Looking for changes in the space between genes

Robert Månsson is attempting to pair the right gene with the right control region in blood cell DNA. The aim is to understand what causes leukemia.

Robert Månsson

PhD, Medical Science

Wallenberg Academy Fellow 2014

Institution:
Karolinska Institutet

Research field:
How genes are controlled in healthy and diseased blood cells

DNA may be likened to a long chain, along which genes are positioned in sequence. But the genes themselves only take up a couple of percent of the chain. Between them are long stretches of what used to be called “junk DNA”.

We now know these spaces are important regions controlling gene activity. And this is precisely why changes in DNA within these regions can sometimes cause disease.

Yet the idea of DNA as a chain, a strand or a ladder only works when the cell divides. In the normal case the long molecules resemble tangled balls of yarn inside the cell nucleus.

“In a ball of yarn two different parts of the thread come into contact. This is why control regions that switch a gene on or off can be located long distances way from the gene itself,” Robert explains. He is a molecular biologist, and heads a research team at Karolinska Institutet (KI), in Huddinge, south of Stockholm.

Started with normal blood development

Robert’s interest in the mechanisms governing how blood cells develop from stem cells began during his time as a PhD student. At KI he has continued to study the normal process through which blood cells mature and divide. His admission as a Wallenberg Academy Fellow will enable him to also to try to understand the cause of leukemia, i.e. blood cancer.

Robert’s team is studying chronic lymphatic leukemia, which is the commonest form of leukemia among adults. In Sweden some 500 people are diagnosed with the disease every year.

This form of leukemia develops slowly and is often only discovered by chance, for example during a routine medical check-up.

If the patient does not display any symptoms, treatment is usually not initiated until the disease progresses.

“The disease is incurable and the prognosis uncertain. Some people may live 20 years without any problems; others succumb quickly to the disease. There is a need for good prognostics so we know who risks dying quickly and who will survive for years even without treatment,” Robert says.

Looking for changes in control regions

Changes in a gene in a cell may cause the onset of disease, e.g. cancer. Researchers have therefore sought to identify specific genes in which changes are common. One reason for this approach has been the financial aspect; it is expensive to map an entire genome.

“Researchers have often studied genetic changes in many patients. But it might not be the genes; it might be the gene-regulatory element that is the common denominator,” Robert points out.

His research team is focusing on identifying altered control regions and the genes they control.

“It is interesting to meet other researchers in the Wallenberg Academy Fellow leadership program. We have much to learn from each other even though we work in different scientific fields.”

“If I can match the right genes with the right control region, I hope to be able to improve our understanding of how leukemia is caused,” Robert explains.

The team is working with hospitals, which collect blood samples from leukemia patients, to identify changes over time. New technology is helping them to distinguish leukemia cells from other blood cells.

“At present we are working on samples from ten or so patients. If we obtain robust results, we will expand our study to around 30 patients in collaboration with University of Oxford,” Robert adds.

Planned to be an engineer

In high school Robert Månsson wanted to study engineering, but his biology teachers got him to think otherwise.

“The subject was so much fun – so interesting. They really wanted to make us understand things, not just learn things by heart, and the tests they gave us reflected that. It suited me,” Robert recalls.

He enrolled to study biomedicine at Lund University, where he was later also admitted to the graduate school.

“I tried out working in a number of laboratories. I carried out a project in one lab, and continued with another in the lab opposite. I learnt a lot from it,” he recalls.

Robert’s supervisor Mikael Sigvardsson gave him a free rein when he was working on his doctoral thesis.

“He trusted me and gave me great freedom, which allowed me to develop.”

After obtaining his PhD, Robert spent three years as a postdoc at the University of California San Diego, USA. He was tempted to go back to Lund when he started to apply for positions in Sweden. In the end he decided to go to Karolinska Institutet where he has now set up his own research team.

“It would have been quicker to set up a lab in Lund. I knew everyone in the area and knew the technician and other people that I wanted to employ. But I had to learn how to recruit people instead” Robert explains.

Learning to delegate

He learnt the difficult art of delegating after his daughter Louise was born just over a year ago. He has been on parental leave part time for most of the year and at first he tried distance working. In the end he set clear boundaries, only checking his e-mails when he is at work.

“Parental leave can be a little frustrating. A research team is like a small business – everyone is dependent on one another. There are no substitutes. At first I tried to do everything exactly as I had before, but it just got too much in the end. I simply had to give in; after all, it’s a heap of fun being at home with my little daughter!” Robert enthuses.

Text Carin Mannberg-Zackari
Translation Maxwell Arding
Photo Magnus Bergström