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Time to burie LADA? Interview with Leif Groop

The dream of finding the “diabetes gene” is dead. However, partly thanks to Leif Groop – professor and multiple award recipient for his ground-breaking research – we will look at type 2 diabetes in a whole new way in the future. He is now retiring, and in an interview with diabetesportalen.se he looks back on his eventful career in research.

The study that since 2006 has been the central hub of the Lund University Diabetes Centre (LUDC) has now been cleared of all personal belongings. Diplomas and awards have been removed from the walls and shelves; binders and cabinets have been emptied. Only the desk looks the same, just as tidy and presentable as always.
Only a few more days until retirement. A long and exceptionally successful career is coming to an end – well maybe not really an end… a quick look at the calendar doesn’t exactly indicate that a normal retirement lies ahead. In August there’s the Botnia meeting in Finland, then the Berzelius Symposium on personalised medicine in Båstad, and the annual European diabetes conference EASD in Munich. And this only takes us through to September – it continues this way some for quite some time.
But first Leif Groop is taking some time off at home in Finland and spending time with his family and grandchildren. And probably doing a little bit of fishing....
Fishing has become a metaphor for the research to which he has devoted his entire career – gene fishing. For over twenty years he has been fishing for genes that cause type 2 diabetes.

Search for the "diabetes gene"

In an interview in an old newspaper article from 1994 when Leif Groop had just arrived in Malmö as a new professor from Finland, he talks about his search for the “diabetes gene”. “Preferably two, but probably even more”, he says.
Today researchers have found more than 80 genes linked to type 2 diabetes, himself taking the lead in the discovery.
“It is a much more complex disease than we thought at the time”, he says.
Technological advances have greatly facilitated the detailed study of the human genome.
Leif Groop describes it as a technological revolution.
“The development has been incredible and totally unpredictable”, he says.
The realisation that there was no “diabetes gene” came gradually, and as the technological developments have continued, his appetite for research has only become stronger.
“A good researcher must constantly reconsider”, he says.

Things really took off when Eric Lander at the Massachusetts Institute of Technology (MIT) in Boston, currently one of President Obama’s advisors, in the mid-90s asked Leif Groop if he wanted to come and do some real fishing – gene fishing. This led to the discovery of the first genes linked to type 2 diabetes.

A few years later, Groop initiated a collaboration with one of Lander’s colleagues, David Altshuler, which resulted in the first mapping of the human genome. The result was named “Breakthrough of the Year” in the journal Science in 2007.
He has been on the high road to success ever since.

In 2006, the Swedish Research Council issued a call for applications for a number of so-called Linnaeus environments where research groups were able to compete for millions in funding for a period of ten years, for the purpose of building strong research environments.
Several research groups at Lund University came together and submitted a joint application, and Leif compares the announcement of the recipients of this highly coveted grant to the announcement of the winner of the Eurovision Song Contest. Each recipient was announced one by one. When only one grant remained, Leif Groop could no longer stay in his seat, but had to leave the room.
Limitless joy erupted in the assembly when it became clear that they had scooped up the final grant. This was the start of what today is known as LUDC.

A strategically important part of the utilisation of the grant was that it would be spent on a common infrastructure, rather than on salaries for individual researchers.

“Skilled researchers should be able to attract funding for themselves”, he says.
Another important initiative that led to the researchers’ huge success was the so-called “action groups” in which researchers came together to solve a key issue which they had identified.
During Leif Groop’s leadership, the number of employees has gone from a few individual research groups to over 300 researchers and TA staff. Today LUDC is the world’s largest centre that focuses on diabetes research, and world-leading in several other areas, not least Leif’s own area – the genetics behind type 2 diabetes.
In May of this year, a major conference was held in Malmö to celebrate LUDC’s 10th anniversary. Many of the world’s leading researchers in the field of diabetes were invited and pointed out the significance of Leif Groop’s research and leadership.

New classification of diabetes

So what has happened over the last 20 years? The dream of being able to use a simple blood test to determine who is at risk for type 2 diabetes is still very much alive. But now there are also serious talks about developing individualised care for diabetes patients based on a new classification of diabetes diseases – something that Leif Groop is behind.
All patients diagnosed with diabetes in Skåne have been invited to participate in the study Andis (All New Diabetics in Skåne) by submitting a blood test and answering questions. To date, the study includes about 14 000 participants. Based on the collected data, a number of different clusters, which divide diabetic diseases in a completely new way, have been identified.
By tracing different conditions to different genes it becomes possible to identify people with an increased risk for various complications at an early stage, before an outbreak.
“Once the symptoms have become visible and a diagnosis is made, tragedy has already occurred. Being able to identify those at risk of developing serious complications in advance enables healthcare providers to deploy their resources to where they are needed at a much earlier stage.”

Today, renal diseases, kidney failure, dialysis and kidney transplants incur the highest costs. Foot ulcers due to circulatory disorders are also a common problem, and amputations are incredibly costly for the healthcare system.
The article written 20 years ago states that 100 million people worldwide suffer from diabetes. By 2030, the number is believed to have increased to a whopping 700 million.
“It is terrible, scary and not something you would expect”, says Groop, adding that:
“We will never be able to afford to treat everyone and there is currently no effective way. The new classification will allow us to focus on those at risk of developing the complications that cost the most, and continue to give others advice on lifestyle changes and regular treatment in the form of insulin and metformin”.

Time to burie LADA...?

Leif Groop’s conviction in that type 2 diabetes is actually a compound of several different diseases has remained throughout his entire career. His thesis from 1982 is entitled “Heterogeneity of Type 2 Diabetes – A Study of Clinical Genetic, Immunological and Metabolic Aspects”.
In the mid-80s, he and his colleague Tiinamaija Tuomi described a new form of diabetes – LADA (Latent Autoimmune Diabetes in Adults). LADA is a mixture of type 1 and type 2 diabetes.  It is an autoimmune disease, just like type 1 diabetes, but milder and only affects the elderly.
In the beginning, however, they faced a lot of resistance from the research community.
“They said ‘It’s just something that Leif has made up…’”.
Today LADA is an established diagnosis and a search on Google returns about 465,000 hits.
The sense that history is in the making can therefore not be denied when he, based on the new classification of diabetes, put LADA behind him.
“It is incredibly important for a researcher to have the ability innovate and reconsider. And since I was the one who helped bring life to LADA, I can also be the one who buries it”, he says.
In order for new knowledge to become established scientifically, the results must first be published and repeated by other researchers, and this has taken time.
“Changing people’s perceptions is difficult, and I’ve learned that the most important results are often those for which gaining support is the most difficult”, he says.

Beginning of the Botnia study in Finland

Another study that has meant a lot for diabetes research is the Botnia study.
As a young physician and researcher in Vasa, Finland, Leif Groop began collecting data from families with diabetes. Today, the register is one of the largest databases of its kind in the world, and has generated large quantities of unique information about the heredity of type 2 diabetes. Together with the American company Regeneron Genetics Center, all participants in the Botnia study will now be exome-sequenced, that it, all of their genes will be identified, which is the first time such a project is carried out in the context of diabetes.
What makes Leif Groop’s research unique is the fact that it is based on families.
“You can’t simply gather a group of people with diabetes and draw conclusions from them, you have to be able to compare them with their parents. This is where the Botnia study becomes an incredibly important resource”, he says, and continues:
“By studying hereditary mutations in families, we can understand what is caused by genetics and what is caused by the environment, i.e. lifestyle”.

More money directly to the research


The agreement with Regeneron Genetics Center is worth several million Swedish crowns, and what makes Leif Groop worry about the future is the funding of major research projects. A certain percentage of all external research grants, so-called overheads, go towards shared costs and are distributed between the vice-chancellor, the faculty and the department to which you belong.
“Applying for major grants and reporting is time-consuming and costs money, and is not paid for by any research project”, says Groop, who argues that the reasonable thing would be to have a portion of the overhead go straight to the project.
“More and more funders are not willing to pay overheads as they want the money to go directly to research. That means we have to find the money elsewhere.
Universities, just like individuals researcher, must be able to adapt to changes in the world”, he argues.
“Why don’t they turn to us and ask themselves what makes us so successful? Everyone is to be treated equally and everything be done in moderation.”
He compares the University to FIMM (Institute for Molecular Medicine Finland) at the University of Helsinki, where he also works.
“There the vice-chancellor and the dean split one part and the rest of the overhead goes back into the project”.
He argues that universities risk ending up in the same situation as record companies did when Spotify was introduced.
“I fear there may be an economic collapse”, he says.

It is time to end the interview. Another meeting is scheduled. Then one more day of work, then retirement. However, in a different part of the building, another room awaits where he will continue as a post retirement professor for a few days a month. More genes are about to be hooked.
“It willl probably be business as usual”, he says with a smile.

Text: Sara Liedholm

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Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00