Quest for the genetics of obesity and diabetes

The Research Relay series has reached health scientist Thue W.Schwartz, who explains to us that some kinds of molecule give you the urge to eat, eat, eat

by Mike Young

We had discussed his research for half an hour before I got round to asking Thue Schwartz, a professor in molecular pharmacology at the Faculty of Health Sciences, what his daily routine was.

I mean, what do you do in a typical day? Are you ever involved directly in the laboratory work?

»Me?«, he laughed. »I just sit here in the office and look out the window«.

With his view from the top of the Panum Institute, this was easy to understand. Copenhagen seemed sprawled out before him like a map of some intricate protein.

This skyline was the backdrop to our conversation, where I, like in all the interviews in the Research Relay series, really only had one question: What do you find fascinating right now?

Lifestyle diseases

Diseases such as diabetes and obesity can be coined ‘diabesity’, according to Thue Schwartz, as they have a lot in common, and are caused by a combination of environmental and genetic factors.

See also article Copenhagen gets grant to combat obesity

It is these subtle genetic components that Thue Schwartz and his colleagues are working on.

In extreme cases, for example, a mutation of a receptor for an appetite hormone can lead to uncontrolled binge-eating.

In all animals there are a group of molecules called the 7TM receptors. 7TM receptors, the largest family of proteins, receive all kinds of signalling molecules within and between animals: Hormones, transmitters, odorants, taste components, light - and regulate the function of our cells.

»Right now we are getting information about all the genetic variants of these receptors. This means that we can find the genetic basis for complex diseases such as obesity and diabetes.« Thue Schwartz explains.

Can lead to individualised treatments

At present he is collaborating on a large project with the the Hagedorn Laboratories here in Copenhagen and the Beijing Genomics Institute.

In the study, a group of 2,000 Danes, half of the group with obesity and type 2 Diabetes, half a control group, will individually have all of their expressed genes totally sequenced.

This is a massive enterprise, according to Thue Schwartz, if you consider that it was only few years ago that the normal human genome as such, was sequenced. The idea now is to find all the variants.

»With this we can point to certain proteins, or to certain signalling pathways - cascades of proteins that link together - that are important for the development of these diseases. This will in turn point to ways to treat them,« he says.

The trouble with many complex diseases is that they may have multiple genetic causes - meaning that it is not the same in all patients.

Thue Schwartz and colleagues research will enable doctors to come up with an individualised drug therapy, knowing that this patient has the disease because of this particular genetic variant, and not another.

Truth is in the variants

»What really fascinates me is that we are now specifically looking at variants which alter the structure and function of the proteins. The fact that the mutations alter the function in vivo - in the patient – often tells us surprising and basic things about the protein as such,« he says.

Thue Schwartz considers his laboratory a world leader in understanding the molecular mechanism of 7TM receptor activation and how drugs act on these proteins.

»We use engineered mutations a lot in the laboratory to change the structure and look at the function of proteins. It turns out we know very little and are not very smart,« he says.

»But then it is as if Nature has pity with us and says – hey – look at this natural disease causing variant, now you should be able to figure out the basic stuff!”

Would have been a great scientist

Thue Schwartz’ work spans from the basic molecular structure of the proteins, to transgenic models in
animals, to the treatment of patients, and he has published and worked in all these fields.

He has diluted his scientific effort, he says with a grin.

»Sometimes I say to myself: If I had only concentrated on the basic structure of the protein, or the biological function of the receptors, or the in vivo function in the animals. If I had only concentrated on any one of these, I could have been a great scientist,” he says, then adds with a laugh:

“But I am having more fun this way!”

miy@adm.ku.dk

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