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Early detection and prevention of liver failure

Driven by obesity and type 2 diabetes, liver disease may soon be the most common disorder in the world. It may become more prevalent than cancer, according to Philipp Kaldis, a recently recruitedprofessor at the Lund University Diabetes Centre who studies metabolism in the liver.
"The ultimate goal of my research is to detect liver damage early and to prevent catastrophic liver failure.”

Philipp Kaldis on a bicycle during vacation in Greece.
Professor Philipp Kaldis loves to do sports, as here during a vacation in Greece. Photo: Privat

About 30 per cent of the world’s population suffers from fatty liver disease.
The disease develops when excessive fat builds up in liver cells.
It consists of two different kinds; fatty liver disease (FLD) due to alcoholic consumption and non-alcoholic fatty liver (NAFLD). Some of the latter patients progress to NASH (inflammation in the liver) and later to cirrhosis when the liver becomes non-functional. And then, eventually, some develop liver cancer.
The reason for this development varies according to the location:
“In the US, it tallies with diet. In Asia, there is a clear correlation with hepatitis viruses. And in Europe, there is an association with alcohol”, says Philipp Kaldis.

The body consists of numerous cell types. Many of them, but not all, continue to grow and proliferate throughout life. The liver cells are among those which do, and if the liver is injured, or if there is a need to remove a part of the liver due to damage or a tumour, the liver actually grows back. However, this does not happen when liver disease becomes chronic, as in the case of NASH, cirrhosis or cancer.. In this case, transplantation might be the only solution. Transplantation entails a lot of risks and difficulties, lifelong medications, etc. But what if there was a way to grow new liver cells from skin cells or stem cells?

Cell growth and proliferation

Philipp Kaldis is an expert on metabolism and cell cycle regulation. What makes the cells grow and proliferate? Central to his research is a family of so-called kinases, more specifically cyclin-dependent kinases (CDKs), which regulate this process.
Before starting as a research team leader at the National Cancer Institute (NCI) in the USA in 2000, he had studied biochemistry at ETH Zürich and done a postdoc at Yale University and knew how to independently analyse proteins and perform experiments in animals. Nevertheless, he was still dependent on collaborations with others.
“I couldn’t do it without the people in the lab. It was, and always will be, teamwork”, he says.
His breakthrough came after publishing new results from experiments in animals that nobody had done before.
“Until then everybody in the field knew that CDK kinases were very important for cell cycle regulation, and no one thought it would work without them. Everyone thought that if one kinase was knocked out, the animal would die.”
But he showed that this was not the case. The mouse in which CDK2 was knocked out survived and Philipp Kaldis discovered that even if you knocked out one kinase, another one would compensate. These findings gave his research a new direction. He established himself as an independent researcher and was able to compete with the very best scientists in the field.

"A tremendous oppurtunity"

The position at NCI, a government-run institute, was perfect  initially. Philipp Kaldis did not have to worry about funding, as all the money came exclusively from the US government.
“I had a tenured (permanent) position, which in reality meant I could stay there my entire life. It was a tremendous opportunity and seemed to be very exciting”, he says.
However, after only one year and some organisational changes, he was facing a new situation.
Philipp Kaldis needed to adapt and the future did not seem to be as bright as before. Luckily, he got a proposal from the former head of the department. Did he want to move to Singapore?
What made him decide to move was the feeling that Singapore was really committed to improving science.
“There were almost no limits to resources. You could do things I could never do at NCI. On the other hand, it was more difficult to hire good people.”

"Coming to Sweden was like coming home"

He stayed in Singapore for almost 12 years and it was here that he started to apply his knowledge to the liver.
“When I look back, I had 12 productive years in Singapore”, he says.
However, he was missing a vibrant atmosphere of critical thinking. And when a new opportunity  arose at the Lund University Diabetes Centre in the south of Sweden, he decided to move again in 2019.
Most people are not very positive about the weather in Sweden – it is either too cold, too windy or too rainy. But for Professor Kaldis, the Swedish weather was a positive factor that made him  decide to move here.
“Singapore was too hot, everything you did made you sweat. For me, coming to Sweden was like coming home”, he says.

"We need to investigate the whole body"

At the Lund University Diabetes Centre, he plans to take his research further and work on human liver cells from the Human Tissue Lab, a facility that gives researchers access to different tissues from deceased human beings who donated their tissues to research. This includes beta cells, which can only be studied when sourced from donors. There are also muscle cells, fat cells and, to a certain extent, liver cells.
Philipp Kaldis is now going to expand the work on liver cells within the Human Tissue Lab.
“Most researchers here are interested in glucose metabolism, but glucose is not only regulated by the beta cells. Other organs such as muscles, fat and the liver also affect glucose metabolism. That is why we need to have a system biology approach – we need to investigate the whole body.”

It changed his view on research

Philipp Kaldis was born and raised in Switzerland. Although his father was a professor of physics and chemistry, he was not actually drawn to science at an early age.
An inspiring biology teacher at upper secondary school changed his mind and he studied biochemistry in Zürich at the ETH. After finishing his PhD, Philipp Kaldis got a postdoc position at Yale University. The time at Yale totally changed his view on research.
“It was fantastic. I could just knock on the doors of famous professors and ask if I could discuss something for five minutes. They were always willing to talk and provide advice.”
What would be his advice to a young student who wants to succeed in research?
“Figure out how your research will have the most impact. Be a team playerand work hard.”
It pretty much sums up his own career!

Text: Sara Liedholm

Translation: Bryan Ralph