Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

KI News

Updated: 21 min 13 sec ago

New insights about the role of myelin-producing cells in MS

Wed, 23/01/2019 - 19:00
Subpopulations of oligodendrocytes, myelin-producing cells in the brain that are targeted by the immune system in multiple sclerosis (MS), are altered in MS and might therefore have additional roles in the disease than previously described. The results are published in the journal Nature, in a study led by researchers at Karolinska Institutet in Sweden and University of Edinburgh in the UK. Around the world 2.5 million people are living with MS. MS develops when the immune system’s white blood cells attack the insulating fatty substance known as myelin, which is produced by oligodendrocytes and coats nerve fibres in the central nervous system. This interferes with the proper transmission of nerve electric signals and causes the symptoms of the disease. Previously the researchers have investigated oligodendrocytes in a mouse model of MS and shown that they might have a significant role in the development of the disease. In the current study they have mapped oligodendrocytes in human samples from post-mortem brains of MS patients. “While we found some similarities between the mouse model of MS and human MS, our results also unveil differences. We found changes in different oligodendrocyte subpopulations in MS, suggesting a more complex role of these cells in the pathology of the disease, but also in regeneration of new cells,” says Gonçalo Castelo-Branco, Associate Professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, one if the lead researchers of the study. The results show that oligodendrocyte precursor cells, which are thought to have a crucial role in relapsing-remitting MS to restore myelin, are depleted in the progressive disease. “In addition, the proportions of different resident oligodendrocytes in the lesions are changed, along with their properties, suggesting that they might have important roles in MS,” says Eneritz Agirre, postdoctoral researcher in Castelo-Branco’s group at Karolinska Institutet. The researchers used single-nuclei RNA sequencing, which allows determination of genetic activity of individual cells, to investigate the cellular composition of MS lesions with unprecedented resolution. Oligodendrocytes are a diverse population of cells “We found that oligodendrocytes are a diverse population of cells and that different types are likely to have different functions in the brain,” says Professor Charles ffrench-Constant, of the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh. “Understanding which types of oligodendrocytes are most beneficial in repairing myelin will be crucial for maximising the chances of developing much-needed treatments for MS,” says Professor Anna Williams of the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh. Novel markers also identified The researchers also found novel markers that can be useful for the neuropathological characterisation of MS. “Our findings illustrate the power of this technology to study the neuropathology of human diseases such as MS. We predict that the widespread use of this technology with larger numbers of samples will further enhance our understanding of MS and lead to revision of current concepts of the disease,” says Gonçalo Castelo-Branco. Another paper is published simultaneously in Nature, from Professor Jonas Frisén’s group also at Karolinska Institutet, arriving at overlapping conclusions, with a different methodology, The study was conducted in collaboration with F. Hoffmann – La Roche, Ltd, where two of the authors are employed. It was financed by several funding bodies, including the Wellcome Trust, UK Multiple Sclerosis Society, European Research Council and Marie-Skłodowska Curie Actions, the European Committee for Treatment and Research of Multiple Sclerosis (ECTRIMS), Swedish Research Council, Swedish Brain Foundation, Swedish Cancer Society, Stockholm City Council, the Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet and La Roche, Ltd. Publication “Altered human oligodendrocyte heterogeneity in multiple sclerosis” Sarah Jäkel, Eneritz Agirre, Ana Mendanha Falcão, David van Bruggen, Ka Wai Lee, Irene Knuesel, Dheeraj Malhotra, Charles ffrench-Constant, Anna Williams and Gonçalo Castelo-Branco. Nature, online 23 January, 2019

Old cells repair damage in the brains of MS patients

Wed, 23/01/2019 - 19:00
A new study shows that there is a very limited regeneration of cells in the brain of patients diagnosed with multiple sclerosis (MS). These findings underline the importance of treating MS at an early stage of the disease progression, when the affected cells can repair the damage as they are not replaced by new ones. The results are published in the journal Nature by researchers from Karolinska Institutet and Uppsala University. Nerve cells in the brain communicate with one another through nerve fibres that form complex networks. Many nerve fibres are insulated by a casing of myelin, which contributes to the high-speed transmission of nerve impulses. Myelin is not formed by the nerve cells but by another type of cells called oligodendrocytes. MS is a disease caused by the body’s immune system attacking the myelin and oligodendrocytes. This leads to deteriorated transmission of signals in the nerve fibres and can entail nerve cell death, a combination that causes serious neurological impairments and in severe cases the patient’s death. Old oligodendrocytes are able to form new myelin The disease progression in MS usually fluctuates between periods of deterioration and periods of remission. Studies in mice have shown that damaged myelin can be reformed, and that this requires generation of new oligodendrocytes that make the myelin. It has been assumed that periods of remission in MS patients are caused by newly formed oligodendrocytes replacing the lost myelin. But in this study, a research group has been able to show that there is no regeneration of oligodendrocytes in MS patients in those areas where the myelin seems to have been reformed. Instead, it appears as if old oligodendrocytes that have survived the attack from the immune defence are able to form new myelin.   “We were highly surprised that humans proved to be so different from the animals that have been studied. In humans, there is very limited regeneration of oligodendrocytes, but they seem to have a greater capacity to contribute to repair,” says Jonas Frisén, Professor at the Department of Cell and Molecular Biology at Karolinska Institutet, who led the study. These new findings indicate the importance of treating MS aggressively at an early stage of the disease progression, in order to prevent the loss of oligodendrocytes. “Since few oligodendrocytes are formed, it is important to save the ones you have as they can repair the damage caused by the disease,” says Jonas Frisén. Used the carbon-14 method to determine the age To determine the age of the oligodendrocytes in the MS patients, the researchers measured the amount of the isotope carbon-14 from nuclear detonations during the cold war, which was stored in the cells’ genome, i.e. the DNA. Since the detonations ceased, there has been a gradual decrease of carbon-14, which acts as a type of date mark for when the cells were formed. This method of determining the age of a cell was developed by Jonas Frisén’s team in the early 2000s. Another paper is published simultaneously in Nature, from Associate Professor Gonçalo Castelo-Branco's group also at Karolinska Institutet, arriving at overlapping conclusions, with a different methodology, The study was funded by the Swedish Research Council, the Swedish Cancer Society, the Tobias Foundation, the Strategic Research Foundation (SSF), the Knut and Alice Wallenberg Foundation, the European Research Council (ERC) and the Torsten Söderberg Foundation.   Publication "Oligodendrocyte generation dynamics in multiple sclerosis" Maggie S.Y. Yeung, Mehdi Djelloul, Embla Steiner, Samuel Bernard, Mehran Salehpour, Göran Possnert, Lou Brundin and Jonas Frisén. Nature, online 23 January, 2019

Research projects with sex-and-gender perspective receive MSEK 16.6

Tue, 22/01/2019 - 11:09
The EU agency GenderNet recently decided on grants for 13 international collaborations. Five of these projects have partners at KI. In total about SEK 16.6 million is granted to KI. The projects include sex-and-gender perspective in their respective subject areas. GenderNet includes 16 organizations from 13 countries. The purpose of the EU agency is to strengthen transnational collaboration that integrates the sex-and-gender dimension into research and promotes gender equality through institutional change. A decision has now been made to finance 13 international collaboration projects within the GenderNet Plus Co-Fund. Ten of the collaborations that have been granted financing include Swedish participants, who will receive funding from the Swedish Research Council. The Swedish Research Council's support for the Swedish participants is a total of over SEK 28 million during the period 2018/19–2021. The five collaborative projects with partners at KI who are supported are: Christopher Cederroth at the Department of Physiology and Pharmacology receives funding of SEK 4 108 562 as partner in the project "The combined role of genetic and environmental risk factors in the gender-specific development of severe tinnitus (TIGER)" Hanna Eriksson at the Department of Oncology-Pathology receives funding of SEK 2 549 874 as partner in the project "Sex differences and side effects of immunotherapy: a study to optimize cancer treatment (GEISHA)" Stefan Fors at the Department of Neurobiology, Care Sciences and Society receives funding of SEK 2 871 750 as partner in the project "Evolving gender differences in health & care across cohorts (FUTUREGEN)" Karolina Kublickiene at the Department of Clinical Science, Intervention and Technology receives funding of SEK 3 081 420 as partner in the project "Gender Outcomes INternational Group: to Further Well-being Development (GOING-FWD)" Mariano Salazar at the Department of Public Health Sciences receives funding of SEK 3 951 457 as partner in the project "Masculinities and violence against women among young people- Identifying discourses and developing strategies for change using a mixed method approach (PositivMas)"

KI, Ferring and Rebiotix extend collaboration to research next generation of microbiome treatments

Tue, 22/01/2019 - 10:43
KI and Ferring Pharmaceuticals announced today a five-year extension of their collaboration to explore the potential of the human microbiome in reproductive medicine and women’s health and gastroenterology. The collaboration brings together specialist expertise from Karolinska Institutet in early stage research, Rebiotix Inc. (acquired by Ferring in 2018), a late-stage clinical microbiome company, and Ferring’s therapeutic area and commercialisation capabilities. The collaboration brings together expertise from Ferring, Rebiotix and Karolinska Institutet to unlock the potential of the human microbiome. The collaboration will investigate the role of the microbiome in reproductive medicine and women’s health and gastroenterology through 10 clinical studies involving approximately 9,000 people. The data collected will support future research and development in areas of high unmet need, including recurrent pregnancy loss, preterm birth and inflammatory bowel disease. The extension includes six reproductive health clinical studies of approximately 6,000 women and babies and four gastroenterology studies of approximately 3,000 adults and children, to further investigate the role of the microbiome in areas of high unmet need including recurrent pregnancy loss, preterm birth and inflammatory bowel disease. “The extension of this partnership presents an exciting research opportunity, bringing together unique capabilities of Ferring, Karolinska Institutet and Rebiotix across the clinical development continuum in the mircrobiome space,” said Lee Jones, Founder, President and Chief Executive Officer, Rebiotix, Inc. “This, together with Ferring’s significant experience in reproductive medicine and gastroenterology, offers the potential to drive future research and development for the next generation of microbiome treatments needed to help more people build healthy families and live better lives.” Up to 5 percent of couples face the heartache of recurrent pregnancy loss and around 15 million babies are born preterm every year around the world, with approximately 1 million children dying each year due to related complications. Over 10 million people worldwide live with the pain and discomfort of inflammatory bowel disease. With reproductive health and inflammatory bowel concerns on the rise, there is a need to increase understanding of their causes and develop new solutions. “This innovative public-private partnership demonstrates our ongoing, shared commitment to investigating the human microbiome,” said Lars Engstrand, Professor at Karolinska Institutet and Director of the Center for Translational Microbiome Research. “It will support the expansion of Karolinska Institutet’s foundation of robust biological data and drive our understanding of the microbiome’s impact on important reproductive and gut health challenges.”  

New study raises hopes of eradication of malaria

Tue, 22/01/2019 - 06:00
After major global successes in the battle against malaria, the positive trend stalled around 2015 – apart from in Zanzibar in East Africa, where only a fraction of the disease remains. In a new study published in BMC Medicine, researchers at Karolinska Institutet in Sweden explain why this was and show that new strategies are needed to eradicate the disease. One of the problems is a change in mosquito behaviour and selection in the parasites. The years around 2000 Professor Anders Björkman described as catastrophic with respect to the global spread of malaria. This triggered a world-wide initiative that was given a boost by new kinds of drug and the widespread distribution of impregnated mosquito nets and domestic anti-mosquito sprays. The outcome was a halving of the global spread of the disease by 2015. “But after that, the decline tailed off,” says Professor Anders Björkman at the Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, who has been running the malaria project for 18 years. “Except for in Zanzibar, where the action taken for its 1.4 million citizens has led to approximately a 96 per cent decline in the incidence of malaria. We’ve optimised these measures with the Zanzibar Malaria Control Programme and can now explain why malaria has not yet been fully eliminated.” Resistant to modern pesticides The study reveals altered behaviour in the malaria mosquitoes, which now bite outdoors instead of indoors. They have also developed a kind of resistance to modern pesticides. Furthermore, there has been a process of selection in the pathogenic parasite, where the remaining form is more difficult to detect but still spreads the disease as before. The researchers have been monitoring 100,000 or so residents of two districts in Zanzibar since 2002. “Both the mosquitoes and the parasites have found ways to avoid control measures,” says Professor Björkman. “We now need to develop new strategies to overcome this if we’re to attain the goal of eliminating the disease from Zanzibar, an endeavour that can prove a model for the entire continent.” What surprised the researchers was the dramatic decline in child mortality in Zanzibar, where malaria control has caused more than a 70 per cent drop in the total child mortality rate. It was previously estimated that only 20 per cent of child deaths in Africa were malaria-related; the researchers now think the reason for this dramatic reduction is that the disease has a greater and more chronic effect on the general health of babies than suspected, thus lowering their resistance to other diseases throughout early childhood. Global initiatives gives hope “Malaria is still the greatest obstacle to a healthy childhood in Africa,” says Professor Björkman. “If you ask African women today, their greatest concern is usually that malaria doesn’t affect their pregnancy and their babies. The global community must continue the fight for improved strategies and control measures. If this happens, I think we’ll be able to reach the goal of ultimate elimination.” Zanzibar was one of the first countries to put the global initiatives against malaria to use and has since been tireless in its work to control the disease. The researchers now hope that these lessons can revive anti-malaria strategies throughout Africa. The study was mainly financed by the Erling-Persson Family Foundation and the Swedish Research Council. Publication “From high to low malaria transmission in Zanzibar - challenges and opportunities to achieve elimination”. Anders Björkman, Deler Shakely, Abdullah Ali, Ulrika Morris, Humphrey Mkali, Abdul-Wahid Al-Mafazy, Khamis Haji, Juma Mcha, Rahila Omar, Jackie Cook, Kristina Elfving, Max Petzold, Michael Sachs, Berit Aydin-Schmidt, Chris Drakeley, Mwinyi Msellem and Andreas Mårtensson. BMC Medicine, online 22 January 2019, doi: 10.1186/s12916-018-1243-z.

Clear link between nurse work environment and patient safety

Thu, 17/01/2019 - 10:33
Lisa Smeds Alenius will defend her doctoral thesis on 22 January 2019 at Karolinska Institutet. Her thesis focuses on factors in the nurse work environment relating to quality of care and patient safety. The thesis shows that the experience of adequate staffing and resources, leadership on ward and hospital levels, and teamwork with physicians are all of great importance for how nurses assess patient safety. The thesis also shows that those assessments are consistent with objective measures of patient safety. Lisa Smeds Alenius is a RN and a doctoral student at the Department of learning, informatics, management and ethics, LIME, at Karolinska Institutet. Why did you want to investigate this topic? “Since the resources available for care, both human and economic, are limited, I wanted to investigate how nurses perceive their work situation to make better and more full use of their competence to benefit both patients and the hospital as an organisation.”   What methods did you use? “The thesis is based on data from the Swedish component of the international, EU-funded project "Registered Nurse Forecasting" (RN4CAST), with survey responses from 11,000 nurses working in medical and surgical wards at all the acute care hospitals in Sweden. Data from the National Patient Register were also used, as well as data on hospitals.” What conclusions did you arrive at? "The factor with the most influence on nurses’ assessments of patient safety on their wards was whether they felt sufficient staff and resources were available. Leadership, both at ward level and at hospital management level, was also influential, as was teamwork with physicians. The thesis also shows that nurses’ assessments of the safety and quality of care can provide an important basis for decision making. When the nurses assessed patient safety and quality of care as excellent, objective measures also showed a clearly reduced risk of patients dying within 30 days. In free-text responses to an open question, many nurses described how they felt they were expected and required to maintain a high level of quality and safety in care, while at the same time they had little opportunity to influence the necessary conditions for care provision. Several organisational factors that make it difficult for nurses to utilise their professional competence to the fullest, were also made visible.” What was surprising? "We saw in the survey responses that nurses had a strong sense of commitment and a desire to make use of and share their knowledge, so it is disheartening to learn that organisational conditions do not really support that. It was also clear that the nurses were very happy with their chosen profession but not necessarily with their place of work. I see that as a force that could be utilised more constructively. Given the right conditions, many might want to continue working as a nurse.” What do you hope your results will lead to? "I hope that the results of the thesis will stimulate nurses and managers at different levels to investigate how nurses’ competencies and capacities are being utilised. Nursing is a central part of patient care and because nurses constitute the largest occupational group in hospitals, it is important their professional knowledge is used in a more strategic and effective way. Nurses should not only be self-evident as indispensable actors in organizing and influencing care processes. It is also about providing the necessary conditions, for example adequate staffing and resources, and supportive organisational structures for care provision. It would also be reasonable to imagine that if there were more opportunities for nurses to make full use of their professional competence, hospitals would become more attractive as workplaces which, in turn would improve chances of recruiting and retaining skilled personnel.” What are you going to do now? "I want to continue researching how healthcare can utilise staff competencies in the best possible ways, which also benefits patients. I also want to explore other professional groups to see how they perceive their work situation and how their skills are utilised.” Text: Helena Mayer

DNA origami: a precise measuring tool for optimal antibody effectiveness

Mon, 14/01/2019 - 17:00
Using DNA origami – DNA-based design of precise nanostructures – scientists at Karolinska Institutet in collaboration with researchers at University of Oslo, have been able to demonstrate the most accurate distance between densely packed antigens in order to get the strongest bond to antibodies in the immune system. The study, which is published in the journal Nature Nanotechnology, may be of significance to the development of vaccines and immunotherapy used in cancer. Vaccines work by training the immune system with harmless mixtures of antigens (foreign substances that trigger a reaction in the immune system), from a virus, for example. When the body is then exposed to the virus, the immune system recognises the antigens that the virus carries and is able to effectively prevent an infection. Today, many new vaccines make use of something called “particle display”, which means that the antigens are introduced into the body/presented to the immune system in the form of particles with lots of antigens densely packed on the surface. Particle display of antigens works in some cases better as a vaccine than simply providing free antigens and one example is the HPV vaccine, which protects against cervical cancer. Antibodies, or immunoglobulins, perhaps the most important part of the body's defence against infection, bind antigens very effectively. The antibodies have a Y-shaped structure where each "arm" can bind an antigen. In this way, each antibody molecule can usually bind two antigen molecules. Were able to accurately measure distances for best binding In the current study, the researchers examined how closely and how far apart from each other the antigens can be packed without significantly affecting the ability of an antibody to bind both molecules simultaneously. "We have for the first time been able to accurately measure the distances between antigens that result in the best simultaneous binding of both arms of different antibodies. Distances of approximately 16 nanometres provide the strongest bond”, says Björn Högberg, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, who led the study. The study also shows that immunoglobulin M (IgM), the first antibody involved in an infection, is significantly larger reach, that is the ability to bind two antigens, than previously thought. IgM also has a significantly greater reach than the IgG antibodies produced at a later stage of an infection.   DNA-origami a relatively new technique The technology the scientists used is based on a relatively new technique known as DNA origami, which has been in use since 2006, that allows precise nanostructures to be designed using DNA. However, it is only in recent years that scientists have learned to use this technique in biological research. The application used in the study is newly developed. "By putting antigens on these DNA origami structures, we can manufacture surfaces with precise distances between the antigens and then measure how different types of antibodies bind to them. Now we can measure exactly how antibodies interact with several antigens in a manner that was previously impossible”, says Björn Högberg. The results can be used to better understand the immune response, for example why B lymphocytes, a type of white blood cell, are so effectively activated by particle display vaccines, and to design better antibodies for immunotherapy when treating cancer. Important insight for tailor-made treatment The research has been conducted in close collaboration with the Laboratory of adaptive immunity and homeostasis led by Jan Terje Anderson, at the University of Oslo and Oslo University Hospital. “We study the relationship between the structure and function of antibodies. Such insight is important when we design the next generation of vaccines and antibodies for tailor-made treatment of serious diseases. We have long been looking for new methods that can help us get detailed insight into how different antibodies bind to the antigens. The collaboration with Björn Högberg has opened completely new doors,” says Jan Terje Andersen. The study was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, the StratRegen/Karolinska Institutet and the Research Council of Norway. Publication "Binding to Nanopatterned antigens is Dominated by the Spatial Tolerance of antibodies" Alan Shaw, Ian T Hoffecker, Ioanna Smyrlaki, Joao Rosa, Algridas Grevys, Diane Bratlie, Inger Sandlie, Terje Enar Michaelsen, Jan Terje Andersen and Björn Högberg. Nature Nanotechnology, online 14 January 2019, doi: 10.1038/s41565-018-0336-3 Film (with subtitles in English) Björn Högberg berättar om DNA origami

The Swedish Childhood Cancer Fund distributes just over SEK 43.5 million to Karolinska Institutet

Thu, 10/01/2019 - 16:33
A little over a third of the SEK 137 million distributed in the Swedish Childhood Cancer Fund major call goes to research projects at Karolinska Institutet. Karolinska Institutet is thus the university that receives the largest part of the total sum. Of the 100 grants, five were awarded to clinical project and 28 to project grants. To find out which projects have received funding, please see below links to the Swedish Childhood Cancer Fund's website.

New insights into a rare type of cancer open novel avenues of study

Mon, 07/01/2019 - 16:01
Undifferentiated uterine sarcoma is a very rare but extremely aggressive cancer type. It can be divided into four groups with different characteristics of clinical importance - a new study at Karolinska Institutet reveals. The results, published in the journal Clinical Cancer Research, also show that the survival rate of patients with a certain type of tumour is better than predicted. Sarcoma is a collective name for 50 different cancers in the body’s mesenchymal (soft) tissues. Undifferentiated sarcoma of the uterus is a cancer with a very poor prognosis, with a typical survival of less than two years. The only treatment of any importance for the survival of a patient is surgery, whereas radiation therapy and chemotherapy do not have any pronounced effect. Since the tumour is so rare, we have limited knowledge of it. In the current study the researchers examined tumour material from 50 patients with the help of both advanced molecular analyses and with more traditional clinical laboratory analyses. The aim was to gain new knowledge about the tumour’s biological characteristics and relate these to the patient’s survival and the routine methods which are used in the laboratory. The tumours could be divided into four groups By means of molecular mapping and analysis of gene expression the tumours could be divided into four previously unknown groups. The four groups had different biological characteristics which are considered by the researchers to be of importance for patients. Firstly, the patients had different survival rates depending on the group that the tumour belonged to. Secondly, the most aggressive tumours were characterised by a distinctive microscopic appearance and protein expression, which makes them identifiable with the help of common laboratory techniques. New potential treatment targets With the help of additional analyses, the researchers were able to identify new potential treatment targets. "It is too early to propose a new treatment that will be useful for the patients today, but the study opens up new avenues for future research, which will create in time new treatment possibilities for women who suffer from these rare tumours," says Joseph Carlson, Associate Professor at the Department of Oncology-Pathology, Karolinska Institutet, who has led the study. The study also shows that some of the patients’ life expectancy is not as gloomy as one thought before the study, since there is a group of patients who survive for a much longer time than two years, and this group can be identified by means of current laboratory techniques.   The study was financed with the support of Radiumhemmet’s research funds, the Stockholm County Council, the Swedish Cancer Society, the Magnus Bergvall Foundation, Thermo Fisher Scientific and the Foundation for Research on Diagnostics and Treatment of Sarcoma at Radiumhospitalet in Norway.   Publication “Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes” Amrei Binzer-Panchal, Elin Hardell, Björn Viklund, Mehran Ghaderi, Tjalling Bosse, Marisa R. Nucci, Cheng-Han Lee, Nina Hollfelder, Pádraic Corcoran, Jordi Gonzalez-Molina, Lidia Moyano-Galceran, Debra A. Bell, John K. Schoolmeester, Anna Måsbäck, Gunnar B. Kristensen, Ben Davidson, Kaisa Lehti, Anders Isaksson and Joseph W. Carlson. Clinical Cancer Research, online 7 January, 2019, doi: 10.1158/1078-0432.CCR-18-2792

Protein map using new method of analysis shared in open database

Thu, 03/01/2019 - 17:01
Researchers at Karolinska Institutet and SciLifeLab have developed a new method of analysis that maps the location of proteins in the cell. The information has been compiled in a database that is accessible to researchers around the world. The method of analysis, which has been published in the journal Molecular Cell, can also provide in-depth knowledge of disrupted cell function in cancer and other diseases. Every cell in the body is made up of thousands of different proteins that are perfectly organised for the cell, and by extension our body organs, to function optimally. Cells can be compared with miniature advanced factories, where each protein has a given function and location. Proteins on the surface of the cell are used for communication between the cell and its environment. Other proteins in the cell nucleus can copy genetic material or protect it from damage. Proteins in the mitochondria produce energy for the cell, while other proteins in the proteasomes, the cell’s waste stations, break down obsolete proteins, and so on. These processes are hugely complex. Mapped the cellular locations of proteins The researchers have mapped the cellular locations of proteins by developing their own method of analysis based on mass spectrometry. This information has been compiled in a large database and released in a new publication. The database can now be used by researchers around the world who are searching for information on proteins whose function is still unknown. "The method we have developed can also be used to study whether certain diseases, such as cancer, are caused by dislocated proteins that disturb normal cell functions. It is also possible to study how cell proteins move from one location to another when the cell’s external milieu changes," says Janne Lehtiö, professor at the Department of Oncology-Pathology at Karolinska Institutet in charge of the study. Protein movement provides important information One example of the latter is the study of how around ten proteins move when cancer cells are treated with specific drugs. This provides important information about which proteins are involved in the cell's response to treatment, and thus knowledge of the drugs’ mechanisms of action. "The method also allows the published database to be expanded by other researchers worldwide, with the aim of mapping the cell’s architecture and protein functions in more detail," says Lukas Orre, researcher at the Department of Oncology-Pathology at Karolinska Institutet and principal author of the study. Complements the Human Protein Atlas The study, in combination with another Stockholm, Sweden, based project, the Human Protein Atlas, that has systematically mapped the human proteome (network of proteins), provides a greater understanding of the cell and a comprehensive map of cell proteins. Database: subcellbarcode.org The study was funded by the Swedish Foundation for Strategic Research, the Swedish Cancer Society, the Swedish Research Council, the Swedish Childhood Cancer Fund, AstraZeneca, the Cancer Research Funds of Radiumhemmet and the Stockholm County Council. Publication ”SubCellBarCode: Proteome-wide mapping of protein localization and relocalization” Lukas Minus Orre, Mattias Vesterlund, Yanbo Pan, Taner Arslan, Yafeng Zhu, Alejandro Fernandez Woodbridge, Oliver Frings, Erik Fredlund and Janne Lehtiö. Molecular Cell online 3 January, 2019.  

New insights into how genes are activated

Wed, 02/01/2019 - 19:00
In a study in Nature, researchers at Karolinska Institutet present a new method for analysing how instructions in the genome control how our genes are activated in individual cells. The results give new insights into how the genome encodes for its own use, which increases our basic understanding of how genes are activated in different types of cell in the body in both good and ill health. Almost all cells in the body have the same set of DNA and can in principle become any kind of cell at all. What distinguishes the cells is the way in which the genes in our DNA are used. All the DNA in a cell is called the genome, our genetic material, but only a very small part of a human’s genome consists of genes. Instead extensive areas of the genome are used to regulate when and in which cells nearby genes are active. These regions contain “enhancers” and the gene sequences located right next to the genes, “promoters”. In a diseased body, these regions are often mutated and a deeper understanding of the function of these regions would bring light to the course of the disease in question. In order for a gene to be used, it must be translated from DNA to copies of RNA. RNA is similar to DNA but its structure is slightly different and it can be used as a template for producing protein. The translation of DNA to RNA is called transcription. Method to sequence RNA in individual cells There are still many things that are not clearly understood about how transcription takes place and how it is regulated. For example, if a gene is used by a cell, the gene’s DNA is not translated to RNA all the time. That would require too much energy. Instead, the transcription takes places in bursts, when the transcription machinery is recruited and several RNA molecules are produced in a short time. The transcription of each gene can be characterised on the basis of the kinetics of this process, that is, the frequency of the bursts and the number of molecules produced during the bursts. ”It used to be difficult to measure the kinetics and how many RNA molecules had been produced by a gene in an individual cell. The methods that have existed up to now were only able to follow a few genes at a time. Moreover, mammals have two sets of almost all their genes so it has been difficult to distinguish between the RNA that comes from the mother’s version of the gene and that from the father’s version,” says Rickard Sandberg, professor at the Department of Cell and Molecular Biology at Karolinska Institutet, who has led the study in question. In the study, the researchers used a method which they had developed themselves to sequence RNA in individual cells. The method makes it possible to measure the number of RNA molecules for almost all the genes used in a cell. Variation found in the genes of two different types of mouse The researchers sequenced cells of connective tissue and embryonal stem cells from a crossbreed of two distantly related mice. With the help of the natural variation found in the genes of the two different types of mouse, the researchers were able to distinguish between the sequenced RNA from the mother’s and the father’s versions of the gene and in that way measure the transcription exactly. They then used a mathematical model to make estimations, for each of the versions, of how often the gene is transcribed and how much RNA is then produced. ”We discovered that enhancers did affect how often a gene was transcribed in the two different cell types but not how many RNA molecules were produced. We also found that certain DNA sequences located at the beginning of a gene can influence how much RNA is produced in a burst. In that way, we have begun to chart how the genome encodes for its own use,” says Anton Larsson, the first author of the study in question and a doctoral student in Rickard Sandberg’s research group.  ”It will be possible to make wide use of our method to chart at a much deeper level how different proteins affect the transcription process,” says Rickard Sandberg. The research was funded with support from the European Research Council, the Swedish Research Council, the Knut and Alice Wallenberg Foundation and the Vallee Foundation. Publication “Genomic encoding of transcriptional burst kinetics” Anton Larsson, Per Johnsson, Michael Hagemann-Jensen, Leonard Hartmanis, Omid R. Faridani, Björn Reinius, Åsa Segerstolpe, Chloe M. Rivera, Bing Ren and Rickard Sandberg. Nature, online 2 January 2018.

SEK 10,5 million have been awarded from the Sjöberg Foundation

Thu, 20/12/2018 - 16:51
Two researchers at Karolinska Institutet have been awarded funds from the Sjöberg Foundation. The foundation promotes cancer research, and research on health and the environment. Simon Ekman, at the Department of Oncology-Pathology, has been awarded SEK 4.5 million for the research project: "Novel therapy using modulation of microRNAs in treatment refractory non-small lung cancer". Mikael Karlsson, at the Department of Microbiology, Tumor and Cell Biology, has been awarded SEK 6 million for the research project: "New immunotherapy for pancreatic cancer by reprogramming macrophages". The funding will be distributed over a three-year period. The foundation aims to promote scientific research with a main focus on cancer, health and the environment. To a lesser extent, other charitable purposes in health and the environment can be promoted.

Learning from rewards is related to dopamine receptor density

Thu, 20/12/2018 - 09:47
New research from Karolinska Institutet shows that our ability to learn from previously rewarded actions is directly related to the dopamine receptor density in the dorsal striatum, a central structure in the dopaminergic circuit in the brain. The study is published in the scientific journal PNAS. The brain’s dopaminergic pathways are thought to enable us to approach rewards and stay away from punishments. During learning, dopaminergic reward prediction errors are thought to reinforce previously rewarded actions, so they become easier to repeat. This dopaminergic activity could lead to a systematic bias by which rewarded actions are more readily learned than rewarded inactions. In the current study, doctoral student Lieke De Boer and colleagues at the Department of Neurobiology, Care Sciences and Society present findings about the organisation of dopamine receptors in the human brain and its relation to learning. What are the most important findings of your study? “We present two important findings. First, dopamine D1 receptors in the cortex, dorsal striatum, and nucleus accumbens provide three distinct sources of variance in the human brain. Second, people learn faster from previously rewarded actions, and the extent to which their learning is accelerated in these situations is dependent on the dopamine receptor density in dorsal striatum, a central structure in the dopaminergic circuit.” ”We are the first to demonstrate this organisation of dopamine D1 receptors in humans. We are also among the first to provide evidence of a direct relationship between dopamine receptor availability and learning from rewards.” What is the long-term significance of your research? “These findings provide important basic evidence of dopamine receptors' involvement in reward learning and decision-making and increases our current understanding of the dopaminergic system.” How did you perform the study? “We used positron emission tomography (PET) imaging, to detect dopamine D1 receptor availability. Then, we let people perform a simple task where they were instructed to learn to correct action (go or no-go) in response to four different stimuli. They were supposed to learn the correct action from the feedback they received (a reward or a punishment). We showed that people learned faster from "go" responses that were rewarded than any other type of trial, and that the extent to which this is true is related to dopamine receptors in the dorsal striatum.” The main supervisor of Lieke de Boer is Docent Marc Guitart-Masip, also last author of the current article. The research has been conducted with support from the Swedish Research Council, the Humboldt Research Award, the af Jochnick Foundation, and the Torsten and Ragnar Söderberg Foundations. Publication Dorsal striatal dopamine D1 receptor availability predicts an instrumental bias in action learning Lieke de Boer, Jan Axelsson, Rumana Chowdhury, Katrine Riklund, Raymond Dolan, Lars Nyberg, Lars Bäckman, Marc Guitart-Masip PNAS, online 18 December 2018, doi: 10.1073/pnas.1816704116

More than SEK 31 million from the Erling-Persson Foundation

Wed, 19/12/2018 - 13:01
Vaccination strategies against pneumococci, cardiovascular research with magnetic camera and an atlas over human cells – these are some of the research projects related to Karolinska Institutet that the Erling-Persson Family Foundation has chosen to support in 2018. More than SEK 31 million goes to four projects led by KI. In addition, KI researchers are included in another project led by KTH Royal Institute of Technology. The Erling-Persson Family Foundation mainly funds research in medicine and healthcare. Important selection criteria for the funding programme are that the research is translational, application oriented, and involves interdisciplinary cooperation. This year's grantees at KI:   Principal investigator: Birgitta Henriques Normark, Department of Microbiology, Tumor and Cell Biology Topic: Developing membrane particles for a vaccination strategy with broader effect than present ones against pneumococcal infections Grant: SEK 9 million over 3 years   Principal investigator: Anders Björkman, Department of Microbiology, Tumor and Cell Biology Topic: Malaria control at Zanzibar, Tanzania Grant: SEK 2 million, one year.   Principal investigator: Stefan Carlsson, Department of Molecular Medicine and Surgery Topic: Treatment against prostate cancer – PSMA/PET controlled treatment compared to conventional radiation therapy, a randomized study. Grant: SEK 7.5 million over 3 years (the study will be carried out at Cancer Center Karolinska).   Principal investigator: Lars Rydén, Department of Medicine, Solna Topic: Cardiovascular research with magnetic camera, MR Thorax Grant: SEK 12.7 million over 3 years.   Principal investigator (co-applicant): Sten Linnarsson, Department of Medical Biochemistry and Biophysics Main applicant: Joakim Lundeberg, KTH Topic: The Human Developmental Cell Atlas Grant: SEK 60 million over 4 years (for the entire project).

Karolinska Institutet's new research building Biomedicum is inaugurated

Tue, 18/12/2018 - 15:19
  November 30 marked the inauguration of Karolinska Institutet's new research building Biomedicum in Solna. The new building houses five departments and was designed to encourage interactions and collaborations between different research fields. Meet a few KI scientists in a video from the day of inauguration. The new 65,000 square meter research building has room for 1,600 researchers and was completed in the spring. The construction work started in 2013, and the move-in process has been implemented gradually over the course of 2018. “Biomedicum unites leading research groups from five different departments. These research groups can now interact across departmental boundaries and take advantage of modern infrastructure,” says the President of Karolinska Institutet, Ole Petter Ottersen. Biomedicum is located between Aula Medica and the Widerström Building and a skyway over Solnavägen directly connects the new structure to Bioclinicum, the clinical research environment at Karolinska University Hospital. With its proximity to Bioclinicum, the new hospital, SciLifeLab, Comparative Medicine and all the other research environments at Campus Solna and Campus Nord, Biomedicum will become a hub for KI's research and a leading international research center. At the inauguration, the Vice President of Karolinska Institutet, Karin Dahlman-Wright had the honor of cutting the ribbon. Byggindustrin magazine has nominated Biomedicum for “Building of the Year 2019,” and is owned and managed by Akademiska Hus. The interior designer was Nyréns Arkitektkontor and Skanska was the general contractor for the construction of the building.

High survival rate among children who have suffered from growth restriction

Tue, 18/12/2018 - 14:01
Almost all children live to see their eighteenth birthday despite a severe growth restriction, as long as they have survived their first month during infancy. This is indicated in a study by researchers at Karolinska Institutet, which is published in the journal PLOS Medicine. Reducing child mortality is one of the UN’s Millennium Development Goals, but the work is progressing slowly. Improved maternal health and a desire to reduce growth restriction during the foetal period could be two ways decreasing child mortality. Growth restriction in foetuses has previously been associated with an increased risk of stillbirth and increased mortality in the neonatal period, but whether or not growth restriction also has an affect on long-term survival in children is unclear. In the study in question, the researchers analysed the relationship between severe or moderate growth restriction and the risk of death later in childhood in a total of 3.8 million live-born children and 2.8 million siblings born in Sweden between 1973 and 2012. Increased risk of death among children with growth restriction The researchers examined the mortality in the range of one month up to eighteen years of age by comparing children who had suffered from growth restriction with children experiencing normal growth. Siblings were also compared, where one of them had been subject to growth restriction. Sibling comparisons make it possible to take into account a variety of environmental factors, such as socioeconomic factors and lifestyle as well as genetic factors from the mother, which may be important with regard to child mortality. Approximately 1 out of 105 children with severe growth restriction died before reaching their eighteenth birthday, compared to 1 out of 202 with moderate growth restriction and 1 out of 289 children with normal development. “This corresponds to 2.6 times or a 160 per cent increase in the risk of death among children with severe growth restriction, both when compared with all children experiencing normal growth and compared with siblings who had normal foetal growth. Moderate growth restriction during the foetal period was also a risk factor for death before reaching eighteen years of age, with these children having a 37 per cent increased risk,” says Jonas F. Ludvigsson, professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, and the study’s lead author. The highest risk of death was observed during the first year for children suffering from growth restriction, where infections and neurological disorders were the most common causes of death. “Growth restriction during pregnancy is not only dangerous for the newborn’s health but has also been associated with an increased risk of death later in childhood. But as a parent, you should still remember that even among children who have experienced severe growth restriction and made it past the first month, 99 out of 100 will get to celebrate their eighteenth birthday regardless,” says Jonas Ludvigsson. The study was funded with the support of Forte and Karolinska Institutet. Publication ”Small for gestational age and risk of childhood mortality: A Swedish population study” Jonas F Ludvigsson, Donghao Lu, Lennart Hammarström, Sven Cnattingius and Fang Fang PLOS Medicine, online 18 December 2018, doi: 10.1371/journal.pmed.1002717

Green leafy vegetables may prevent liver steatosis

Mon, 17/12/2018 - 21:00
A larger portion of green leafy vegetables in the diet may reduce the risk of developing liver steatosis, or fatty liver. In a study published in PNAS researchers from Karolinska Institutet in Sweden show how a larger intake of inorganic nitrate, which occurs naturally in many types of vegetable, reduces accumulation of fat in the liver. There is currently no approved treatment for the disease, which can deteriorate into life-threatening conditions such as cirrhosis and liver cancer. Liver steatosis, or fatty liver, is a common liver disease that affects approximately 25 per cent of the population. The most important causes are overweight or high alcohol consumption and there is currently no medical treatment for the disease. Researchers at Karolinska Institutet have now shown how a greater intake of inorganic nitrate can prevent the accumulation of fat in the liver. “When we supplemented with dietary nitrate to mice fed with a high-fat and sugar Western diet, we noticed a significantly lower proportion of fat in the liver,” says Mattias Carlström, Associate Professor at the Department of Physiology and Pharmacology, Karolinska Institutet. Their results were confirmed by using two different cell culture studies in human liver cells. Apart from a lower risk of steatosis, the researchers also observed reduction of blood pressure and improved insulin/glucose homeostasis in mice with type 2 diabetes. The research group’s focus is the prevention of cardiovascular diseases and type 2 diabetes through dietary changes and by other means. Previous studies have shown that dietary nitrate from vegetables enhances the efficiency of the mitochondria, the cell’s power-plant, which can improve physical endurance. It has also been shown that a higher intake of fruit and vegetables has a beneficial effect on cardiovascular function and on diabetes. “We think that these diseases are connected by similar mechanisms, where oxidative stress causes compromised nitric oxide signalling, which has a detrimental impact on cardiometabolic functions,” says Dr Carlström. “We now demonstrate an alternative way to produce nitric oxide, where more nitrate in our diet can be converted to nitric oxide and other bioactive nitrogen species in our body.” Even though many clinical studies have been done, there is still considerable debate about what properties of vegetable make them healthy. “No one has yet focused on nitrate, which we think is the key,” continues Dr Carlström. “We now want to conduct clinical studies to investigate the therapeutic value of nitrate supplementation to reduce the risk of liver steatosis. The results could lead to the development of new pharmacological and nutritional approaches.” While larger clinical studies are needed to confirm the role of nitrate, the researchers can still advise on eating more green leafy vegetables, such as regular lettuce or the more nitrate-rich spinach and rocket. “And it doesn’t take huge amounts to obtain the protective effects we have observed – only about 200 grams per day,” says Dr Carlström.“ Unfortunately, however, many people choose not to eat enough vegetables these days.” The study was financed by the Swedish Research Council, the Swedish Heart and Lung Foundation, Novo Nordisk, the European Research Council and Karolinska Institutet. Two of the authors, Jon O Lundberg and Eddie Weitzberg, are coinventors on patent applications related to the therapeutic use of inorganic nitrate. Magnus Ingelman-Sundberg is cofounder of the contract research organisation (CRO) HepaPredict AB. Publication “AMP-activated protein kinase activation and NADPH oxidase inhibition by inorganic nitrate and nitrite prevents liver steatosis”. Isabel Cordero-Herrera, Mikael Kozyra, Zhengbing Zhuge, Sarah McCann Haworth, Chiara Moretti, Maria Peleli, Mayara Caldeira-Diaz, Arghavan Jahandideh, Han Huirong, Josiane Cruz, Andrei Kleschyov, Marcelo Montenegro, Magnus Ingelman-Sundberg, Eddie Weitzberg, Jon O Lundberg and Mattias Carlström. PNAS, online 17 December 2018, doi: 10.1073/pnas.1809406115.

KI students won award for best environmental project

Wed, 12/12/2018 - 12:49
Students at Karolinska Institutet (KI) have, together with students from KTH and Konstfack, developed a method for cleaning wastewater from antibiotic and other drug residues before reaching the sea. The idea and prototype was presented in an international competition in synthetic biology, where the Stockholm team won the first prize in two categories. The Stockholm team, which is called iGEM Stockholm, participated in the annual competition in Boston, founded by MIT, in October. iGEM ​​Stockholm won gold and also became total winners in the “Best Environmental Project” and “Best integrated human practices” categories, which deals with how the project affects community needs and how to deal with aspects such as sustainability and ethics. iGEM ​​Stockholm focused on the Baltic Sea's problems with the release of antibiotics and drugs from wastewater. "We managed to show that laccase, an enzyme found naturally in yeast which breaks down wood, could break down antibiotics with well-prepared protocols and experiments. This, combined with our completed project where we went beyond the lab by integrating community and expert opinions and suggesting a product on the market, made us stand out from the rest of the teams in our track, says Els Alsema, a master student in the biomedicine program at KI. In the global scientific competition iGEM in synthetic biology, approximately 350 teams participated. The competition is being conducted during the summer with a final in Boston this fall. The student teams will solve any problem they formulate themselves, for example in therapy, diagnostics or the environment using molecular biology methods by applying their knowledge.

New method for studying ALS more effectively

Wed, 12/12/2018 - 07:00
The neurodegenerative disease ALS causes motor neuron death and paralysis. However, long before the cells die, they lose contact with the muscles as their axons atrophy. Researchers at Karolinska Institutet have now devised a new method that radically improves the ability to study axons and thus to better understand the pathological development of ALS. The method is described in the scientific journal Stem Cell Reports. All neurons have a fibre-like projection called an axon, and those of motor neurons can be extremely long – over a metre – as they have to stretch from the spinal cord to the muscles of the arms and legs. It is known that in ALS the motor neurons die “backwards” and lose functionality where the axon meets the muscle before gradually atrophying completely. By examining the presence of RNA in a cell, it is possible to discover which genes are switched on and off and thus the cell’s function and general condition. In long-axoned neurons, there is a buffer of RNA in the axon that enables them to quickly interact with their environment – e.g. muscle cells. Scientists are keenly interested in investigating the repertoir of RNAs in motor axons of healthy individuals and ALS patients to gain deeper insight into disease processes. However, this has proven to be very difficult as the amount of RNA in axons is minute. If just one single cell body gets into the axon study material, it will contaminate it with its own RNA, making it impossible to see what the axon’s RNA reservoir looks like. “We have now developed a greatly improved method for this called Axon-seq,” explains Eva Hedlund,  associate pofessor at the Department of Neuroscience, Karolinska Institutet. “It’s a relatively cheap, simple and highly sensitive method that we’ve described in detail in our study so that it can be used by other researchers interested in studying neuronal processes.” Examine motor neurons Her research group has used the method to examine motor neurons generated from mouse and human stem cells. Their results show that the axon’s reservoir of RNAs differs significantly from that of the cell body, which is a new discovery. The researchers also examined the transcriptome of ALS-diseased motor neurons and found that in neurons with the mutated version of the SOD1 gene that causes ALS, the axon’s RNA profile differed fromthat of healthy cells. “Many of the genes we found dysregulated in ALS are needed for the normal function of the axon and its contact with the muscle,” says Jik Nijssen, doctoral student and joint first-author of the study with Julio Aguila Benitez. “Many of these genes present possible targets for future therapies.” The study was financed by the Swedish Research Council, the EU Joint Programme – Neurodegenerative Disease Research (JPND), the Strategic Research Area in Neuroscience at Karolinska Institutet (StratNeuro), the Birgit Backmark endowment for ALS research at Karolinska Institutet in memory of Nils and Hans Backmark, the Åhlén Foundation, the Ulla-Carin Lindquist Foundation for ALS Research, the Magnus Bergvall Foundation, the Swedish Society for Medical Research and the Swedish Brain Fund. Publication Axon-seq decodes the motor axon transcriptome and its modulation in response to ALS  Jik Nijssen, Julio Aguila Benitez, Rein Hoogstraaten, Nigel Kee, Eva Hedlund Stem Cell Reports, online 11 December 2018, DOI: https://doi.org/10.1016/j.stemcr.2018.11.005.

Cured cancer patients in focus when Nobel Laureates lectured at KI

Tue, 11/12/2018 - 17:45
The Nobel Lectures held by the laureates of the 2018 Nobel Prize in Physiology or Medicine saw the Erling Persson Hall in Aula Medica at Karolinska Institutet filled to the brim. In addition to 1,000 audience members in the hall, people around the world were able to watch the live broadcast when James P. Allison and Tasuku Honjo talked about their research, the results of which have led to the ground-breaking immune checkpoint therapy for cancer treatment. The grey and drizzly December weather did not prevent expectant students and others from forming a queue that stretched down Solnavägen for a little over an hour before the Nobel Lectures in Physiology or Medicine began this year. Karolinska Institutet’s (KI) President Ole Petter Ottersen gave a welcoming speech and emphasised that tonight is a celebration of research that is about testing boundaries. He thanked the Laureates for their discoveries, after which Edvard Smith, KI Professor and member of the Nobel Committee, presented the Laureates in more depth with an introduction that provided both a personal and professional background. No biology without Darwin Smith spoke about James P. Allison, born in the United States in 1948, with an early interest in research and dissecting frogs, but with no inclination to follow in his father’s footsteps and become a physician. Allison was in jeopardy of not graduating high school after protesting his teacher’s decision not to teach evolution in class, because biology without Darwin was an impossibility. In the end, it was resolved through a correspondence course from a university, and Allison was able to proceed to higher studies and basic research within immunology. James P. Allison dedicated his lecture to all students, research colleagues, physicians and patients with whom he has worked. He spoke of how during the 1990s he had studied CTLA-4, a protein on the surface of the T cells. Early on, he had had an idea that it should be possible to deceive the body’s own immune system in order to attack tumour cells. Researchers at the time knew that CTLA-4 worked as one of the T cells’ brake pedals, and Allison developed a way to block CTLA-4 through treatment with an antibody that binds to the CTLA-4 protein. The T cells could then be released and thereby fight tumour cells. Cancer-free after receiving antibodies In 1994, Allison conducted the first experiment on mice, and in 2010 a study was published that showed good results in patients with disseminated malignant melanoma, or skin cancer. Among other things, Allison highlighted one case with a woman who was severely ill from skin cancer and who participated in a clinical study in 2001. No traditional cancer treatment had helped, and Allison shows a computed tomography image of her lungs which were full of metastases, or daughter tumours. The woman received a single antibody injection in the study. “At that point, the survival time after being diagnosed with metastatic malignant melanoma was eleven months, essentially a death sentence. In this computed tomography image ten years later we can see that all metastases in the woman’s lungs are gone. The woman is still cancer-free almost nineteen years later, it’s amazing,” says James P. Allison. The school thought his questions were too difficult Edvard Smith continued to introduce the second Nobel Laureate, Tasuku Honjo, born 1942, who grew up in Japan in difficult conditions surrounding World War II, yet still managed to educate himself. Like Allison, his time as a student at school was not without its complications. The teachers did not think that he was a good, obedient student because he often asked questions that were too difficult and found the school books to be too easy.  Tasuku Honjo likes music, museums and painting, tells Smith. He is also a devoted practitioner of tennis, baseball, basketball, table tennis and golf, with a handicap of 14. Every year he plays golf with the former Nobel Laureate from 2012, Shinya Yamanaka. To start with, Tasuku Honjo spoke about his father who was a surgeon and described his mother as his beautiful, warm-hearted guardian goddess. It was when the mother gave Honjo a biography of Hideyo Noguchi, a prominent physician and researcher in bacteriology and serology, that he decided to become a physician and then a researcher in immunology. “It’s a stroke of luck that people are fortunate enough to have an immune system with acquired immunity. Otherwise, cancer immunotherapy would have been an impossibility,” says Tasuku Honjo. Discovery of a protein with the same type of brake pedal In parallel with James P. Allison, Tasuku Honjo discovered that another protein, PD-1, which is also found on the surface of T cells, also acted as a brake pedal for the immune system. Animal experiments showed that blocking PD-1 was another possible strategy for cancer therapy.  The strategy proved to be very effective during clinical trials in 2012 and can be used to treat, for example, lung cancer, renal cancer, lymphoma and skin cancer. Additionally, a combination of blocking both PD-1 and CTLA-4 in skin cancer has been shown to have an even greater effect. As with Allison, Honjo referred to several cases where patients who had been close to death due to severe cancer had been cured using antibody therapy. Chart after chart depicts the levelling out of curves with increasing long-term survival. Paradigm shift within cancer therapy Tasuku Honjo described the arduous journey undertaken to understand the function of PD-1 and how the knowledge can be used. He compared the mechanisms of being able to brake and accelerate the immune system with the same functions in a car. At the same time, it is a tightrope act that must be performed when treating cancer with this method. “If you accelerate too much during cancer treatment, there is a risk that the body will have an autoimmune reaction and begin attacking itself,” says Tasuku Honjo. He proceeds to talk about the paradigm shift now taking place within cancer therapy. In addition to surgery, radiotherapy and chemotherapy, immunotherapy has been established as a fourth cornerstone in cancer treatment. The benefits, among other things, are that normal cells are not affected by the method, it is effective for many types of cancer (and more than 1,000 clinical trials are ongoing around the world) and the effect is lasting even after the treatment of patients has been discontinued. “Cancer will not completely disappear, but it can be controlled using immunotherapy, and it may become one of the many other chronic diseases that you can live with,” says Tasuku Honjo, who finished by humbly thanking all he had collaborated with through the years. Text: Helena Mayer  

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