Novo Nordisk Foundation strengthens protein research at the Department of Biology

In recent years, ground breaking advances in protein science have led to new knowledge, theory, experimental techniques and revolutionary understandings of how proteins function. These advances help explain why people may become ill when proteins malfunction, whether due to protein instability, aggregation or the inability of proteins to find and bind with the right partners inside the cell. Once unimaginable opportunities for scientific and biomedical discovery are the result.

The Novo Nordisk Foundation’s awarding of Challenge grants to these Department of Biology professors reflects a shift towards the enormous potential in understanding proteins and their structure and dynamics. (Read the Novo Nordisk Foundation press release)

Strengthened protein research at and beyond the university
Grant recipients Professor Kresten Lindorff-Larsen and Professor Birthe B. Kragelund work at the Department of Biology’s ‘Linderstrøm-Lang Center for Protein Science'. Both began their research careers at the legendary Carlsberg Laboratory and are used to working together despite focusing on different areas in the field of protein chemistry. At the Linderstrøm-Lang Centre, they are surrounded by a group of highly experienced colleagues who collectively tackle a broad swath of topics in protein research. The Centre’s collaborative environment and strong research focus on fundamental aspects in protein science has played an essential role in shaping their current research.

Both researchers understand that answering deep and fundamental questions in protein science and identifying new opportunities requires thinking big. As such, they have also established international collaborations with leading researchers in a range of scientific disciplines: biology, chemistry, physics, artificial intelligence, bioinformatics, and genomics. Unravelling the secrets of proteins is a challenge so great that it necessitates access to every available resource.

PRISM – a centre that focuses on the understanding and prediction of hereditary diseases
Kresten Lindorff-Larsen received a DKK 60 million Challenge programme grant for the project, 'PRISM – Protein Interactions and Stability in Medicine and Genomics'. The PRISM centre aims to understand and eventually predict how changes in our DNA can lead to disease. The primary focus will be to understand which genetic variation causes changes in the proteins in our cells, and render them unstable or unable to bind to their intended interaction partners. While recent advances in DNA sequencing and analysis have led to an explosive growth in the amount of data, there is relatively little understanding of the biological consequences of the genetic variations found in an individual human genome. PRISM seeks to shed light on the processes that take place in cells, as they deal with the unstable proteins. A better understanding of these processes will improve the possibilities for using genome analyses to diagnose patients and ultimately, for developing more effective therapies.

• “I am extraordinarily happy and somewhat proud that we have been awarded a grant from the Novo Nordisk Foundation’s Challenge programme. The new project is rooted in our basic research in protein chemistry and cell biology, which we almost serendipitously discovered to be of great practical relevance,” says Kresten Lindorff-Larsen. “This grant ensures that we can establish completely new high-throughput methods to study thousands of protein variants simultaneously, and then combine the results using computational methods from protein biophysics and machine learning, and study them in detail in a cellular context. We will use the results to guide the interpretation of how the thousands of genetic changes found in every human affect their risk of acquiring various hereditary diseases. Along with this very practical goal, we hope to gain a much better understanding of the basic processes that cells have developed to detect and degrade misfolded proteins, and that in the long term, we can use this information to develop new strategies for treating diseases,” concludes Kresten Lindorff-Larsen. 

The participants in PRISM’s are: Rasmus Hartmann-Petersen, Amelie Stein (University of Copenhagen), Torben Hansen (University of Copenhagen and Steno Diabetes Center), Douglas M. Fowler (University of Washington) and Michele Vendruscolo (University of Cambridge).

REPIN – a centre focusing on disordered proteins
Birthe B. Kragelund has been awarded a Challenge programme grant for her project, 'REPIN – Rethinking Protein Interactions'. The REPIN centre aims to shed light on an entirely new branch of protein chemistry that deals with functional proteins without fixed structures. This class of proteins disrupts the conventional wisdom that has been taught in biology and chemistry classes for decades - that structure and function go hand in hand - a view that continues to be the general perception of life's fundamental building blocks.

A few years ago, a very different reality emerged for researchers in protein laboratories worldwide. Quite suddenly, the way they had been studying proteins crumbled into disarray. It turned out that 30-40% of all the proteins made in cells were not structured into the familiar three-dimensional structures that they had grown accustomed to. In fact, it became apparent that proteins are extremely dynamic and assume a multitude of structures – but never without function!

As researchers begin getting used to the new reality, the significance of this paradigmatic shift for understanding biology remains perplexing for the majority of people.

The REPIN Centre focuses on these types of proteins, namely, the structureless disordered proteins that we knew almost nothing about 20 years ago. These 'Intrinsically Disordered Proteins (IDPs)' challenge the conventional understanding of biomolecular communications. An important key to unlocking the enigmatic characteristics of IDP’s is the development of an array of appropriate experimental methods, mechanistic models and a coherent conceptual framework.

• “At the REPIN Centre, we reconsider protein interactions with the aim of expanding the current paradigm so as to manage, study and evaluate molecular communication, in cases of structural disorder as well. We will tackle this challenge through an extensive, multidisciplinary approach, coupled with a distinct selection of specialized experimental techniques, appropriate molecular systems and key expertise. We will address structural disorder using methods that range from individual atoms and single molecules, over ensembles to the study of biology of living cells. I am proud and moved by the fact that the Novo Nordisk Foundation is honouring such a new field of research, and am delighted beyond words to explore its potential,” says Birthe B. Kragelund.

REPIN co-applicants are professors Karen Skriver and Rasmus Hartmann-Petersen (University of Copenhagen), and Professor Benjamin Schuler (University of Zurich). Professor Lise Arleth (University of Copenhagen) and Robert Best of the US National Institutes of Health(NIH) are the key collaborators.

Professor Birthe B. Kragelund also received one of the Novo Nordisk Foundation’s 'Research Infrastructure' programme grants for DKK 23 million, along with section head, Associate Professor Kaare Teilum and Professor Kresten Lindorff-Larsen, for the project, 'The Copenhagen Centre for Open NMR Spectroscopy – cOpenNMR'. The grant ensures that the NMR Facility at the Department of Biology will be strengthened and expanded, and be able to support protein research within and beyond the department. cOpenNMR will complement the X-ray crystallography, cryo-electron microscopy, and small-angle X-ray and neutron scattering. Situated in the heart of the Copenhagen-Lund structural biology 'powerhouse', cOpenNMR will, together with the ESS and MAX-IV facilities, constitute part of a complete structural biology instrument package available for Copenhagen-based protein researchers.

Kresten Lindorff-Larsen is also partner to a DKK 6.6 million grant from the Novo Nordisk Foundation’s ‘Research Infrastructure' programme for 'ROBUST: Resource fOr BiomolecUlar Simulation, where Professor Birgit Schiøtt of Aarhus University as the primary applicant. Project funding will go towards establishing a state-of-the-art computer infrastructure based on graphics cards to simulate complex biomolecules.