Published: 05-10-2016 09:20 | Updated: 05-10-2016 16:55

Four projects to share 143 Million from Knut and Alice Wallenberg Foundation

Knut and Alice Wallenberg Foundation (KAW) has granted SEK 143 Million for a period of five years to four research projects at Karolinska Institutet, considered to be of the highest international level, and potentially leading to future scientific breakthroughs. The principal applicants of these four projects are Patrik Ernfors, Katja Petzold, Nils-Göran Larsson and Sten Eirik Jacobsen.

Project funding from KAW is granted primarily for basic research in the field of medicine, technology and the natural sciences. In all, the foundation has granted SEK 752 Million in project funding to 22 research projects in 2016.

“The project grants are the largest annual funding made by the foundation. The grants go to cutting-edge independent research in Sweden. We want to give researchers the opportunity to try out new and bold ideas over an extended period,” says Peter Wallenberg Jr, Chairman of Knut and Alice Wallenberg Foundation, in a press release.

Decomposition of pain into cell types

Project: Decomposition of pain into cell types
Grant awarded: SEK 17,175,000 over five years
Principal applicant: Professor Patrik Ernfors, Department of Medical Biochemistry and Biophysics

Over twenty-five per cent of people over the age of 20 have problems with pain; twenty per cent have chronic pain, and roughly 7 per cent disabling pain. Every day, Millions of people in Europe and around the world experience chronic pain, causing considerable suffering to them and great costs to society in terms of care, rehabilitation and loss of productive work. While acute pain often represents a normal sensory function of the nerve system to alert the body to possible damage, chronic pain is something altogether different. It is long-lasting and caused by the abnormal activity of sensory nerves owing to injury or inflammation.

Despite the many attempts made, no conceptually new form of pain relief has yet been developed. This is because the relationship between different kinds of nerves/neurons and pain is still unknown; because most studies on pain have been conducted on rodents with little knowledge of their relevance to humans; and, finally, because identical experiences of pain can have very different mechanical origins. In their project, Professor Patrik Ernfors and his colleagues will be exploiting the latest molecular, cellular and genetic technologies in an extensive, impartial strategy designed to fill these knowledge gaps.

The researchers hope to be able to identify the precise cellular origin of pain in different pain syndromes. Even though different pain syndromes seem similar as regards the experience of pain, they are likely caused by distinct cellular mechanisms. The researchers will also examine the relationship between the pain-signalling neurons in primates and their analogues in rodents, which could give results from research in rodents a clinical relevance.

“We believe that our results will lead to a brand new start for the development of conceptually new drugs that target the pain cells that actually generate pain in various pain syndromes,” says Professor Ernfors.

MicroRNA control of neural development: Dissecting biological function with atomic resolution

Project: MicroRNA control of neural development: Dissecting biological function with atomic resolution
Grant awarded: SEK 33,520,000 over five years
Principal applicant: Assistant Professor Katja Petzold, Department of Medical Biochemistry and Biophysics
Co-applicant: Assistant Professor Emma Andersson, Department of Biosciences and Nutrition

In this project, the researchers, led by Assistant Professor Katja Petzold, are examining how a single microRNA (miRNA) can regulate the neural development of the brain. A single miRNA can control an entire network of different messenger RNAs (mRNAs), and thus fine tune protein levels. Despite the fact that over half of mRNA is regulated by miRNA, it remains a mystery how the miRNA “decides” what happens to the mRNA – whether it is broken down or locked in a dormant form. miRNA binds to certain mRNA like an inferior strip of Velcro. The researchers’ hypothesis is that the miRNA-mRNA bond is controlled by structural principles and not just by the sequence complementarity, as is currently believed. They also think that the miRNA structure is fluid and can adapt to different environments, like an extra control mechanism for finding the right mRNA.

Since the miRNA structure needs to be physically manipulated and its role in the brain assayed, it has not been possible to test this hypothesis. However, with the new methods they have developed, the researchers are uniquely placed to find the answer to one of the biggest conundrums in biology: how are the functions of RNA regulated in a living organism?

“In collaboration with Emma Andersson, who is a developmental biologist here at KI, and together with two external experts in synthetic organic chemistry and molecular modelling, we can now discover and define if and how the structure of a miRNA controls function", says Dr Petzold. “We’ll be analysing the role of a specific miRNA in brain development and are using miR-34a for its well-studied ‘targetome’. We already know which mRNA it attaches to, but not what happens then, or why.”

She continues: “This multidisciplinary project will produce revolutionary tools for analysing and identifying important interactions that regulate miRNA biology in living organisms with atomic resolution.”

Regulation of mammalian mtDNA gene expression

Project: Regulation of mammalian mtDNA gene expression
Grant awarded: SEK 47,000,000 over five years
Principal applicant: Professor Nils-Göran Larsson, Department of Medical Biochemistry and Biophysics

Our bodies contain a large number of specialised cell types that need constant access to energy in order to perform a wide range of functions. The mitochondria are often referred to as the cell’s power plants since they convert the energy from food to the energy-rich substance ATP. Mitochondrial regulation is essential to the normal functioning of our cells: to ability of the neurons of the brain to transmit signals, for example, or the myocardial cells’ ability to contract and pump the blood through our arteries. The failure of the mitochondria to produce energy is the cause of many hereditary diseases that attack the human nerve system, muscles, heart and other organs. Reduced mitochondrial function is also thought to play an important part in the pathogenesis of different types of age-related disease, such as diabetes and Parkinson’s, as well as in the ageing process itself.

The research programme led by Professor Nils-Göran Larsson describes a number of basic scientific experiments designed to better understand how the mitochondria regulate the expression of their own DNA (mtDNA) and thus the cell’s energy supply. Even though mtDNA is relatively tiny and only codes for 13 proteins, without it, the cell’s energy supply would not function. Several hundred genes in the cell nucleus code for proteins that are imported into the mitochondria to regulate the expression of mtDNA, a process that is therefore extremely complex and appears to take place on many levels.

“In our research programme we’ll be carrying out a series of advanced experiments to identify different mechanisms that control mtDNA and its expression,” says Professor Larsson. “Understanding more about how mtDNA expression is regulated will help us understand how the energy supply is controlled during different physiological processes and study disease processes and ageing.”

Characterization, Surveillance and Targeting of Cancer Stem Cells

Project: Characterization, Surveillance and Targeting of Cancer Stem Cells
Grant awarded: SEK 45,250,000 over five years
Principal applicant: Professor Sten Eirik W. Jacobsen, Center for Haematology and Regenerative Medicine, Department of Medicine, Huddinge; Department of Cell and Molecular Biology, Karolinska Institutet, and Haematologic Centre, Karolinska University Hospital
Co-applicants: Senior researcher Yenan Bryceson, Professor Eva Hellström-Lindberg, Professor Seishi Ogawa and Assistant Professor Petter Woll

Cancer relapse after an initially successful treatment is still a major problem and the toughest challenge for modern cancer therapies. Such late relapses are thought to be caused by the existence of rare cancer stem cells, which, in being demonstrably resistant to treatment and capable of forming new tumours, play an important part in the onset and development of the disease. It is therefore imperative that they are the target of all future cancer therapies.

Myelodysplastic syndrome (MDS) is a form of blood cancer deriving from the stem cells in the bone marrow, and leads to a lack of mature blood cells in the circulatory system. For many patients, the disease intensifies over time and can turn into acute leukaemia with a worse prognosis. The researchers behind this project have recently identified the cancer stem cells in MDS as well as several significant genetic mutations in.

The grant from KAW will allow Professor Sten Eirik W. Jacobsen, who received the 2014 Tobias Prize along with a grant from the Tobias Foundation for his work on MDS, and four other leading research groups at Karolinska Institutet’s new Centre for Haematology and Regenerative Medicine (HERM), to address several important biological and clinical aspects of MDS. These include the biology behind MDS induced anaemia, the MDS transformation tendency into acute leukemia, the development of immunotherapy, and the significance of recently discovered mutations in MDS.

“Our joint objective is to get a better understanding of the disease MDS both in terms of disease mechanisms, stem cell biology, immunology, and the molecular mechanisms behind MDS. We will conduct studies in animal models as well as in patients. By combining our respective expertise in the five research groups, we hope to develop therapies that more specifically and effectively can eliminate the MDS stem cells, but also through other approaches give rise to more lasting therapeutic results and remedies for MDS,” says Professor Jacobsen.

Even though the cancer stem cells in other blood cancers and tumours will probably differ significantly from the MDS stem cells, the researchers hope to glean from these studies a better understanding of cancer stem cells and of the development of cancer stem-cell therapies for cancer more generally.”