Better medicine against glioblastoma cancer A MAGAZINE FROM SCILIFELAB
#2 –– 2018
More Inside Getting close to solving the mystery of the salamander’s unique abilities Birth – vital to the immune system Mapping the mystery of aging Deeper knowledge of new-found bacterium
Delving deeper into
textile recycling
Foreword Research communities show SciLifeLab’s way forward
Photo: Mikael Wallerstedt
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o be able to offer Swedish researchers invaluable life science technologies and expertise, we continuously work to develop SciLifeLab’s infrastructure. Helping us in this task are our fantastic researchers and experts in the facilities, internal committees and host universities, as well as a national committee and an international advisory board. The national committee consists of representatives from universities with SciLifeLab infrastructure outside of the Stockholm-Uppsala region, while the international advisory board comprises leading life science researchers from universities around the world. This international board has visited SciLifeLab on two previous occasions and, in spring 2019, they will return to once again evaluate operations and advise on the continued development of the infrastructure. In other words, a very rewarding visit with invaluable advice is coming up! In this issue of Synergy, you can read about how many of the technologies SciLifeLab provides have benefited the Swedish research community. We hope that it will give you some ideas about how you can use our services in your own research. Meet Anna Peterson at Chalmers University of Technology, who is trying to find new methods to recycle textiles, a topic increasingly important to both the fashion industry and consumers. András Simon at Karolinska Institutet also tells us about his work on mapping the genome of the salamander, which has proven to be a full six times larger than mankind’s! We also meet Ulf Bremberg, Chief Scientific Officer at Beactica, the company that received help from SciLifeLab to identify a substance that may lead to new treatment opportunities for patients with an aggressive form of brain tumor.
Editorial staff
Synergy is a magazine about research, published by SciLifeLab twice a year in Swedish and in English. The magazine may be ordered free of cost, or read online at scilifelab.se/infrastructure/synergy Editor: Karin Nedler Editorial committee: Camilla Breiler, Lars Johansson, Susanna Appel Design and production: zellout.se Printing: Danagård Litho Contact: synergy@scilifelab.se
Tag along! Annika Jenmalm Jensen, Infrastructure Director, SciLifeLab annika.jensen@scilifelab.se
SciLifeLab (Science for Life Laboratory) started its activities in 2010 as a collaboration between KTH Royal Institute of Technology, Karolinska Institutet, Stockholm University and Uppsala University. In 2013, SciLifeLab was commissioned by the Swedish government to create a national center for molecular biosciences. The aim was to be able to offer researchers throughout Sweden access to technology and expertise for advanced research at a reasonable cost. SciLifeLab is fully integrated into the universities’ activities and is non-profit. Its vision is to be a national hub for molecular biosciences. Today, more than one thousand research teams use the center’s services every year.
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A magazine from SciLifeLab
Contents 05 11 16
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12 15
#2 –– 2018 02 / Foreword
06 / Reportage
14 / Insight – Cancer
Research communities show SciLifeLab’s way forward
Love for clothes and chemistry led to research on textile recycling
Better medicine against glioblastoma cancer
04 / In brief
11 / Insight – the Immune system
Deeper knowledge of new-found bacterium
Mobilized expertise, germ cells’ cell division and SciLifeLab at LinkedIn
Birth – vital to the immune system
05 / Insight – the Salamander
Mapping the mystery of aging
Getting close to solving the mystery of the salamander’s unique abilities
A magazine from SciLifeLab
12 / Portrait
15 / Insight – Bacteria 16 / Hello there! Mattias Jakobsson, whose team has discovered that modern man has existed twice as long as researchers previously thought
Synergy #2 –– 2018
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In brief Did you know that during 2017, the SciLifeLab facility NGI (National Genomics Infrastructure) has had about ...
All scientific publications associated with each article in Synergy can be found at scilifelab.se/infrastructure/ synergy
Photo: Johan Spinnell
500 13 individual users, plus
Male and female germ cells’ cell division
types of instruments for nextgeneration sequencing and genotyping, and has processed
49 478 32 sequencing samples, and organized
educational activities.
Ana Agostinho and Christer Höög at Karolinska Institutet have investigated how male and female germ cells differ in their machinery for sorting genetic material during cell division. The image, taken by SciLifeLab’s Advanced Light Microscopy facility and Ana Agostinho, Karolinska Institutet, shows spermatocytes from mice imaged with Stochastic Optical Reconstruction Microscopy, STORM.
Save the Date SciLifeLab Science Summit 2019, May 15, Uppsala. Follow program updates on scilifelab.se
Connect with us!
@SciLifeLab at LinkedIn
Express your opinion! What would you like to read about? Tell us at synergy@ scilifelab.se
Photo: Mikael Wallerstedt
Expertise and technologies mobilized around seven research themes
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To facilitate internationally competitive, cutting-edge collaborative research, SciLifeLab supports seven Research Community Programs – networks that connect top researchers across Sweden with each other and with the SciLifeLab infrastructure. In 2018, SciLifeLab launched a national call for Research Community Programs (RCPs) and seven applications from different research areas were approved by the SciLifeLab board. These programs will receive one MSEK/year over a three-year period for coordination, scientific interaction and community-building around their respec-
tive topics. Examples of supported research areas include precision medicine, tumor microenvironments and aquatic microbiomes. “I am delighted that we have approved funding to the seven first RCPs and thereby defined key scientific areas across the SciLifeLab community”, says Olli Kallioniemi, Director of SciLifeLab. “Our infrastructure will continue to be open and accessible to all scientists in all areas. However, these and future RCPs represent a new way to connect the best scientists in the country with each other and with the SciLifeLab infrastructure”.
A magazine from SciLifeLab
Insight
Text: Lisa Thorsén / Photo: Mikael Wallerstedt
Getting close to solving the mystery of the salamander’s unique abilities A research team at Karolinska Institutet recently succeeded in mapping the Iberian ribbed newt’s complete genome. With new analysis methods, they have come closer to understanding the amphibian’s unique ability to heal injuries and regenerate lost body parts.
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alamanders are known for being masters of regeneration, recreating not only lost tails and other extremities, but also heart and brain tissues, for example. András Simon, Professor of Cell and Molecular Biology at Karolinska Institutet, has studied salamanders for more than 20 years. His research team has previously shown that salamanders can recreate all dopamine-producing nerve cells in the midbrain in one month. If the corresponding nerve cells die in humans, they never grow back, which is the main cause of Parkinson’s disease. In their current project, the researchers are delving deeper into the mystery of regeneration. Since the salamander’s genome is much larger than mankind’s, mapping it has been a major challenge. “The most exciting part of this project is the actual analysis of sequence data. We already know a great deal about the salamander’s regenerative ability, but we have not had enough molecular information to understand how the regeneration process takes place. Now we have come closer to this realization,” says András Simon. The finding he particularly highlights is the discovery of a large number of copies of a special type of microRNA that in mammals mostly exists in embryonic stem cells and cancer cells. This microRNA can reprogram regular cells into pluripotent stem cells, which can further develop into several different cell types. “We see that the activity in these microRNA molecules increases as a response to injury, which is interesting especially in terms of wound healing. Now we are conducting functional studies and additional DNA analyses with the aim of understanding what happens in the healing processes and with what target genes this group of microRNA interacts.”
András Simon is performing basic research, but his work evokes many questions about what it may lead to. Will the understanding of the salamanders’ ability to regenerate dopamineforming nerve cells lead to new treatments for patients with Parkinson’s disease? Are novel therapies for patients with burn injuries on the way? Is it possible to even regenerate a lost arm? “Our goal is to understand more and our findings certainly have potential, but we are far from clinical trials. Hopefully, we will eventually be able to identify some key mechanisms that are crucial in terms of finding new strategies in regenerative medicine,” says András Simon. It was Manfred Grabherr, now active at National Bioinformatics Infrastructure Sweden (NBIS), SciLifeLab’s platform for bioinformatics, who helped András Simon’s research team to analyze the Iberian ribbed newt’s genome. “Above all, what we have done is to create an environment where researchers with various backgrounds work together. For example, András is an expert in functional evolutionary biology while I am a bioinformatics specialist with a background in software development and physics. Involving researchers with different backgrounds in the same project opens up access to expertise that a single research team may lack,” says Manfred Grabherr.
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Technology and service This project was supported by, among others, the National Bioinformatics Infrastructure Sweden (NBIS), which assisted in the analysis work. It also received valuable support from the diversity of research expertise offered by SciLifeLab’s network.
Synergy #2 –– 2018
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Reportage
Love for clothes + chemistry = Research on textile recycling
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AA magazine magazine from from SciLifeLab SciLifeLab
Anna Peterson performed the first experiments in what later developed into the process Blend Re:wind, a unique way of recycling blended polyester and cotton fabrics. “I fell in love with this field of research! It feels both meaningful and timely.” Text: Lisa Thorsén / Photo: Mikael Wallerstedt
A magazine from SciLifeLab
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nna Peterson works at Kemigården 4 at Chalmers University of Technology’s campus in Johanneberg, Gothenburg. It is clear that she feels at home with the university’s motto: ‘Chalmers – for a sustainable future’. Today, she is earning her PhD in material science by researching the cellulose-reinforced thermoplastic composites used in many industries that require light, strong and environmentally-durable components. In the Blend Re:wind project, she also worked with blends of cellulose and synthetic polymers, although it then concerned an entirely different material, namely textile fibers. The early experiments that later developed into Blend Re:wind were part of Anna Peterson’s Master’s thesis project. When the results were published, neither scientific articles describing similar results nor any patents could be found. The process was unique. “It’s really fun that the experiments were so successful. When it turns out that the results can be applied, research is fantastic. For me, the results were extra exciting since the work was part of my thesis project. In that kind of work, you’re often just a cog in the wheel, with less autonomy and no guarantee of publication. I probably saw it more as an exercise in research rather than the ‘real thing’ and had no expectations about the results,” explains Anna Peterson. The project gave her interest in chemistry an extra dimension. “I love everything to do with clothes, but at the same time, I have a problem
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with the throwaway culture. So, having been involved in a project that may help us to actually recycle part of our clothes feels really good.” The majority of the textiles we use today comprise either cotton or polyester. A lot also consist of a blend of these materials, such as the large volumes of sheets and towels that are used in healthcare and the hotel sector. “It is the large volumes in these sectors that make the textiles extra interesting from a recycling perspective,” says Anna Peterson. In general, we are not particularly good at giving textiles several lives. Today, much of what we dispose of is burned or put in landfills. There are still no large-scale processes for recycling cotton and polyester blends. Finding solutions to achieve this goal is usually described as the search for the fashion industry’s holy grail. Seeking ways to chemically separate the fibers has attracted the attention of several players. As early as 2011, Mistra Future Fashion, one of the world’s largest research programs about recyclable fashion, initiated the work that has now led to the unique separation process Blend Re:wind. Researchers from Chalmers, the Swedish national research institute RISE and the forestry industry company Södra participated in the initiative. The project, led by Hanna de la Motte, who works both at RISE and within Mistra Future Fashion, resulted in several scientific publications. Anna Peterson did her Master’s thesis within the scope of the project and Anna Palme, also from Chalmers, did her PhD on it. In Blend Re:wind, cloth consisting of a cotton and polyester blend is recycled in three circular product streams. The cotton
goes in one stream and is recycled into viscose filaments that can either become cloth made of viscose or of lyocell. The separated remnant from polyester goes into two streams and emerges as new polyester. The next step in the project is to scale up the process from lab to industry. Blend Re:wind has been developed with the aim of being integrated into industrial processes that are already in place within the paper pulp industry or other sectors. In this way, both the environmental and financial costs will be minimized. In what phase did you join the project? “In the first experiments, when we needed to see if the idea worked at all. I mainly worked on the separation part where we wanted to separate the polyester without ruining the cotton. Cotton is namely a natural polymer, and if we reduce it to small pieces, we cannot make a new fiber out of it. Polyester, on the other hand, is a synthetic polymer. When we take it apart, a functioning system for building it up and making a fiber out of it again already exists.” Together with Anna Palme, Anna Peterson then developed the method for material separation, a key aspect of which was to discuss and decide what parameters were of interest to change – time, water temperature and chemical content – and then test them in relation to each other. In the experiments that led to Blend Re:wind, sheets and towels from the service sector were used. At the SciLifeLab facility Swedish NMR Centre, some of the material characterization was done with NMR (nuclear magnetic resonance) technology. Pure cotton, pure polyester and sheets of both cotton and polyester were studied. This characterization provided a ‘fingerprint’ for each of the three materials.
“It’s really fun that the experiments were so successful. When it turns out that the results can be applied, research is fantastic.” A magazine from SciLifeLab
Reportage
In the Blend Re:wind project, Anna Peterson worked mainly with separating the polyester without ruining the cotton. Cotton, which namely is a natural polymer, can not be made into a new fiber if it has been taken apart.
Diana Bernin at the Swedish NMR Centre was one of those who assisted the project. “We can provide the expertise the researchers need and help them ask the right questions. In this case, we used NMR technology to verify that the investigators actually had the materials they thought they had before the experiments began, and afterwards to see what they had obtained. They wanted to be sure there were no detectable impurities,” she says. In the experiments, which began in 2014, Anna Peterson worked with extremely small pieces of sheets that were ground down so that as much of the sample as possible could react with a solution of hot water and sodium hydroxide (lye) in the presence of a catalyst. In experiment after experiment, she studied the same parameters in order to find the right balance that gave optimal cotton fiber quality. How much chemicals should be used? How hot should the liquid bath be and for how long should the cloth soak?
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What was it like, doing all these experiments? “It’s exciting since we are constantly trying out ideas that we can either confirm or discard. We have a main hypothesis about how we should separate cotton from polyester. Based on that, we formulate small hypotheses around, for example, whether we will get cotton remnants out of the solution and, if so, how we will detect them and with what accuracy.” Anna Peterson is intrigued by both fashion and the recycling vision and feels
that Mistra Future Fashion is making a strong contribution by looking at every aspect of the industry – from raw materials production to recycling. If products are to be recycled and reused, both designers and manufacturers need to think about it long before actual production begins. When fashion designer Ralph Lauren said that he does not design clothes, but rather dreams, he probably did not have recycling in mind. But high-flying quotations can gain new, more earthly meanings. ➔
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Reportage
Did you know that... According to the Swedish Society for Nature Conservation, Swedes buy on average around 13 kilograms of textiles per person per year, and the average lifespan for an item of clothing is just over two years. Cotton accounts for 40–50 percent of the world’s textile fibers, at the same time as every kilogram of cotton requires 10,000–30,000 liters of water while the crops themselves are located in dry areas that suffer from water shortages. Regarding polyester, it is most often made of fossil oil that is non-renewable, and the fiber cannot be broken down naturally in nature. Source: Swedish Society for Nature Conservation
Anna Peterson is very interested in clothes, but she does not believe a society unlimited in terms of consumption creates lasting happiness. Instead, she thinks we need to consume less and reduce our environmental footprint.
“A society unrestricted in terms of consumption and economic growth does not create lasting happiness.”
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“Of course, products are designed for use, but it’s necessary to also have recycling and reuse in mind. In terms of chemical recycling, we generally need to have very pure fractions for it to work.” Extending the life of clothes by simply using them longer is one way for consumers to avoid overly depleting the earth’s resources. Anna Peterson and her friend tried to cut back on clothing purchases when they realized that we annually buy an average of 50 items of clothing per person in Sweden. They wanted to give away clothes and shop less. “Fifty items of clothing sounds crazy, but when we started to look at what we buy ourselves, it was pretty accurate. We then tried to radically cut back on the amount of clothes and have no more than forty items in our closets, but it was hard. I got the feeling that there was nothing left.” How much do you think about your own buying behavior? “Quite a bit. If I want to have any credibility when I say that the research I conduct has a positive environmental impact, it has to fall in line with what I do myself.” So, Anna Peterson sees two mindsets. One says that new technology will solve everything so that we achieve emission neutrality in our transport sector as well
as electricity and commodity production. Then we could continue consuming without it affecting the environment negatively. The other mindset says that we have to limit ourselves in order to reduce our environmental footprint – fly less, drive less, consume less and eat more vegetarian food. “I feel more at home with the latter approach. I doubt that an unlimited society would be the happiest. A society unrestricted in terms of consumption and economic growth does not create lasting happiness. If we instead would have been unlimited in our consideration of other people and taken the earth’s resources into account, we would not have had the same problems.” Even though Anna Peterson has completed her work with Blend Re:wind, she is still very interested in the project. And through her doctoral studies in material science, she is given many opportunities to think about recycling. “It’s extra fun to work with material development if you also consider recycling.” Technology and service Swedish NMR Centre assisted this project by analyzing the textile materials.
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Insight Text: Henrik Möller / Photo: Mikael Wallerstedt
Birth – vital to the immune system The immune system’s adjustment from the mother’s womb to the world outside is the most revolutionary in life, according to pediatrician and researcher Petter Brodin. “The adaption of newborn children’s immune system is vital, just like it’s vital that they open up their lungs and begin to breathe.”
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etter Brodin has previously
shown that it is almost solely environmental factors, such as bacteria, viruses and diet, rather than hereditary factors, that determine how our immune system develops. In an on-going project, his research team is studying how children’s immune systems develop from birth to three years of age. One hundred children are participating in the study. “We hope that the results will eventually be able to help give all newborns’ immune systems an optimal start in life and prevent many of the allergies and inflammatory conditions that today are caused by incorrectly calibrated immune systems,” he says. Previous studies have been based on blood from the discarded umbilical cord. The problem is that the umbilical cord is removed before the immune system has had time to develop a sense of its new environment outside the mother’s uterus. “An incredible number of immunological events occur in the first hours and days of life. So far, we have studied this development in the child’s first three months and we see that things are happening all the time.” Petter Brodin’s team discovered that at birth, children’s immune systems undergo a transformation to adapt to the billions of bacteria and viruses that surround us. The researchers studied both full-term and prematurely-born babies, as the latter have a higher risk of severe infections
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as well as inflammatory complications. “However, we were surprised to see that the children in both groups followed the same rapid development after birth, and that their immune systems were similar at just a few days age.” So far, the study indicates that the development of the immune system follows a strict pattern in all children. How well the transformation goes depends on when the birth takes place, if the child is delivered through cesarean section or vaginally, and what bacteria and other environmental factors it encounters during its first few days of life. “We already know that the bacteria to which newborn children are exposed will differ and we also know that the risk of immune-mediated diseases, such as allergies and type-1 diabetes, is higher with cesarean sections.” The study shows that the immune system’s transition is mainly driven by bacteria, from, for example, the intestinal flora. “With vaginal delivery, the child first encounters bacteria from the mother’s birth canal and intestinal flora. If born by c-section, the child instead first encounters bacteria from the parents’ or the hospital staff’s skin. This is probably not optimal. On the other hand, c-section can be life-saving,” Petter Brodin points out.
This type of study of the complex immune system has become possible only recently due to a new analysis technique
called mass cytometry, which is available at SciLifeLab’s facility Mass Cytometry. Petter Brodin is in charge of the facility, where millions of white blood cells can be analyzed simultaneously. “Thanks to mass cytometry, we can detect around 50 different markers and proteins for each white blood cell. The measurements tell us something about what cell type and cell subcategory we are dealing with, if the cells are activated or not, if they are dividing, and if they are stressed or dormant.” The technology thus enables the researchers to study what biological processes are activated at different time points, which helps them understand the underlying mechanisms. In the future, this knowledge can hopefully be used to rectify immune systems that have deviated from their preprogrammed development. “Perhaps in the future we can develop a test that senses if the child’s immune system doesn’t follow the predetermined ‘choreography’ and, if so, administer vaccines, certain bacteria or nutrients that get the child back on track again,” says Petter Brodin optimistically.
Technology and service Mass Cytometry assisted with cell analysis technology and advanced blood analyses. Plasma Profiling helped generate and interpret high-dimensional plasma proteomic data.
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Portrait
Text: Henrik Möller / Photo: Mikael Wallerstedt
Mapping the mystery of aging With new technology, Maria Eriksson’s research team has found thousands of stem cell mutations that give rise to our normal aging. In the long run, the discovery may contribute to new drugs and exercise programs that can help the body keep diseases at bay in the later years.
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ver since her doctoral studies in neurology at Karolinska Institutet, she has focused on genes and genetics and dreamed about leading her own research team. “I have always wanted to have an opportunity to cultivate my own thoughts and ideas. Therefore, there was just one alternative, and that was to move abroad and earn more qualifications,” says Maria Eriksson, Professor at the Department of Biosciences and Nutrition at Karolinska Institutet. She traveled to the National Institutes of Health in Bethesda, US, for a post-doc position and came into contact with genetic research on aging. During her time there, Maria Eriksson discovered the gene that causes progeria, a rare disease that causes premature aging. When she returned to Sweden in 2003, the extensive interest in her work enabled Maria Eriksson to form her own research team. How does it feel to lead your own team? “It’s such a privilege. I love my job. Thinking freely, innovatively and ‘outside the box’ and sharing ideas with competent and committed people is extremely stimulating.” You have recently published an article in Nature Communications about mutations in skeletal muscles. What did you discover? “Above all, that there are more mutations than previously known. A healthy 70-year-old’s skeletal muscles carry more than 1000 mutations in every stem cell. But certain regions in the genome – those important to the cell’s function or survival – are more protected from degradation. However, this protection, which enables the cells to repair their DNA, declines with age. We don’t yet know exactly how or why.” Can aging be postponed? “Our research is more about creating keys so that we will be
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able to have good quality of life in an aging population for as long as we live. This is important basic research that hopefully enables us to prevent age-related diseases. In the future, it might be possible to prevent certain kinds of cancer by understanding the mechanisms that lead to the mutation accumulation and then limiting them. We cannot affect the actual aging process in itself.” Why has nobody done this before? “The technology for this kind of massive mapping of mutations in stem cells simply didn’t exist. If you look at two stem cells next to each other, they have thousands of different mutations; it’s complex and their structure is extremely heterogeneous. Today, we can map this structure with new sequencing technology at SciLifeLab.” How did you collaborate with SciLifeLab? “We sent DNA samples to SciLifeLab for sequencing. SciLifeLab offers expertise and covers the labor costs, we only pay for the reagents needed. We also received very valuable support from NBIS in Linköping, Uppsala and Umeå for the bioinformatics analysis work.” Björn Nystedt is in charge of Bioinformatics Long-term Support, a facility of National Bioinformatics Infrastructure Sweden (NBIS), SciLifeLab’s bioinformatics platform. Here, experts combined and adapted software to study mutations and mutation patterns in individual cells. “The results have provided exact positions in the genome where it is possible to see how one cell differs from all other cells,” he explains. Björn Nystedt thinks the project is a good example of how SciLifeLab can collaborate with research teams that have not previously worked with large-scale sequencing projects. “We provide not only the technology, but can also raise the level of knowledge in the analysis work,” he says.
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Karolinska Institutet’s building in Flemingsberg where Maria Eriksson’s team works is new and aptly named Neo. Laboratories and office spaces are bright and colorful, and the team’s own office smells of newly unpacked plastic. Behind a generously-dimensioned window, birch trees with leaves already yellow after the dry summer sway in the wind, and on the table, there is a bundle of A4 pages with comments in the margin. “We have now proceeded with a study that maps mutations in kidneys, adipose tissue and skin. Soon it’s time to submit it for publication,” she explains. The new samples of tissue from kidneys and fat have been taken from individuals through collaboration with clinical researchers from the transplant unit at the Karolinska University Hospital in Huddinge. Here, healthy volunteers donate one of their kidneys, often to a relative. “We have benefitted from the kidney, fat and skin samples coming from the same individuals. This is very interesting since they then have the same environmental exposure.” By studying the entire genome, the researchers discovered signs that stem cell populations have different numbers of mutations that follow different patterns. Now, Maria Eriksson wants to go further and sequence cell samples from individuals who have undergone different exercise programs. The hypothesis is that an individual can affect the formation of new cells, and thereby his or her own mutation burden, by exercising. “Is it beneficial for the elderly to exercise and ‘clean out’ stem cells that collect too many mutations? We hope to find out.”
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“In the future, it might be possible to prevent certain kinds of cancer by understanding the mechanisms that lead to the mutation accumulation and then limiting them.” Technology and service National Genomics Infrastructure (NGI) assisted this project with DNA libraries, whole genome sequencing and bioinformatics support. National Bioinformatics Infrastructure Sweden (NBIS) contributed with further analyses and expertise.
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Insight Text: Henrik Möller / Photo: Mikael Wallerstedt
Better medicine against glioblastoma cancer Glioblastoma cancer is an aggressive form of brain tumor with a poor survival prognosis for those afflicted. The Uppsala-based company Beactica is aiming to develop a substance that forces the tumor’s stem cells to enter apoptosis – a programmed cell death.
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atients with the cancer form Glioblastoma Multiforme (GBM) live, on average, for 15 months after they have been diagnosed. The first counter-measure is usually to surgically remove the tumor, but it is difficult to get rid of all cancer cells. Further treatment with Temozolomid, the most common therapeutic agent for glioblastoma cancer, kills a large number of the cancer cells that remain after surgery, but resistent cells survive and most often lead to the tumor growing back. The substance that Beactica is developing into a drug, a modulator of the target protein LSD1, may be the solution to this problem. This substance has been tested on more than 50 cancer types and has proven to be particularly effective on glioblastoma cancer cells. “It is specifically on resistant cancer stem cells – those with the ability to re-establish a more difficult-to-treat tumor – that our substance is most effective,” explains Beactica’s Chief Scientific Officer Ulf Bremberg. “Beactica’s LSD1 modulator forces the cancer stem cells to enter apoptosis, a programmed cell death.” The company’s LSD1 modulator project, which began in 2013, has received support from Vinnova and the EU fund SME Instrument and is being conducted
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in collaboration with Uppsala University and SciLifeLab. With extensive experience from the pharmaceutical industry, Ulf Bremberg knows that a lot of work remains on the road to an approved drug. “I know that we have found something valuable, but it’s hard to know if it will lead all the way to a drug. Either way, I’m convinced that these substances may be useful to treat cancers, and GBM is a pressing disease to begin with.” Developing a drug is a strictly regulated process that usually takes 10 to 12 years. “Optimistically, I see a clinical trial on patients around 2019–2020, but a lot has to happen before then. We’ve seen what we can do with cultured tumor cells, but we also need to show that our substances can cure this kind of cancer in animals. The results from a very exciting glioblastoma study in mice are expected this autumn.” Beactica was founded in 2006 based on research at Uppsala University, and the company has developed a unique drug discovery platform based on measuring extremely weak interactions between target proteins and small fragments of drug-like molecules. By studying the binding of disease-relevant proteins and small pieces of molecule
fragments, promising fragments can be identified, optimized and gradually transformed into drug candidates using medicinal chemistry. “We can detect very weak protein-fragment interactions. Then we put the jigsaw pieces of fragments together to build complete drug molecules that then need to be adjusted many times to ultimately become an approved drug,” says Ulf Bremberg. It was when research on epigenetics gained speed in the early 2010s that Beactica began studying the target protein LSD1. Epigenetics relates to changes in gene expression that are independent of the DNA sequence and serves as a link between heredity and environment. “Epigenetics is like a layer on top of DNA. Our substances that affect LSD1 disrupt the cancer cells’ epigenetic machinery so that they die,” Ulf Bremberg explains. A future LSD1 modulator drug may be extra beneficial in combination with an immunological preparation of the type that has recently revolutionized cancer treatment by triggering the immune system to attack the cancer tumor. A synergistic effect with several factors that interact, according to Ulf Bremberg. In the on-going work of developing
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the drug, several factors are motivating. “If this discovery can help thousands or millions of people who would otherwise die, it is very meaningful. It’s also intellectually stimulating to be part of this journey. It literally stretches our researchers’ capability and creativity to the limit of what we can achieve.” In the project, Beactica has collaborated with several facilities of SciLifeLab’s infrastructure, including In Vitro and Systems Pharmacology which has been crucial to the project. Head of Facility Vendela Parrow has assisted the project by studying how the substances affect cell cultures from different tumors.
“Determining dose and time correlations is important in drug development. We provide several different methods to measure cell death as a function of time and we analyze changes in the gene expression of cells to understand how the substances work,” she says. Ulf Bremberg is pleased with the overall collaboration. “The collaboration with SciLifeLab is very important to us. SciLifeLab has a critical mass of researchers with expertise and advanced equipment that can make a difference for Sweden as a whole – both industry and academia. We could not have done this without SciLifeLab.”
Technology and service In Vitro and Systems Pharmacology supported this project with studies of functional mechanisms and cellular effects. Cell Profiling and the former SciLifeLab facility Fluorescence Correlation Spectroscopy contributed with mechanistic analyses. The facilities Protein Expression and Characterization and Biophysical Screening and Characterization assisted with instruments.
Insight Text: Lisa Thorsén / Photo: Adobe Stock
Deeper knowledge of new-found bacterium Christine Wennerås and her colleagues were among the first in the world to discover the tick-borne bacterium Candidatus Neoehrlichia mikurensis in humans. These bacteria can cause severe difficulties, especially among people with impaired immune systems. The researchers have now got up to speed in the work of building up the actual bacterial chromosome. Christine Wennerås is a doctor and researcher in infectious diseases and hematology at the Sahlgrenska Academy at the University of Gothenburg. It was in 2009 that she came across a case where an older man with an impaired immune system fell ill during a canoe outing. He had been struck by acute diarrhea and fever and had lost consciousness. Once at the hospital, it was also discovered that he had several blood clots. The patient sought emergency care numerous times during the following months, but despite suspicions of infection, no microbe was found. It was through PCR technology that Christine Wennerås’ research team ultimately succeeded in discovering a large amount of bacterial DNA in the patient’s blood. She was, however, puzzled. Here was
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a bacteria that she did not recognize. When the DNA was matched against a web-based gene bank, it turned out that the disease-causing agent had previously only been detected in ticks and rats, never in humans. The sensation was a fact – the man had been struck by a previously undiagnosed infectious disease. The causal bacteria, estimated to be present in approximately one tick in ten, can be effectively eliminated with the right antibiotic therapy. “Since this discovery, we have managed to determine the sequences for six bacterial genes. But it has been hard to make further progress since so far the bacteria have been difficult to culture,” explains Christine Wennerås. What’s more, the bacteria need to grow inside cells. So for the sequencing to be successful, the researchers need to have sufficient material and also be able to determine what DNA belongs to the bacterium and what doesn’t. Per Sikora at SciLifeLab’s Clinical Genomics facility in Gothenburg has supported the project with bioinformatics expertise. Specifically, he has developed a method to identify and put together small amounts of bacterial DNA in the extensive amounts of data generated by next-generation sequencing, the new technology for DNA sequencing.
“One of the things we’ve done is to tag bits of DNA in new ways prior to sequencing, so that we know what DNA strand they come from. Then it’s quite clear what belongs to the bacteria’s DNA and what doesn’t. We haven’t heard of anyone else using this technique the way we are, so it feels exciting,” he says. Now the researchers are building the actual bacterial chromosome. “We are incredibly happy that we can do this on site in Gothenburg and learn together. There’s infinitely much more that we still don’t know about this bacteria and it’s fantastic to be able to study it in greater detail. I can compare this with putting together hundreds of thousands of jigsaw puzzle pieces. We now hope that we will be able to learn how the bacteria cause disease and to develop diagnostics to discover it,” says Christine Wennerås.
Technology and service Clinical Genomics provided bioinformatics support and customized equipment so that it could be applied to the study. The facility also prepared the DNA libraries and helped with sequencing and analysis.
Synergy #2 –– 2018
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Hello there! Text: Henrik Möller / Photo: Mikael Wallerstedt
Mattias Jakobsson ... ... Mattias Jakobsson, Professor of Genetics at Uppsala University. Your research team has discovered that modern man has existed twice as long as researchers previously thought. How did you go about this?
“What we did was to extract DNA from individuals living 2000 years ago and belonging to the San people, a population in southern Africa. We expected their DNA to be nearly identical to today’s San people, but this was not the case. San people today have additional genetic material from groups who migrated southwards from East Africa around perhaps 1500 years ago. Thus, previous estimates of how long modern man has existed appear incorrect. Based on this premise, our next step was to recalculate.” How did you do that? “By using calculation methods specific for population genetics, we were able to estimate how far back in time the branching among populations in mankind’s family tree stretched. Simply put, we compared DNA from two individuals and looked at when their oldest common relative lived. Previous comparisons were based on DNA from today’s San people, but since the individuals who
lived 2000 years ago lacked the East African genetic material, we based our comparison on their DNA instead. Then the figures turned out entirely different.” What conclusions were you able to draw? “That the branching of mankind’s populations extends much further back than researchers previously believed, with common ancestors dating all the way back to 350,000–260,000 years ago. What this tells us is that what we call modern man – both behaviorally and genetically – was fully developed already back then.” How are you able to analyze such old bone samples? “It took more than two years to get permission to take the samples. From South Africa, we were able to take a few hundred milligrams of bone material from which we extracted DNA and built DNA libraries with special methods available in our Ancient DNA facility. Then we sequenced the DNA libraries
at SciLifeLab’s NGI facility. We thereafter mapped the sequence data against the human genome and, after careful checks, were able to build up the entire genome of a few individuals who lived in southern Africa 2000 years ago. In this way, we have been able to work out how far back the branching extends.” How do you proceed now? “We have a new study under way from another archaeological excavation in Africa with even older material. Since nobody knows which people lived in these areas several thousands of years ago, we don’t know what we will find. It’s always exciting when we perform the first preliminary analyses and see results no one else has seen before!” Technology and service National Genomics Infrastructure (NGI) assisted the project by sequencing the DNA libraries and generating the analysis’ raw data.