Medical Device Daily Contributing Writer
and MDDs

Scientists have identified a crucial metabolic complex: If you put all the pieces together, you get fat; if you pull them apart, you get thin.

In cystic fibrosis, some of the pieces have fallen apart — people with the disease are thin — but it seems that each piece of the complex acting alone can cause increased rates of diabetes and cancer.

The lynchpin of the complex has been called the “fat controller” by the researchers who discovered it. It lies, they say, at the confluence of central metabolism.

Anil Mehta, a leader in child health at the department of maternal and child health sciences at the University of Dundee in Scotland, who led the research, told Medical Device Daily's sister publication, BioWorld International: “This finding opens up new avenues, new treatments, new ways of thinking about all these conditions. I can see in my mind's eye how to make people who are overweight lose weight, and I can see how you might be able to make the protein complex come back together in cystic fibrosis — though I don't know how to do it yet.”

His team is currently looking for collaborative partnerships with industry to help them develop drugs that target the molecules they have identified. The University of Dundee holds patents on the molecular mechanisms involved. An international conference on the implications of the discovery will be held in Dundee in September 2007.

A report of the team's most recent publication appears in the August issue of Molecular and Cellular Biology. An earlier paper appeared in Cellular Signalling online in February.

Mehta said the work reported in the papers by his team could have a major impact on research into cystic fibrosis, cancer, diabetes and obesity. “We have opened up a whole new area of research, which links these conditions and from here on in, researchers looking at cancer, diabetes, obesity and cystic fibrosis should all be working with each other and looking at what the other is doing, because it is all linked together.”

Mehta, who has worked in cystic fibrosis research for 15 years, had never been able to reconcile the fact that the CFTR protein (the gene that is mutated in cystic fibrosis) is only a chloride channel, with his observations about his patients with cystic fibrosis.

His observations were that these patients were too thin and lose weight very easily, and that about half of them, as adults, have an odd form of diabetes with insulin resistance. “I could not understand how mutations in a chloride channel could bring about these effects,” he said.

Mehta went to Dundee University to work with Professor Grahame Hardie, an expert on fat regulation and metabolism. Hardie discovered the enzyme acetyl coenzyme A carboxylase 1 (ACC1), a regulator of fat metabolism, and its regulator AMP-activated protein kinase (AMPK) during the 1980s.

Once there, Mehta embarked on a long series of experiments, many of them funded by the Cystic Fibrosis Trust and the Wellcome Trust to try to explain the conundrum he had observed.

Some of his most recent experiments are reported in Molecular and Cellular Biology and in Cellular Signalling. They demonstrate a link between CFTR and another enzyme called nucleoside diphosphate kinase (NDPK). NDPK is known to convert the cell's energy currencies into different forms, but also acts as a suppressor of cancer metastasis and G-protein function.

Mehta found that if CFTR was mutated, NDPK in the vicinity stopped working. Different mutations in CFTR affected the function of NDPK in different ways.

“To cut a long story short, we then found that NDPK controlled ACC1, via the enzyme earlier discovered by Hardie, called AMPK. This gave us the direct link between CFTR and fat metabolism, which we had been looking for,” Mehta said.

Further studies presented at recent international conferences in the U.S. confirmed that in people with cystic fibrosis, neither NDPK nor AMPK nor ACC1 interacted normally with each other.

Other groups have found that diabetes develops in rats lacking a functional copy of NDPK. Knocking out NDPK in mice stops them producing breast milk — an important function of ACC1 is milk fat production.

Future work will involve, as Mehta put it, “unraveling the complex, taking it apart into little pieces, and understanding what sticks to what, with a view to understanding how best to make it fall apart or come back together again.”

His team, which includes Russell Crawford and Kate Treharne, is busy doing just that, having been awarded new grants from the Wellcome Trust and Cystic Fibrosis Trust.

London hospital orders Gamma Knife Perfexion

Cromwell Hospital (London), that city's leading independent hospital with more than 500 specialists covering more than 70 specialties, has confirmed to Elekta (Stockholm, Sweden) its order to install the Leksell Gamma Knife Perfexion later this year.

“The Gamma Knife Center at Cromwell Hospital has been a success, with over 1,000 patients treated since inauguration in 1998, benefiting British and overseas patients,” said Christer Lindquist, MD, PhD, director of the Gamma Knife Center. Lindquist, who was a Gamma Knife pioneer together with Professor Lars Leksell in the 1970s and 1980s, said the Perfexion is “a quantum leap in dosimetry, ease of use as well as patient and staff comfort.”

He added: “By installing the new Gamma Knife at our center, we will be able to provide more conformal treatment options in less time, automate the record and verify procedure, dramatically improve patient throughput and treat lesions which previously could not be reached.”

Leksell Gamma Knife Perfexion was introduced to the neurosurgery and radiation oncology communities at the 13th International Leksell Gamma Knife Society Meeting, in Seoul, South Korea, in the latter part of May and Elekta said the initial response has been “overwhelmingly positive.”