular ‘flavours’ to the basic mix.

It’s like a baker producing a selection of chocolate, lemon or vanilla cupcakes, but instead these biological flavours ensure the full range of different types of blood cell gets made.

Mixing it up

Of course, cells don’t use cocoa powder, lemon zest or vanilla essence to modify the recipe – instead, the researchers discovered that a process called alternative splicing allows blood cells to make these changes.

The alternative splicing process allows a single RNA recipe to be read and copied in lots of different ways. It does this by cutting out and swapping different bits of the recipe – some bits are left in, others are taken out. It’s as if Bake Off contestants were to leave out ingredients from the original recipe, include some extra ones, or use a different ingredient altogether.

When baking, swapping in the wrong ingredient could lead to a kitchen disaster, such as the dreaded soggy bottom, or cabbage-flavoured cupcakes. Scientists are interested in alternative splicing for the same reason – they know that if the wrong bits get swapped into the RNA recipe, they can cause cancer. For example, errors in alternative splicing during white blood cell production can lead to the development of blood cancers such as CLL.

In this study, researchers found that each blood stem and progenitor cell has its own unique set of RNA recipes – called transcripts – which ensure the correct type of blood cell is made. They are also important in making sure viable, healthy cells are produced.

So far, researchers have only focused on healthy cells. But future work comparing the RNA recipes that make different types of healthy blood cells with those that make leukaemia cells will reveal what goes wrong when the disease develops – and could lead to more effective, targeted treatments.

The end result

Making blood cells – Cancer Research UK #sciencecakes competition -Belfast entry

When trying to understand what triggers cancer, scientists and doctors generally look for faults in DNA and genes. As this study shows, it’s clear that identifying mistakes in RNA are just as important.

Dr. Francesca Pellicano, who investigates the role of stem cells in chronic myeloid leukaemia at the Paul O’ Gorman Leukaemia Research Centre, Glasgow said this work has “opened the door to the investigation of RNA transcripts rather than genes, highlighting the importance of alternative splicing and the machinery underlying it.”

Professor Tessa Holyoake, who also works at the Centre, said: “This research will offer insights into normal blood cell development and help us understand how healthy cells go wrong in cancer”.

Watching the Bake Off contestants grapple with the challenge of producing perfect pastry might make for interesting water-cooler chat, but getting to grips with the inner workings of cells is a much more important technical challenge – and the end result could mean life-saving new cancer treatments.

The findings of this study show why it’s so important to do this kind of fundamental research into the biology of how cells work. By unravelling healthy blood cell production we can improve our understanding of how blood cancers develop – and ultimately find new ways to tackle these diseases and beat cancer sooner.

Áine

Reference

• Chen, L., et al. (2014). Transcriptional diversity during lineage commitment of human blood progenitors Science, 345 (6204), 1251033-1251033 DOI: 10.1126/science.1251033

Images

• Dough image by Tiia Monto (Own work) licensed under a CC-BY-SA-3.0 license, via Wikimedia Commons
• Blood cell image by Cancer Research UK licensed under a CC-BY-SA-4.0 license, via Wikimedia Commons
• RNA image by Corentin Le Reun (Own work) [Public domain], via Wikimedia Commons
• Making blood cells cake image courtesy of Margaret Carr, Cancer Research UK