Finding differences between identical cells

Although their genes may be identical, bacteria or cancer cells, for example, may react differently to a given drug. Vicent Pelechano is studying the underlying mechanisms involved. This knowledge will open the way for developing therapies that are effective against even the most vigorous cells.

Vicent Pelechano

PhD Molecular Biology

Wallenberg Academy Fellow 2016

Institution:
Karolinska Institutet

Research field:
Gene expression and genomics

“Imagine trying to kill cells with a drug – maybe cancer cells or bacteria. Most of them die, but a small proportion may react a little differently and survive – even though their genes are identical. We want to understand how this happens,” Pelechano explains.

For many years now, researchers have been studying how genes control cell characteristics. But genetic information alone does not explain individual cell behavior. Cells that are genetically identical may react differently to the same stimulus.

For instance, during a bacterial infection some bacteria may develop resistance to the antibiotic being used, even though a gene analysis has shown that they should be susceptible to the drug. The ability of certain cancer cells to elude treatment that, genetically speaking, should kill them may be explained by similar processes.

Pelechano and his research team at SciLifeLab in Stockholm are researching into the molecular mechanisms underlying this phenomenon.

“We’re trying to find the molecular details that help genetically identical cells to adapt their response to their surroundings, causing them to behave differently.”

Unexpected variation

Cells control their behavior via gene expression, i.e. the process whereby the genes’ DNA sequence is transcribed to the messenger molecule, RNA, which is then decoded to form proteins. Pelechano’s team is studying several levels in this process, including the step when DNA is copied to RNA. During his time as a postdoc at EMBL (the European Molecular Biology Laboratory) in Heidelberg, Germany, he discovered that the process was not as previously had been thought.

It was then known that a degree of variation could occur when DNA is transcribed to RNA – the RNA molecules formed are sometimes missing a tiny fragment at the beginning, sometimes at the end. But Pelechano demonstrated that the variation was much greater than expected. His findings were published in the highly respected scientific journal Nature.

Some of the RNA variants were also revealed to be more long-lived than others, a factor that impacted cell behavior.

“It was then that we realized that even in an organism as simple as yeast, the DNA decoding process gives rise to a wide diversity of RNA, which may change the way the cell may react. Our research has now shifted to mammalian cells and cancer cells so we can learn more about this.”

Fond of developing techniques

Having discovered how much RNA could vary, Pelechano had to develop a technique for measuring RNA molecules. And development of new techniques is also central to the work of his current research team.

“To gain a better understanding, we must look beyond what is currently possible, which will require new techniques. We will be able to use them to answer new questions, as well as to open new research paths by sharing our methods with others. I like developing techniques – nearly everyone in the lab has a project where we are doing so.”

Pelechano has an abiding interest in understanding how things work. Growing up in Valencia, Spain, he removed parts from his grandfather’s tractor to see what would happen. He enjoyed science, and studied molecular biology at university.

“I didn’t really know what it was, but it seemed interesting.”

It was a good choice. Having received his PhD in Valencia, he worked for seven years at EMBL in Heidelberg. In 2016 he moved to Karolinska Institutet in Stockholm to set up his own research team, currently comprising eight people.

“The grant gives me the freedom to make big plans – to think outside the box and do the best research I can. I have the confidence to commit to projects offering great potential gains, but also involving substantial risks. I am new to Sweden, so the project funding also gives me access to an important network of capable researchers.”

Getting the cell to forget

One project the team is pursuing is to study the ability of cells to forget stress to which they have previously been subjected. This is of interest because it has been found that if a cell needs to decode a certain gene to resist the effects of a given drug, the second time the cell is exposed to the drug it somehow remembers this, and is able to defend itself more quickly.

In discovering an unexpected pattern in the way RNA is broken down in the cell, Pelechano has seen indications that this memory function is controlled by RNA molecules.

“That’s our hypothesis, but we don’t fully understand it yet. It’s an exciting line of research because no one has done it before. If we find factors affecting this process, that knowledge could be used between the first and the second round of treatment to make the cells more susceptible – to make them forget. But we have a long way to go.”

Another of the projects the team is working on involves studying differences in the way the long DNA strand is packed in the cells, and how this impacts gene expression.

Stockholm – a hotbed of research

Pelechano stands in front of one of SciLifeLab’s powerful DNA sequencing machines, reflecting that his field has seen dramatic technical innovations over the past few years.

The ability to analyze millions of genetic building blocks in parallel enables the team to pose research questions that would have been unthinkable a few years ago. But computations are needed to understand the information, and Pelechano describes his team as a lab for biological experiments and computation. The availability of expertise in these two areas was one of the things that attracted him to Stockholm.

“It’s a key factor that many of us here work in the field of genomics. The necessary critical mass can be achieved,” he explains.

Text Sara Nilsson
Translation Maxwell Arding
Photo Magnus Bergström