The nanomachinery of nature

Magnetic Resonance Spectroscopy, MR imaging, and Nanotechnology work together in understanding the smallest building blocks of human biology. The work is carried out in Center for insoluble protein Structures (inSPIN) in Aarhus, Denmark.

“We are dealing with science that is not yet mature for production of medicine. But it is our hope, that in the future we may facilitate the development of drugs that may diagnose and heal deadly diseases such as dementia, heart attacks, diabetic, and strokes,” says Niels Chr. Nielsen. He is leading professor at the laboratory for Biomolecular Spectroscopy and director of inSPIN.

Insoluble proteins cause disease, and one of the major challenges in the post genome era is to understand the insoluble proteins. “In connection with dementia and diseases such as Alzheimer’s and Parkinson we are dealing with the problem of fibrillation of proteins. Under certain conditions thousands of proteins come together and form plaque, insoluble structures that is a signature of disease,” says Niels Chr. Nielsen.

Professor Niels Chr. Nielsen and his team want to understand the mechanisms behind these structures, how are they formed and how can they be prevented? Is it the plaques themselves that are dangerous, or is it during the formation of the plaques they are dangerous? For the moment it is believed that they are most dangerous in the early stages, but the scientists are not in a position to determine exactly how they are built and explain which states are most toxic and best amenable to treatment.

“It is our vision to develop methods that allow us to understand the mechanisms behind the atomic structure: How the atoms are placed in the molecular structures determines their function.

The smallest building blocks

By understanding the structure of insoluble proteins, such as membrane proteins and protein aggregates, scientists will reach new understanding of the smallest building blocks of nature and our biological system. The membrane proteins in the cell walls are the keyhole to understanding how the transportation of fluids, salts, and molecules functions. What are for example the processes that administer the balance of water and salt in the cells? Such mechanisms are vital in many diseases and in our everyday life in connection with malfunctions such as incontinence. Understanding such processes will put us in a better position in designing drugs that alter these processes.

There is an enormous potential in this field of science. The human genome encodes for around 100,000 proteins and one third of these are membrane proteins. Today, the structures of only a dozen of these proteins are known!

“This number is in stark contrast to the fact that more than half of all pharmaceuticals in the world target membrane proteins. We still know very little about the details of many of their underlying processes. This does not mean that drugs are designed in the blind. They are designed by clever chemistry, biophysical experiments, experience, and by tests on animals and human beings. But if we can understand in detail the structure and dynamics of the membrane proteins it may help us designing new medical approaches when combined with chemistry and molecular biology. It is such details we want to obtain using a new technology, called solid-state nuclear magnetic resonance spectroscopy, which allows structures to be determined with a resolution down to less than one tenth of a nanometre. A major part of our mission is to develop this technique to explore the machinery of the proteins with a resolution where the individual atoms can be seen.

Revolution through bioimaging

Over the past decades biological imaging such as MRI scanning (magnetic resonance imaging) has found widespread applications in medical research and hospitals. It has revolutionised our ability to investigate disease processes and to provide early diagnoses. Bioimaging has also been used to verify that drugs are delivered to the right tissues and to plan individual pharmaceutical treatment of patients.

“MRI provides much lower resolution than the methods described above, but they offer important additional information through spatial localisation. Our vision is to design nanoparticles that enable imaging of specific cells and tissues, which are subject to drug treatment or gene therapy. Nanoscience is an exciting field where you can develop new materials and processes of unseen functionality.”

To make the vision come through, Niels Chr. Nielsen and his team are designing MRI-visible nanoparticles with specialised surface properties in order to target cells specific to certain diseases. An example is vulnerable atherosclerotic plaques in patients suffering from vascular disease. These plaques may rupture at any time causing myocardial infarction or a cerebral stroke. By detecting vulnerable plaques and fibrillations at an early stage, patients can be saved from severe disease or even death.

“The vision is to use the same particles for diagnosis and treatment. For medical therapy the nanoparticles will be loaded with drugs and targeted for delivery to the right spot. This will enable administration of much lower doses than today, reducing the risk of adverse side effects. But safety is crucial, and years of testing lie ahead before they can be used in patients,” he says.

Interdisciplinary alliances

Today Niels Chr. Nielsen has formed an interdisciplinary unit with spectroscopists, chemists, molecular biologists, and biophysists joining together in the inSPIN research centre, being an integrated part of the Interdisciplinary Nanoscience Center (iNANO). The MRI projects are performed in collaboration with Center for Functional Integrative Neuroscience CFIN, Lundbeck A/S, The Department of Experimental Oncology and The Department of Cardiology at Aarhus University Hospital.

“Using this interdisciplinary setup we are in the best possible shape to address these problems,” Niels Chr. Nielsen concludes.

JENS FONNESBECH
Journalist