Page 1

A magazine from Karolinska Institutet

English Language Edition

2018

Smart Machines How artificial intelligence could improve our health

ALSO: FRIENDLY BACTERIA / CELL ATLAS / BLOOD SCENT


KI Alumni & Friends Join 15 000 fellow alumn i!

ki.se/en/alu mni KI Alumni & Friends is a professional and social network for everyone who is or has been engaged in Karolinska Institutet. Together, all of our former students and employees, constitute a vast network of experience and expertise with contacts in all parts of society in over 50 countries. Students are also very welcome to join the network!

Are you an excellent student? Do your PhD at Karolinska Institutet! The high standard of the research conducted at Karolinska Institutet is recognised around the world, and our doctoral education is an integral part of that research. We currently have positions available for doctoral students and we are looking for the best suited candidates. As a doctoral student you are offered a stimulating environment for research and education, an individual research project, a welleducated supervisor and the opportunity to be part of leading research groups, as well as a competitive salary. Be part of tomorrow’s breakthroughs and become properly equipped to succeed in a competitve global arena.

Visit us online regularly – new positions become available all the time ki.se/doctoralpositions


Contents—2018 4

Meet the President

Advances 5 6 8 9 10 43 47 48

Scary blood scent Greenery as medicine An atlas of our cells Around the body: Cell types Research in brief The evil origins of cancer Scientific language increasingly unclear Top publications

28 All over us. Everything about the bacteria that populate us and why we need them.

Focus 7 The brain on music 18 Sexual orientation and health: Openness is key 16 Life-saving killer cells 20 The art of keeping pace 38 Curious about artificial intelligence 44 Tinnitus can be hereditary 46 Emma Frans: “We must safeguard science”

The researchers 12 24 50

Three researchers: doing animal-free science Professor Emily Holmes: “A picture is worth a thousand words” A moment with Helena Nordenstedt: “I meant well, but it went wrong”

In depth 28 32 37

Our friends the bacteria Sufferer: “I was desperate” Scientists respond: This is how they have changed their eating habits

Attitudes. He studies how norms influence health.

18 46

Taking on the troll. How to fact check.

50 Local interest. When she understood the importance of asking.

20 Clockwise. Get to know your inner rhythm.

Medical Science–2018

3


President of Karolinska Institutet

D

EAR READERS, Research at Karolinska Institutet spans the entire medical field, from basic experimental research to patient-oriented and care sciences. This year’s edition of Medical Science, will give you a glimpse of some of the many exciting examples of research projects being conducted at our university with the aim of improving human health. Not long ago, everyone – including doctors and experts – mainly considered bacteria, funguses and viruses as being something undesirable, only causing trouble and disease. Now we know better. In this issue you will learn, among many other things, why researchers believe that a diverse microbiome is good for our health. Medicine might be about molecules, but it is first and foremost about human beings, wherever in the world they may live. Our responsibility as a university reaches far beyond our nation’s borders. Health is synonymous with global health but still, the distribution of health risks and access to health care worldwide remain extremely and unacceptably uneven. This is an issue that is close to my heart. Our timeframe for Karolinska Institutet´s upcoming new strategy and vision – 2030 – is chosen with care. 2030 is also the timeline for the UN’s Sustainable Development Goals (SDGs). These goals should inspire our research and have a key role to play when we take on the global challen­ ges that lie before us, including the inequities in health referred to above. The complexity of the tasks at hand is such that we have to bolster the dialogue between academia, government, business, and civil society. The SDGs challenge us to think and work across sectors and disciplines. Implicitly they ask higher education institutions to forge new alliances – alliances that might be seen as unconventional and unorthodox at first glance. We also need to reflect on how technologies and new knowledge should best be absorbed and put to good use by individuals and society at large. We need critical thinking, as well as we need ethics, and we need insight from the social sciences and the humanities. With insight, engagement, and collaboration across geographical, institutional and disciplinary boundaries we can do much to bring about vital change.

4

Medical Science–2018

Medical Science is an annual English language edition of the Karolinska Institutet popular science magazine Medicinsk Vetenskap. Here you can read selected examples of current research at our university. Editor-in-chief Marie-Louice Isacson Acting Director of Communications Karolinska Institutet Editors Ola Danielsson Cecilia Odlind medicinskvetenskap@ki.se Art Direction Lisa Sigebrand, Content Innovation Contributors Anders Kjellberg, Martin Stenmark, Johan Sievers, Mårten Göthlin, Maja Lundbäck, Mattias Ahlm, Rebecka Uhlin, Emma Hanquist, Fredrik Hedlund, Annika Af Klercker, Marcus Glijnis, Felicia Lindberg, Björn Öberg Cover: Björn Öberg Print Stibo Graphic A/S Translation Semantix Web ki.se Communications and Public Relations Office, Karolinska Institutet, SE-171 77 Stockholm, Sweden ISSN 1104-3822 Follow us on Facebook! Facebook.com/ karolinskainstitutet

Photography: Erik Cronberg

Ole Petter Ottersen:


The latest in medical research

Photo: iStockphoto

Scent of blood triggers inner warning signals The smell of blood is important to a large number of animal species, predators and prey alike. Scientists therefore think that the smell of blood might originate in a single, evolutionarily preserved “food and warning molecule”. Researchers at Karolinska Institutet now report that they might have identified this molecule, called E2D. In experiments, flies liked the smell as much as the smell of real blood. When wolves detected the scent of E2D, which had been wiped onto a piece of wood, they licked, bit and protected it as if it were an actual prey. When the scent was then tested on mice, the reaction was different. The mice displayed flight behaviour and tried to avoid the smell just like when they detect the smell of real blood. When human participants detected the smell of E2D they recoiled as if to avoid it,

even though it was not perceived as unpleasant. Their hands also perspired more. They also performed better when asked to locate images of faces that could be perceived as emotional on a computer screen as quickly as they could, an ability that is augmented in threatening situations. The results suggest that people subconsciously perceive the smell of blood as a threat. Next, the researchers intend to study whether E2D can affect even more complex behaviours such as decision-making. “This would be extremely important for people who have to take difficult decisions in their daily jobs while exposed to the smell of blood, such as trauma surgeons and nurses,” says Associate Professor Johan Lundström at the Department of Clinical Neuroscience, who led the study. Felicia Lindberg Scientific Reports oktober 2017 Medical Science–2018

5


Advances  5 questions FREDRIK ULLÉN

Professor in cognitive neuroscience at Karolinska Institutet and internationally renowned concert pianist.

How is the brain affected by culture? Music changes the brain, but how does it do it, and what can we learn from this? Fredrik Ullén is Scientific Director of a new centre for Culture, Cognition and Health. Text: Johan Sievers Photo: Mattias Ahlm

What is the purpose of establishing a research centre on the cultural brain?

”To coordinate, develop and strengthen research in this area. Artistic activities provide excellent models for understanding general mechanisms of cognition and learning. One important element of the research deals with clinical aspects, for example how artistic engagement can contribute to successful aging, both in relation to cognition and health.” Can you give examples of any ongoing research projects?

”Currently, we are three research groups at Karolinska Institutet and one at the Royal Institute of Technology in Stockholm. One joint project involves attempting to understand the interaction between heredity and the environment in regard to learning, motivation and the effects of training on the brain, and how this is linked to well-being and health. There will be many sub-projects under this umbrella.” So far, a lot of research has focussed on the effect of music on the brain. Which 6

Medical Science–2018

Art can help us to understand the brain, believes Professor Fredrik Ullén, whose own preference is for listening to Mozart on his headphones.

other cultural forms are interesting?

”In the context of our health and how we feel, all forms of culture are interesting, such as art and literature. From a learning perspective, music and dance in which one learns well-defined cognitive and motor skills are very rewarding to study.” What is your research about?

”I am studying expertise: How do we become very good at something through years of training? To give one example, we have a new study on identical twins where one of them has been shown to be more proficient in music than the other.” There we can see how certain

areas of the brain, such as those for hearing and motor skills, are more developed in the one who has practiced playing. So, here for the first time, we have evidence that training can make a difference even if the genetics are the same. Where does your interest in the cultural brain come from?

”It comes from many places. For starters, I am a musician myself, but I am also interested in learning, creativity and how we can develop our potential and become excellent at something. Engagement and intrinsic motivation appear to be key factors in this process.”


3 × Food as medicine  Advances

Can green vegetables lower blood pressure? Green leafy vegetables are thought to be good for our hearts and blood vessels. Researchers want to find out if a previously much-maligned substance is the source of these health benefits. Text: Maja Lundbäck All green salad contains plenty of nitrate.

EVERY WEEK, patients with high

blood pressure will come to Karolinska University Hospital to collect a bag of vegetables. Some will receive a bag with a high content of nitrate, while others will get a bag containing vegetables with a very low nitrate content. In addition, the patients will be given a pill containing either nitrate or a placebo, which is an inactive substance. The study, which is led by Professor Jon Lundberg at the Department of Physiology and Pharmacology at Karolinska Institutet together with Professor Eddie Weitzberg at the same department and colleagues at Karolinska University Hospital, will clarify if nitrate can reduce blood pressure, and if the effect is the same if it’s ingested as a pill or vegetables.

Photo: iStockphoto

2 times a day Mattias Carlström, researcher at the Department of Physio­ logy and Pharmacology, and his colleagues will serve beetroot juice to patients with kidney disease or diabetes. Among other things, this is to see how it affects blood pressure, kidney function and insulin sensitivity.

“Some patients are already taking medication to reduce blood pressure, but these are not always 100percent effective. We want to see whether we can enhance the effect in these patients,” comments Jon Lundberg. Several smaller studies on animals and humans have shown that nitrate-rich vegetables give positive health benefits. “We also know that nitrate, after being converted into nitric oxide in the body, not only causes blood vessels to

dilate and blood pressure to drop, but also helps the mitochondria to utilise oxygen in the body more efficiently,” says Jon Lundberg. About forty years ago, nitrate were feared as a potential carcinogen. Many people still have questions about this. “Nitrate has had a very bad reputation and still does, but there is no scientific evidence at all which supports that nitrate from normal vegetables is harmful to health,” states Jon Lundberg.

“It will be exciting to see if the results improve if the nutritional drink is administered together with dietary advice and physical activity.” Professor Miia Kivipelto on their study in Lancet Neurology demonstrating that treatment with nutritional beverages, while not improving the memory of Alzheimer patients, did seem to slow down the brain’s degeneration. Now, in a new study, they will administer the beverage in other combinations, for instance with a Mediterranean diet, which has previously been shown to reduce the risk. Source: Dagens Medicin Medical Science–2018

7


Advances  Cell atlas What makes each cell type unique? It will be possible to find the answer in a new atlas.

300 million cells will be included in the atlas.

30

million cells from the most important organ systems will be mapped in an initial draft which will be ready in 2020.

The human body consists of hundreds of different cell types. In the international initiative Human Cell Atlas, researchers want to map each type. Sten Linnarsson at Karolinska Institutet is participating in the project. Text: Mårten Göthlin

HUNDREDS OF international researchers will cooperate to map millions of cells in all tissues of the body. The aim is to create a three-dimensional map of all cell types in the body and decide which characteristics make each cell type unique. The most essential work will be mapping which genes are active in different cells and where in the body they are located. 8

Medical Science–2018

Other properties, such as the shape of the cells, their electrical properties and interaction with other cells will be added gradually. The results will be available directly and can be accessed by everyone. Initially cells from a few individuals will be analysed for each tissue. At a later stage, analyses of more individuals will allow the study of, for example, geographical differences and certain diseases. Sten Linnarsson, Professor at the Department of Medical Biochemistry and Biophysics, is a part of the initiative’s steering group and is one of the researchers behind development of the techniques which enable the project. His plan is for Sweden and Karolinska Institutet to be responsible for the mapping of cells which control development of the embryo and the human nervous system. “I personally feel that the interaction between cells which control this is very interesting. And Karolinska

million euro is required to complete the first draft. The estimated cost of the complete atlas is tenfold.

Institutet also has the technology and several strong research teams within development biology which may be beneficial for the project,” he says. Similar to the Human Genome Project which mapped all human genes in the 1990s, researchers hope that the Atlas will increase understanding of the mechanisms behind many diseases. “Until now the focus has mainly been on which genes are linked to diseases. Now we want to find out where and when they are active and how interaction of different cells contributes to a disease progression. The Atlas can allow progression from a list of genes to a concrete hypothesis of how diseases occur,” he says. So far 17 organisations and companies across the globe are financing partners of the initiative, including the Chan Zuckerberg Initiative, founded by Mark Zuckerberg and Priscilla Chan. The states Japan, Australia and India are also participating.

Illustration: SciencePhotoLibrary, Noun Proejct/Gorkem Oner. Photo: Ulf Sirborn.

Mapping the body - cell by cell

100


Cell types  Around the body For us to function, cells with many different types of functions are required. We list five cells which you did not know you have. Text: Mårten Göthlin

RADIAL GLIAL CELLS

They lead the way

Radial glial cells are the source of the adult brain cells. They are also necessary for the cells of the nervous system to travel to their right place in the body during the embryonic development. They may assume many different forms and functions. They remain in some areas of the adult brain and continue to form new nerve cells.

E P E N DY M A L C E L L S

They keep pumping Ependymal cells are located in the brain’s cerebrospinal fluid filled cavities, the ventricles, and form a membrane between the brain and cerebrospinal fluid. Their most important function is to produce cerebrospinal fluid and pump it around with its projections, the cilia. If ependymal cells are isolated, they continue to pump mechanically outside the body. In 1999, Jonas Frisén’s research team also found that they are stem cells which can develop to new nerve cells.

RETINAL GANGLION CELLS

They are messengers of light

Retinal ganglion cells are important, among other things, for our ability to see details, movement and contrast. They occur in different forms and each cell type sends a specific visual message to the brain. So far researchers do not know how many types of retinal ganglion cells exist or which images their signals send in the brain.

TUFT CELLS

Photo: Istock Photos.

They taste the intestine content

Tuft cells only comprise a small percentage of all epithelial cells in the intestine, but can easily be recognised due to their ”tuft” of microvilli projecting into the lumen of the organ. For a long time researchers have tried to understand why these cells have the same signal system which the tongue uses to detect certain tastes. In 2016 researchers found that they increase during parasitic infections and that the signal system for tastes may be decisive for fighting infections.

MERKEL CELLS

They make us sensitive to touch

The rare Merkel cells are found in the more sensitive areas of the skin such as the fingertips and lips. They are often located close to nerve cells and are important for feeling light touch and detailed structures. It is also thought that the cells are involved in growth and the development of other skin cells.

Sources: Moll, Ingrid, et al. European journal of cell biology, 2005, Howitt, Michael R., et al. Science, 2016, Gerbe, F., and P. Jay. Mucosal Immunology, 2016, Woo, Seung-Hyun, Ellen A. Lumpkin, and Ardem Patapoutian. Trends in cell biology, 2015, Baden, Tom, et al. Nature, 2016. Medical Science–2018

9


Advances  In brief Research news from ki.se

“A true scientist who can’t carry on their research for a week or two almost suffers from withdrawal symptoms” Karolinska Institutet’s new President, Ole Petter Ottersen, on his research addiction. He does however understand that, as he takes up his new post, it may at first prove difficult to find time for his own research. Source: Läkartidningen

Blood-thinning drugs linked to reduced risk of dementia

Disaster medics assist WHO Expertise. The Centre for Research on Health Care in Disasters at Karolinska

Institutet has been designated a WHO Collaborating Centre by the World Health Organization. The centre will provide expert advice to the WHO in connection with disasters and conflicts, as well as work on policies and research regarding WHO initiatives. The centre has already collaborated with the WHO on a number of occasions, for example during the West African Ebola epidemic, the earthquake in Nepal and, more recently, during hostilities in Mosul, Iraq. The centre has also contributed expert knowledge when the WHO drew up its guidelines for international field hospitals in disaster areas. “The fact that our collaboration with the WHO is now on a more formal footing is also proof that our activities are important to the WHO,” says Johan von Schreeb, a researcher at the Department of Public Health Sciences and specialist in disaster medicine. According to Johan von Schreeb, operations must be based on expertise, rather than good intentions. “Aid work must have quality and the resources must be used efficiently and effectively,” he explains. The World Health Organization collaborates with over 700 organisations in over 80 countries that have been designated as Collaborating Centres. In Sweden, there are seven such collaborations. Learn more at: ki.se/en/phs/about-kckm

10

Medical Science–2018

the Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, have studied the link between blood-thinning drugs and dementia in patients with atrial fibrillation. Among approximately 440,000 patients with atrial fibrillation during the years 2006-2014, patients taking blood-thinning drugs for the entire study period had a 48 per cent lower risk of suffering from dementia. Although they cannot prove a causal relation­ship, the researchers believe that the results strongly suggest that blood-thinning drugs protect against dementia in these patients. “Patients on oral anticoagulation for stroke prevention often stop taking the drugs after a few years. Doctors should explain to their patients why they should use these drugs,” says Associate Professor Leif Friberg. European Heart

Journal October 2017

Photo: Istock photo.

Protection. Researchers at


Nursing shortages increases patient mortality Patient safety. The results from a new doctoral thesis show a clear correlation between patient mortality and lost nursing activities due to low nurse staffing levels. According to the research­ ers, this suggests a In Sweden, 74 per causal link. The thesis cent of the surveyed nuralso shows that low ses reported that they had levels of registered failed to perform necessary nurse staffing cannot nursing activities due to lack be compensated for of time. The corresponding by other healthcare figure in the UK was staff – the volume of 86 per cent. omitted necessary care remains unchanged. “What surprised me most while working on my thesis is that staffing levels differ a great deal between different departments and hospitals,” Smith of the Department of “It also surprises me that Laboratory Medicine. more attention isn’t paid When oligonucleotides to low nurse staffing levels were added to cell lines from given that patient safety is patients with Huntington’s threatened and lives put at Disease, the production of risk.” says Jane Bell, doctoral mRNA and proteins destudent at the Department of Learning, Informatics, Mana- creased considerably. The next step will be to test the gement and Ethics. Learn more at publications.ki.se method on mice. Nucleic Acids Research February 2017

Hope for treatment of incurable disease

Illustration: Istock photo.

Genetic problems.

Huntington’s Disease is caused by the repetition of a DNA sequence that codes for the huntingtin protein. The protein, and the messenger RNA (mRNA) formed from the mutated genes, damage nerve cells in the brain and cause them to degrade. One treatment currently in the research phase is antisense therapy, whereby short strands of DNA are synthesised that bind to and deactivate mRNA so that no harmful proteins are formed. “We have created oligonucleotides that bind directly to the damaged DNA, thus preventing production of both the mRNA and the protein,” explains Professor Edvard

New weapon against resistant bacteria Silver bullet. Researchers at

Karolinska Institutet have discovered that a combination of silver and the drug candidate ebselen can be used to kill multidrug resistant bacteria. Professor Arne Holmgren at the Department of Medical Biochemistry and Biophysics and his colleagues

have previously demonstrated that ebselen alone can kill certain multidrug resistant bacteria by blocking the cell’s thioredoxin system, crucial in the growth of certain bacteria. Other bacteria use glutaredoxins and therefore remain unaffected. Research­ ers have now shown that ebselen in combination with silver can knock out bacteria with both of these systems. Among these are gramnegative bacteria, responsible for the majority of deadly infections and in the process of becoming resistant to currently available antibiotics. Researchers now hope that the method, so far only tested on mice, can be developed into a new drug. EMBO Molecular Medicine June 2017

23 000 women die worldwide each year as a result of unsafe abortions. With changing attitudes, knowledge and more groups of healthcare professionals being trained to perform safe abortions, maternal mortality can be combated, shows a doctoral thesis from the Department of Women’s and Children’s Health. Learn more at publications.ki.se

Influenza medication safe during pregnancy No risk. Seasonal influenza occurs every year and millions of pregnant women risk severe illness during seasons with a more aggressive strain. Regulatory agencies in Europe and the USA therefore recommend neuraminidase inhibitors for pregnant women to prevent and treat influenza, despite limited knowledge on their safety and effectiveness during pregnancy. Researchers at Karolinska Institutet have now conducted the largest study to date to assess potential risks of taking antiviral drugs during pregnancy and found no increased risk of adverse outcomes. “The study supports previous findings in demonstrating that there appears to be no risk for serious complications for the child if the mother takes influenza medication,” says Sophie Graner, obstetrician and researcher at the Centre for Pharmacoepidemiology at the Department of Medicine, Solna, who led the study. BMJ February 2017 Medical Science–2018

11


Three researchers Replacing animal testing

They seek alterna Animal testing is a part of medical research. However, work is continuously ongoing to reduce the number of animals, improve technology and replace animal testing with other methods. Meet three researchers breaking new ground. As told to: Maja Lundbäck Photo: Annika af Klercker

12

Medical Science–2018


ANNA DOMOGATSKAYA Title: Senior Researcher at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet. Researches: Finding good medicines for diabetes patients.

”Treat animals like patients”

tives

”I want to be able to tell my children that I work with animal testing without feeling guilty. That’s why I think about treating animals like they are small patients. It’s important that we make an effort so that the animals don’t need to suffer. If animals get the same care as human beings who undergo surgery, then animal testing is fine. But even though we have strict laws in Sweden, animals may be used unethically here and in other parts of the world. If we develop good and cheaper alternatives for animal testing in our research, we can reduce the suffering of animals throughout the world. I’m studying what is referred to as pancreatic islets, natural ‘micro-organs’ inside the pancreas. These microorgans, which we remove from dead animals, have long been used for diabetes research as they produce insulin. Now I want to develop human micro-organs artificially and ensure that they are similar to pancreatic islets. They are extracted from normal skin cells which have been reprogrammed to stem cells, referred to as iPSCs. If we succeed then they will be more ethical, economical and perhaps even better at predicting how us human beings react to medicines than the micro-organs derived from mice. Animal tests are still required for pharmaceutical testing. We shouldn’t really say to patients that we don’t know whether the medicine they have been given is safe and effective. Animal testing is a part of our current control system.” Medical Science–2018

13


Three researchers Replacing animal testing

LENA PALMBERG Title: Senior Researcher at the Institute of Environmental Medicine, Karolinska Institutet. Researches: Developing a 3D model of the lung to study effects of air pollution.

”It’s time to find options” ”Recent years have witnessed the emergence of stronger social involvement against animal testing. I personally feel that animal tests are ethically questionable and that it’s time to find good options. But already today, we have come quite far in terms of preventing unnecessary animal tests. In order to understand the lung diseases chronic bronchitis and COPD, I have developed a 3D model of human cells which contain many of the cell types which we have in the upper respiratory tracts. In a study I used small particles from exhaust fumes which I subjected the models to. The particles were distributed evenly above the surface, but after a while I could see how they came together to one point, which indicates that the model’s defence mechanism functioned. I think that the particles were captured in the mucus layer and pushed together by the cilia. I haven’t done animal testing since I took my doctorate. But to evaluate our 3D models, I’m planning to conduct a comparative study where I expose both laboratory animals and our models to harmful small particles from, for example, air pollution and compare with known effects they may have on human beings. If my models have similar responses as animal models, then animal testing could decline. But pharmaceutical testing in models of individual organs cannot replace animal testing fully, as you only examine one organ, not an entire body.” 14

Medical Science–2018


”Liver in test tube can replace animal testing”

VOLKER LAUSCHKE Title: Assistant Professor at the Department of Physiology and Pharmacology, Karolinska Institutet. Researches: The effects of medicines, but also how liver diseases occur and can be prevented.

”I want to reduce the risks of new medicines for patients. Liver toxicity is one of the most common causes of medicines being withdrawn. Currently it is required for drugs to be tested on two types of animals, for example, rats and rabbits, before it is used in humans. But the regulations also encourage the development of alternative methods which can predict the effects of medicines, as animal tests do not answer how they function in a human patient’s liver. By using excess liver cells from liver donations, my colleagues and I have developed a 3D model which is functionally similar to a human liver. The model can be used for many weeks and serves as an alternative method to animal tests. Hopefully, in the future we will not need to use animals to find out how a medicine affects the human liver. Instead our or similar methods with human liver cells in test tubes will replace animal testing. However, more research is required so that we can be certain that our 3D liver system is at least as good as animal testing at predicting the risks of medicines. I think that it is an added bonus if animal tests can be avoided, but that is not my primary goal. The most important aspect is finding the most reliable way to predict the effects of a medicine before it is tested on human patients.” Medical Science–2018

15


Facts: About 2 billion natural killer cells are in circulation in the body. In contrast to cells in the specific immune system, they can kill cancer cells and virus-infected cells directly, even if they haven’t encountered them before. They also help to control how the other immune cells react to intruders.

Killer cells that save lives

The 1970s Background noise When KI researchers Rolf Kiessling, Eva Klein and Hans Wigzell were studying how T-cells recognise and kill cancer cells in mice, they discovered something more than ordinary T-cell killing of cancer cells, but it was disregarded as “background noise”.

Less than forty years ago they were considered to be unimportant - today natural killer cells are used in advanced cancer therapy. Karolinska Institutet has been part of the entire journey through controversy, criticism and exciting progress. Text: Mårten Göthlin

1975 The cells are discovered After some years, the same research group show that the background noise in the study is caused by previously unknown immune cells that can kill cancer cells directly. The cells were given the name natural killer cells, or NK cells.

1970

1975

1980

1978 Virus killers Researchers at the Wistar Institute and Karolinska Institutet show that NK cells are activated by proteins from the virus-infected cells. This paves the way for large numbers of studies that show that NK cells are important in the defence against a whole number of viral infections.

1985

1981 Hypothesis proposed In his PhD dissertation, Klas Kärre at Karolinska Institutet presents a hypothesis on how NK cells differentiate between own and foreign cells: The foreign cells are attacked not because they display an unknown protein, but because they lack a cell surface protein, a selfmarker. The hypothes is considered speculative but is developed in future publications. 16

Medical Science–2018

1990

1985 and 1986 Protein hunt Klas Kärre and doctorate Hans-Gustaf Ljunggren discover that mice, which had been injected with cancer cells lacking a membrane protein, MHC class 1, did not develop tumours. In subsequent studies, it became apparent that NK cells killed the cancer cells that lacked the protein, hence verifying Kärre´s hypothesis.

Photo: Istockphoto

Timeline  NK cells


Photo: Stefan Zimmerman

Photo: Istockphoto

1997 Submarine similarity How the NK cells worked was compared to how the inhabitants of the Swedish archipelago could differentiate between Swedish and foreign submarines: Instead of learning the attributes of all foreign submarines they could report those submarines that do not have Swedish characteristics.

2000

2005 Hans-Gustaf Ljunggren. T O D AY

1995

2002 Difficult to live without them Individual cases of patients without NK cells show that it is very difficult to survive without them. Causes of death include herpes virus infections at a young age. This virus has mechanisms for avoiding the T-cells, and the NK cells are therefore even more important in the defence against it.

Future challenges

2005–2007 Cell therapy In a clinical trial by Jeffrey Miller, five of 19 patients with the disease acute myeloid leukaemia were cured using donated NK cells. This is the first time that NK cells functioned effectively as immuno­ therapy and results in extensive mapping of how NK cell therapy­of the future can be designed.

Improved adaptation Researchers can stimulate NK cells to attack cancer cells. But for them to be effective as a drug against various types of cancer and other diseases, the researchers must learn more about how the NK cells can adapt to different tasks. Finding the way Guiding activated immune cells to tumours in patients is difficult. If the researchers could help the NK cells find their targets, it should be possible to use them against more cancer types than those in the blood.

2020

Logistics and price Developing new types of drugs that activate NK cells against cancer requires close collaboration between academics and industry in order to resolve the issues of logistics. Sources: Santoli, Trinchieri & Koprowski, The Journal of Immunology 1978, Biron et al., Annual review of immunology 1999, Cerwenka & Lanier, Nature Reviews Immunology 2016, Kiessling, EFI Newsletter 2005, Kärre, Immunological reviews 1997, Caligiuri, Blood 2008, Parham, Nature Reviews Immunology 2005, Kärre & Ljunggren, EFI Newsletter 2006.

Promising clinicial trials in progress Even before the researchers were aware of their existence, NK cells helped at the first bone marrow transplants against leukaemia in the 1970s. Now, the next form of immunotherapy is under development; here, NK cells are being modified to specifically attack the patient’s unique tumour cells. “A large number of clinical trials are currently being held around the world,” relates Hans-Gustaf Ljunggren, Professor at the Department of Medicine, Huddinge. Together with Karl-Johan Malmberg, Evren Alici and other researchers, he has worked for more than ten years on developing treatments using NK cells for patients with different forms of blood cancer. “Currently, we are evaluating the first clinical trials that started five years ago. In these, patients with acute myeloid leukaemia and myeloid plastic syndrome have received NK cells from related donors which have been activated in a variety of ways to kill the tumour cells. The results look very promising,” says Hans-Gustaf Ljunggren. Simultaneously, there is an ongoing collaboration between researchers from Karolinska Institutet and several companies in growing specialised NK cells. “This started with 15 years experi­mental research in mice, followed by a further 15 years studying NK cells in people and developing treatments, and soon we will be in goal. I hope the next 15 years will see our research benefiting the patients too,“ states Hans-Gustaf Ljunggren.

Medical Science–2018

17


In focus  Health and sexual orientation

“What matters most is how open one can be” By studying gay men, lesbians, and bisexuals in 28 European countries, researchers have demonstrated how a country’s laws and attitudes directly impact the health of its citizens. In Sweden, the health of this group has improved in parallel with changes to legislation and greater acceptance of homosexuality in the population at large. Text: Johan Sievers Photo: Rebecka Uhlin

O

VER THE PAST decade, the national public health survey, conducted annually in Sweden, has included questions on sexual orientation. The survey clearly shows that lesbian, gay, and bisexual (LGB) individuals as a group experience worse health than heterosexuals. They are approximately twice as likely to suffer from depression and the risk of suicide is 2-4 times greater. The risk of substance abuse is also higher than among heterosexuals. The positive news is that we are heading in the right direction. Over the past ten years, the

18

Medical Science–2018

percentage of lesbians and gay men subjected to threats and violence has decreased and mental health in the group has improved. This has taken place in conjunction with legislative improvements, such as the inclusion of sexual minorities in hate crime legisla-

tion, protection against discrimination in the workplace and gender-neutral marriage. From a research perspective, it is of interest to study this correlation more closely; in what way might social factors influence the large differences we see between the health of LGB individuals and heterosexuals? What do these mechanisms look like? RICHARD BRÄNSTRÖM, researcher in health psychology at Karolinska Institutet’s Department of Clinical Neuroscience, has studied the situation facing LGB individuals in 28 European countries. By reviewing legislation and measuring the population’s acceptance of homosexuality, he has evaluated the level of stigmatisation LGB individuals face in these countries. This has been compared to the results of questionnaires in which LGB individuals have responded to questions about their life-satisfaction. “We see a clear correlation. The more a country stigmatises LGB individuals, the worse their mental health. It is unusual to see such a strong correlation between a country’s laws and attitudes, and the health of its citizens,” says Richard Bränström. Ill-health among members of vulnerable minorities is often explained by the fact that they are exposed to specific stress factors in the form of the society’s attitudes, discrimination, social exclusion, threats and bullying. Individual factors also come into play. Those who expect to be treated badly often internalise the negative attitudes prevalent in their environment and, in so doing, denigrate themselves as much as the society around them does. “The factor that above all others affects mental health is how open one can be about one’s sexual orientation. Openness explains most of the

LGB individuals risk a lesser life-satisfaction The Swedish national public health survey shows that, in many areas, lesbian, gay, and bisexuals have a worse life situation than heterosexuals. LGB individuals: Are more frequently exposed to violence, or the threat of violence. Significantly more often experience financial problems and low incomes. Have risk-related alcohol habits to a greater extent. Suffer worse general health. Suffer from considerably worse mental health, with bisexual women most at risk.


”We see a clear correlation. The more a country stigmatises LGB individuals, the worse their mental health.” differences we see in life-satisfaction between European countries.” Here, there are enormous differences. In countries such as Rumania, Latvia and Lithuania, only 20 per cent of lesbians, gay men, and bisexuals are open with their sexual orientation. This is the result of discriminatory legislation and negative attitudes to LGB individuals. By hiding their sexual orientation, people reduce the risk of threats and violence – this does however come at the price of poor mental health. IN SWEDEN, THE situation is better, with 80 per cent of LGB individuals being open with their sexual orientation. They also enjoy better health than their counterparts in the majority of EU countries. Sweden has made great strides in creating a tolerant society for the 2-4 per cent of the population that identifies as lesbian, gay, or bisexual. We have fewer discriminatory laws, attitudes are becoming ever more positive and, in many parts of society, people receive training in these issues. In parallel with these developments, the health of the group has improved. “This demonstrates that if we are successful in changing legislation and attitudes and decreasing discrimination within a society, we also have a direct influence on the well-being of people. It is important to understand this as in Sweden we have a clear policy of equality in health,” says Richard Bränström. However, LGB individuals still suffer from worse health than heterosexuals. This applies not only to mental health, with surveys showing that LGB individuals also have worse preventable physical health, for example forms of cancers strongly linked to tobacco smoking. “We must develop preventative measures primarily to combat mental illness, as this is in turn linked to physical health. We need a coordinated strategy,” explains Richard Bränström. Richard is currently a visiting researcher at Yale University in the United States, where he is continuing his work

According to Richard Bränström, the link between a country’s attitudes and the health of its gay and bisexual citizens is a largely unexplored and politically important area.

on European data. Researchers at Yale are working to develop online support for LGB individuals who live in countries where they feel far too vulnerable to visit a clinic. “A pilot project is underway with a chat-based support network for LGB individuals in Rumania. This is aimed at improving physical health and redu-

cing sexual risk-taking.” Richard Bränström would like to continue his research on the health of gay, lesbian, and bisexual individuals from an international perspective. “How do societal norms ‘get under the skin’ and influence health? For me, as a health psychologist, this is an exciting question,” he says. Medical Science–2018

19


Perspective  Circadian rhythm

Our body clock controls us more than we realise. If 2017 year’s Nobel-Prize-winning discovery has a wider breakthrough, it can change everything from when the school day will start to what medicines we take and when. Text: Fredrik Hedlund Illustration: Emma Hanquist

P

EOPLE, ANIMALS, plants and even some bacteria and single-cell organisms all have an internal clock. A 24-hour system that regulates functions in the cells so that they take place at the right time for the organism. Researchers call this the circadian rhythm after the

20

Medical Science–2018

Latin circa diem – “around one day”. Anita Göndör, researcher at the Department of Oncology-Pathology at Karolinska Institutet, and her research team have studied the circadian rhythm since 2014 and she sees many challenges ahead. “There is a lot that we don’t know. For example, we don’t entirely understand the principles that produce the period length of 24 hours.

THE MODERN HUMAN’S possibility to be able to be up later at night thanks to electric lighting is, however, something that researchers are now increasingly beginning to understand can lead to problems. It has been shown in human studies that a delayed daily rhythm can lead to changes in glucose tolerance, insulin sensitivity and appetite control, which by extension can lead to obesity and diabetes. An elevated risk of cancer, depression and other psychiatric disorders, as well as cardiovascular disease in people with a delayed daily rhythm, due for example to shift work, have also been seen. “Electric lighting has an extensive

Photo:Ulf Sirbom.

The art of keeping pace

There’s also a lot more to discover about how cellular processes, such as metabolism and mechanical signalling, collaborate with the circadian clock to create stable daily rhythms,” she says. However, it is clear that there is a central clock in the brain – the suprachiasmatic nucleus. This structure takes in information about light and dark from the eyes and adjusts the entire system. It is the central clock that resets the system when one changes time zones travelling across the Atlantic, for example. But exactly how the central clock controls and communicates with the other cells of the body, which have their own clock functions, is not clear. Different people also have different preferences in terms of the circadian rhythm. Some are larks who wake up early and are then tired in the evening while others are night owls who are more energetic in the evening and more tired in the morning. The researchers say that they belong to different chronotypes. Many researchers are looking for the genetic explanations behind the chronotypes, at the same time that it is also known that the preferences for going to bed and getting up early are not necessarily constant through life. For example, it is clearly shown that young people generally have a delayed circadian rhythm and go to bed later at night and are more tired in the morning, something that disappears when they get older.


“What would happen in Sweden in the winter if everyone went to bed at three in the afternoon? Of course, that’s unrealistic.” effect on our circadian system,” says Anita Göndör. So there are extensive indications that the possibility of postponing the natural day/night cycle with electric lights is harmful to us. But the question is whether it is practically possible, or even desirable, to turn the clock back to the time before the light bulb in our modern societies. “I don’t know if I would want to go to bed when the sun goes down. What would happen in Sweden in the winter if everyone went to bed at three in the afternoon? Production as a whole would grind to a halt. Of course, that’s unrealistic,” says Barbara Canlon, Professor at the Department of Physiology and Pharmacology at Karolinska Institutet. Instead, she believes that our modern lifestyle is in all likelihood here to stay, as well as its consequences. “A delay of the circadian rhythm causes long-term stress that in turn causes other problems, so directly and indirectly this leads to a number of health problems. But we simply have to learn to live with them,” she says. At the same time, she believes that some things in society could be improved without having such extensive effects on the social structure. Such as adapting the school days to adolescents’ delayed circadian rhythm, which generally makes them too tired at 8:30 a.m. when school begins. “School could begin at 9:30 a.m. instead,” she says.

Photo:Ulf Sirbom.

AT THE SAME TIME, a lot is unknown

regarding how sensitive different people are to shifts in the body clock. There is an interesting hypothesis that is based on growing research indicating that the amount of daylight during the period one is born in and has one’s early development has a long-term effect on the stability of the circadian rhythm.

The hypothesis is based on those who are born in the summer with a long day and short night having an easier time to adapt to seasonal shifts, shift work and jet lag compared with those born in the winter with a short day and a long night. “There are a lot of mice and rat studies about this. When it comes to humans, larger studies are needed, but there are trends that show that some diseases can be affected by both the season and the latitude at birth, since it determines the length of the day,” says Anita Göndör. An entirely different aspect of the circadian rhythm is the fact that if the body’s cells change their function over the time of day, there can be different times that are differently suited to take medications at. This area of research is called chronopharmacology and is also relatively new. However, it is already being successfully applied within cancer care to optimize the attacks on the cancer cells when they are multiplying the most. Cell division can vary over the hours of the day and is thereby used to distinguish health and cancer cells at

Background: The discoveries of circadian rhythms In the first half of the 18th century, French scientist Jean-Jacques d’Ortous de Mairan demonstrated the circadian rhythm in the mimosa plant that continued to open its leaves in the morning despite being placed in the dark. In the early 1970s, a gene was found that controls the circadian rhythm by Seymour Benzer and Ronald J. Konopka. The recipients of 2017 year’s Nobel Prize in physiology or medicine, Jeffrey C. Hall, Michael Rosbash and Michael W. Young, showed how the body clock worked in purely molecular terms. It involves a negative feedback mechanism where the protein that is made by the gene slows its own production when it reaches an adequate concentration.

different points in time. This way, the treatment can provide both a better effect and fewer side-effects. In the same way, chronopharmacology is used in rheumatology where one can administer anti-inflammatory cortisone at night when the inflammatory process is most active. Barbara Canlon has conducted research on the ear and hearing damage throughout her entire research career. More or less randomly, she began, together with her colleague Gabriella Lundkvist, to look for a possible circadian rhythm in the ears of mice. “And we found a clear rhythm. The activity increased at night and decreased during the day since mice are nocturnal animals. Until then, nobody had even asked the question if there is a daily variation in the ear,” she says. The researchers were then able to show that the mice’s ears are more sensitive to sound trauma during their active period at night than what they were during the day. Translated to humans, it should be the opposite, was the researchers’ continued reasoning. “The active phase for humans is the day and the resting period is in the evening/night so our ears should be more sensitive during the day,” says Barbara Canlon. This would mean that it is more harmful to subject the ears to strong noise, like a rock concert, during the day than in the evening. She also feels that the new findings about the ear’s circadian rhythm must have the consequence that one begins to also weigh in thoughts of chronophramacology in the treatment of hearing damage. With this new approach, she believes that there is a possibility to streamline the pharmaceutical treatment for the hearing impaired patients. STREAMLINING pharmaceutical treatment is also the objective of Andrea Carmine Belin, Associate Professor at the Department of Neuroscience at Karolinska Institutet. She conducts research on cluster headache, an uncommon and severe headache with an unknown cause that strikes around one in one thousand people. The disease is more Medical Science–2018

21


Perspective  Circadian rhythm

ANITA GÖNDÖR AND her research team have instead studied how the Nobel Prize winners’ model works in the cell nucleus. They have been able to show how two proteins control the activity of circadian genes by transporting them from an active state in the centre of the cell nucleus to an inactive state 22

Medical Science–2018

Facts: Know your rhythm

Blood pressure, pulse and body temperature are the highest during the day.

Parts of the immune system are extra active late at night and very early in the morning.

on the edge of the cell nucleus. This information is another piece of the puzzle for understanding how the circadian system works. In connection with this finding, she is now investigating if cancer cells can hijack the circadian system to more easily adapt to changes in their surroundings. Something that could be used to develop future treatments against cancer. In the future, Anita Göndör sees how one investigated the body clock of cancer patients to determine both what treatment should be given and when.

Lung function is the best in the afternoon and worst 12 hours later, just before dawn.

The stress hormone cortisol increases before one wakes up and remains high until around 11 p.m., while growth hormone is instead mostly secreted at night.

She also believes that the body clock will become just as natural in future studies as it is today to distinguish between effects in men and women, young and old. “It will simply be impossible to do studies without taking the circadian system into consideration. This vision of the future is not as far off as one might think. Since the idea and awareness of this has been evoked in connection with this year’s Nobel Prize, I am very optimistic about the future,” says Anita Göndör.

Illustration: Emma Hanquist, Pictogram: Nerea Martínez Orduña/Noun Project

common in men than women and usually arises at between 20 and 40 years of age and often subsides after 65. It also has clear ties to the circadian rhythm. “A majority of the patients, around two thirds, say that they have their attacks at the same time every day. The attacks are most often between 2 and 4 a.m. at night and least common at midday. Patients have reported that if they travel west, to North America, the attack is shifted to the same time, local time,” she says. Andrea Carmine Belin and her research team have now found a strong connection to a genetic variant in the CLOCK gene that affects the length of sleep. “The people who have this genetic variant have a much higher activity of the CLOCK gene. So it is something that is happening at a daily rhythm level,” she says. Cluster headache is occasionally called suicide headache since the pain is so intense. But treatment does exist. Migraine medicine helps some; lithium, which is normally used for bipolar disorder, has a preventive effect mainly for chronic sufferers and in some cases, it can work to provide acute treatment with oxygen, but the effect of the pharmaceutical treatment is often inadequate. Something that Andrea Carmine Belin believes may be due to the knowledge of the various variants of the disease being incomplete and that the effects of medication can vary across the day. “The disease is now divided into episodic and chronic cluster headache. But I believe that there are even more subtypes, such as those who have daily rhythm-regulated attacks,” she says. Andrea Carmine Belin is now trying to find patterns to more easily be able to recognise the patients who really benefit from various treatments and when during the day they should be taken for the best effect.


Photo: Tomas McKenna

GIVING TO KAROLINSKA INSTITUTET Our vision, to contribute significantly to improving human health, is what drives research and education at Karolinska Institutet. Thanks to generous gifts from Swedish and international friends, we are continuously breaking new ground. If you share our vision and wish to join us in creating a future with better health and quality of life for everyone, then we welcome your support. Please contact us and let us know how you would like to become involved in helping us achieve tomorrow’s medical breakthroughs. Welcome to contact us at the Development Office; E-mail: development-office@ki.se Phone: +46 8 524 800 00 ki.se/donations

Donate online: ki.se/donations

For US citizens: Make your donation via our partner organisation King Baudouin Foundation United States (kbfus.org) and choose KI.

Program and Registration w w w.sls.se/ globalhealth2018

Berzelius Symposium 98

The Swedish Global Health Research Conference 2018 How can Sweden contribute to the Sustainable Development Goals? From research to action!

April 18-19 2018 at Karolinska Institutet, Stockholm The conference is organized by the Swedish Society of Medicine in cooperation with

annons_medicinskvetenskap.indd 1

2018-01-19 11:25:18


Interview  Emily Holmes

The power of mental images Combining insight with inexhaustible curiosity, Emily Holmes is trying to understand more about our psyche. Her objective: To develop new psychological treatments that can reach sufferers of trauma without needless delay.

Text: Cecilia Odlind Photo: Martin Stenmark 24

Medical Science–2018


VISIONARY

There is enormous power in our ability to think in images, and we should make greater use of it, says Emily Holmes.

Medical Science–2018

25


Interview  Emily Holmes

A PICTURE IS WORTH a thousand words. This old adage is one of Emily Holmes’ favourites, and her research shows that a picture really can have a considerably stronger influence on our feelings than words that describe the same situation. Without thinking about it, we regularly experience mental images – this could, for example, be a visual memory of something we’ve recently experienced, such as a disagreement with a friend or a kiss from a new love. “These mental images can have a powerful effect on our emotional state by throwing us backwards and forwards in time. The fact that they have such a strong emotional effect on us makes them particularly interesting to study – not least among people who suffer from various types of psychological problems,” says Emily Holmes, psychologist and newly-appointed professor at the Department of Clinical Neuroscience at Karolinska Institutet.

HER INTEREST IN mental images and their connection to mental health began when, as a newly-qualified clinical psychologist, she started treating refugees suffering from post-traumatic stress disorder (PTSD). PTSD is a form of psychological disorder that can arise following a traumatic experience. It can occur as a result of events where an individual has experienced a lifethreatening situation. Anybody who is involved in a traumatic event – such as a serious car accident or a traumatic child birth, for example – can potentially be affected. People with PTSD often experience intrusive memories from the traumatic event (colloquially known as ‘flashbacks’), where images or sequences of images present themselves involuntarily. 26

Medical Science–2018

“What is typical for these intrusive memories is that they are image-based, they appear suddenly, and they are difficult to avert. Many people after trauma experience intrusive memories initially, and they can be important in helping us to avoid ending up in similar situations in the future. But when these intrusive memories impair functioning in our daily lives and become more permanent, then help is needed,” says Emily Holmes. For people with fully-developed PTSD, effective treatments are now available in the form of trauma-focused cognitive-behavioural therapy and EMDR – eye-movement desensitization and reprocessing therapy. Such evidence-based treatments are both relatively time-consuming and resource-intensive. There is still a lack of effective preventive treatments which could be used directly after a trauma has been experienced. “If we can find ways of reducing the magnitude of the problem at an early stage, we would be in a much better position”, says Emily Holmes. THERE HAS ALSO BEEN a lack of basic knowledge about why certain traumatic experiences result in intrusive memories and why some people, but not all, are affected. Neither gender, genetics nor age seem to have notably large effects on the risk. But one thing is apparent: if other people are involved in the trauma, there is a significant increase in the risk of developing PTSD. “Of the people that have been caught up in natural catastrophes, such as an earthquake, relatively few go on to develop PTSD, whilst the risk is consi-

Name: Emily Holmes Title: Professor at the Department of Clinical Neuroscience, Karolinska Institutet. Also active at University of Oxford, United Kingdom, where she was one of the first female professors to be appointed in the field of psychiatry. Age: 45. Family: Partner and an 8-year old daughter. Favourite ways to relax: Painting, hiking, spending time with friends and family. Best quality for research: Curiosity. Outstanding characteristics according to colleagues: Driven, warm-hearted and equipped with an ability to think in new ways.

derably greater following experiences such as rape, assault and torture”, says Emily Holmes. In order to understand more about intrusive memories, she and her colleagues have studied the phenomenon in the laboratory using films featuring traumatic events – for example, a public safety film warning about the effects of drink-driving. “This is an established method to create temporary intrusive memories that we can then investigate to help understand and develop treatments,” says Emily Holmes. For many years, this method has enabled them to study the phenomenon of intrusive memories. Among other things, the researchers are able to register the participant’s brain activity before, while and after they watch the film. Some of the results have surprised Emily Holmes; for example, by observing the changes in the flow of blood to the brain, it is possible to predict which scene in the film will later appear in the form of an intrusive memories. This can be predicted even before the person has actually experienced a flashback. “I find this incredibly fascinating,” says Emily Holmes. HER RESEARCH GROUP has also shown that it is possible to reduce the occurrence of intrusive memories by making the participant in a study perform a certain type of task shortly after they have watched the film. In order to achieve the desired effect, the task needs to involve using mental imagery, such as the computer game Tetris, for example. “We are exploiting the fact that the brain is not able to hold in mind two images simultaneously.” Their studies show that by making the participant play Tetris at the same time as they relive their memories of the event, the occurrence of intrusive memories can be reduced. “It is not so much a question of deleting the memories, but is more about making the memories less intrusive,” says Emily Holmes. The research group has taken this further and tested the hypothesis in real-life situations – including with trauma patients at a hospital emergency-care clinic and, in a smaller study, with newly-arrived refugees. “In recent years, many refugees have


arrived in Sweden and a significant proportion of them have intrusive memories of traumatic events, which can affect their ability to concentrate. At the same time, they are trying to learn a new language and are expected to integrate into their new country. In coping with these challenges, many would benefit from advances in evidence-based psychological treatments,” says Emily Holmes. EMILY HOLMES ’ research also includes other psychological conditions. Interestingly enough, our general capacity to conjure up mental images also applies to potential future events, in the form of what her group has called ‘flashforwards’. Research shows imagining future events in the form of a picture – a flashforward – can increase the subjective probability of the event occurring and drive behaviour. In this way, flashforwards can serve to support us in the practical implementation of the plans that we have considered. But they can also cause problems. “A person with bipolar disorder who is experiencing a manic period might see clear images of the future in his/ her mind. This could, for example, be a picture of the person in a new sports car. If the person is in a depressed state, however, the image could be of their own suicide,” says Emily Holmes. She believes that we underestimate the strength and effect of these internal pictures, and has long incorporated mental imagery into her cognitive behavioural therapy with patients as a complement to verbal therapy. One example is her work with depressed patients, where the objective is to get the patient to imagine positive pictures of future events. But it is not simply a matter of ‘thinking positively’. “Thinking of positive statements in

Emily Holmes on  …

EMPATHETIC

“Refugees and people suffering from mental illness are just like everyone else, except that they are suffering. And we can all suffer,” says Emily Holmes.

word form can actually have the opposite effect. But by using pictorial thinking, a more positive effect on emotion can be achieved,” she says. According to Emily Holmes, a great deal of knowledge is still lacking from the overall research field of mental health. Worldwide, one in four individuals suffers from mental health problems and this figure looks set to

… a role-model The chemist Dorothy Hodgkin was the first – and, so far, only – British woman to be awarded the Nobel Prize. She mapped the crystal structure for insulin and penicillin. Her interest in images and basic science resulted in practically useful knowledge.

… a good quote “Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.” This is attributed to the French scientist Marie Curie – two-time recipient of the Nobel Prize and the first female laureate.

increase. Considering the scope of the problem, she believes that research in this field is scandalously underfunded. “With increased resources, we would be able to both develop better treatments and learn more about how the brain works. We are all at risk of experiencing trauma or suffering from mental illness, so we could all benefit from such investment,” says Emily Holmes.

… the importance of collaboration I am passionate about increasing the dialogue between people in general. I myself have worked together with various disciplines from mathematicians and philosophers to voluntary organisations and artists.

… being an academic citizen Research must be able to be used if it is to resolve important problems in society. In turn, this demands that researchers must communicate, inspire and become engaged beyond their own immediate sphere of interest. Medical Science–2018

27


In depth  Our friends the bacteria

Diversity rather than simplicity Lots of bacteria live on and inside our bodies. We would quickly get ill without them. But precisely how do they affect our health? One thing seems to be clear: Having varied microbiota is good. Text: Fredrik Hedlund Illustration: Björn Öberg

SKIN Microbiota on the skin is impacted by, among other things, where we live. Those who live in the countryside have a more varied composition than those who live in cities and this is positive for their health.

INTESTINES Approximately 80 per cent of the bacteria which live in our bodies are in the intestine. Several common bowel diseases are the result of an imbalance of the microbiota.

VAGINAL FLORA The vagina contains bacteria which make the environment inhospitable for other harmful microbes by lowering the pH-value.

28

Medical Science–2018


BRAIN

MOUTH Bacteria in the mouth live in a complex interplay with each other. Sugar and smoking are examples of environmental factors which can change microbiota.

During tests on mice, researchers have shown that intestinal bacteria can affect the brain development of animals and also impact their social behaviour.

Medical Science–2018

29


In depth  Our friends the bacteria

N OT VERY LONG AGO everyone, regular people as well as researchers and doctors mainly considered bacteria, funguses and viruses as being something undesirable. It is certainly true that some of them were used to manufacture certain dairy products, for fermentation of bread and alcohol, but in general microbes were something negative which, if they caused problems, were to be wiped out with a course of antibiotics, antifungal agents or other treatment as quickly as possible. We now know better. Knowledge of the role of microbes for our development and our well-being has exploded dramatically over the past decade. There is still a lot to learn and researchers are working hard to figure out how it is all connected. Research on the importance of bacteria is one of the hottest research areas right now. But there are already a lot of facts which are fairly amazing to understand. There are roughly 100 trillion microbes inside and on every human being and of these microbes 80 per cent are located in the intestine. This means that all of us are carrying around roughly ten times as many microbes as our cells in the body. The gut flora contains hundreds of different bacterial species which together have roughly 150 times as many genes as our human genome. Now there is increasing evidence that the genes of bacteria code many important and necessary substances in the body. For example, it has been illustrated that the majority of the signal substance serotonin, which many drugs against depression try to impact, is manufactured by microbes in the intestines.

30

Medical Science–2018

“Some people even say that two-thirds of everything which circulates in the body comes from the microorganisms. They are in the intestine and produce products which impact us in different ways even in the brain”, says Lars Engstrand, Professor of infectious disease control and clinical bacteriology at the Department of Microbiology, Tumor and Cell Biology and Director of the Centre for Translational Microbiome Research (CTMR) at SciLifeLab and Karolinska Institutet. It is now clear that there is two-way communication between the intestine and the brain. In the past it was believed that only the brain gave orders to the intestines on movement and emptying of the intestines and similar, now we know that orders are also given in the other direction. Researchers do not yet fully understand how the communication takes place, but simply the thought that bacteria in the intestines have some sort of functional authority on the brain for certain issues affects the self-image of human beings and may lead to you questioning who really decides. “In discussions researchers have focused on the influence of microbe genes, whether we are ten per cent human and 90 per cent microbes or whether it is more 50/50”, says Lars Engstrand, without being able to provide a definitive answer. He says that many researchers and doctors now consider microbes on and inside the body, referred to as the microbiota, as a separate organ which you need to consider. The fact that microbes contribute to our well-being in a number of different ways is crystal clear. And we get ill when there is an imbalance.

Micro glossary Microbe, generic name for microorganisms such as bacteria, funguses and viruses. Microbiota, the microbes in a specific area comprise a microbiota. Microbiome, the genes which these organisms have.

A RELATIVELY NEW THREAT against the bacterial balance is antibiotics, which target a pathogenic bacteria, but which effectively wipe out a large amount of bacteria everywhere in the body. “It’s important to realise that we shouldn’t only discuss the resistance problem in terms of the overuse of antibiotics, but also that we’re knocking out our good bacteria. You can say that antibiotics should really be used to save lives, not as a general treatment”, says Lars Engstrand. Many researchers claim that there is a link between disorders in the microbiota and conditions which have become increasingly common, for example, asthma, allergies, diabetes, obesity and depression. However, they do not yet know how these links are structured and precisely how they function. Therefore, one of the most important assignments now is to map and understand how the normal flora is structured, that is, which microbes are located on and inside a healthy human being as well as the relationship of the microbes to each other. “That’s mainly what we’re doing now, gathering large populations of healthy individuals and finding out how their gut flora, oral flora, vaginal flora or skin flora is structured. Then we have a reference”, says Lars Engstrand. “We’re at the forefront with this in Sweden as our population is very positive towards participating in such studies


Photo: John Sennet, iStockphoto

“Antibiotics should really be used to save lives, not as a general treatment.” and we also have registers which allow us to monitor patients and see what they have developed”, he continues. A difficulty of mapping the gut flora is that the intestines are long and a lot of important things happen in the small intestine where it’s difficult to take samples with current methods”, says Lars Engstrand. “For example, when you take a stool sample it doesn’t show what’s going on in the small intestine. Therefore the small intestine is a seven meter long black box. We need to find new methods to examine this important part where much of the exchange between the microorganism and the host, that is us, takes place”, he says. The question is, what do you mean by a healthy normal flora? Microbes have probably played an important role for the life and health of mammals for many millions of years. We have only noticed their role now when it seems as though our lifestyle, diet and use of antibiotics has changed the normal flora of many people. “We don’t know what the situation was in Sweden 200 years ago, perhaps we’ve already selected an abnormal gut or skin flora. But if we define health as the lack of illness and study what is normal based on the current conditions in Sweden, then we have some sort of reference base”, says Lars Engstrand. However, there is a lot to indicate that the original normal flora no longer exists. “Researchers have gone out in the jungle to populations which have never been in contact with antibiotics or a western lifestyle. They have a much richer flora than us. The western gut flora has less diversity than the indigenous people”, he says. And diversity specifically seems to be a keyword for a well-functioning microbiota. “I usually say that you should think about diversity and not be simple”, says Elisabeth Norin, Associate Professor of medical microbial ecology at the

Over the years, widespread use of antibiotics has led to the depletion of microbiota in large parts of the world.

Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet. She is somewhat of a pioneer within the area in Sweden and is an expert in faecal transplant. Exactly, transplant of stool. Something which is becoming increasingly common. “I’ve worked with this intestinal microbial world throughout my active research time, but it’s only over the last 8-10 years that others have also started to get interested. It’s a hot topic at the moment and it’s really fun”, she says. THE MOST COMMON REASON for doing a faecal transplant is that a patient

gets an antibiotic-associated infection of the bacteria Clostridium difficile. During regular antibiotic treatments large parts of the gut flora are wiped out and if you are unlucky then you have the resistant and opportunistic bacteria Clostridium difficile in the intestines. It then grows, resulting in severe diarrhoea attacks which often make the patient completely homebound. The standard treatment is more antibiotics of another kind, but if the Clostridium bacteria is resistant to this as well then you will experience problems. Faecal transplant is an old technique which is first said to have been performed in China 1,700 years ago. The method has also been used by veterinaMedical Science–2018

31


“I suddenly got diarrhoea in the spring of 2012. I couldn’t go out and had to be close to a toilet all day. After two weeks with the problem my family doctor sent me to Södersjukhuset, where I was hospitalised. I stayed there for 11 days. Antibiotics didn’t help and I was examined for various ailments. But no cause was identified and I was sent home. CHARLOTTA At home I continued JAKOBSSON to feel bad, not least Age: 36 Profession: Journalist mentally as there was no explanation for my symptoms. I wondered whether I would ever recover. The diarrhoea didn’t stop and so I was hospitalised again. Several examinations were performed, including a capsule endoscopy, in which you get to swallow a camera, the size of a pill, which takes photos from within the intestines. But it didn’t provide any new explanation. Then I got to try codeine, a painkiller which reduces intestinal motor function as a side effect. It helped against diarrhoea so I could function better in everyday life. But taking codeine all the time, which is converted to morphine in the body, made me nauseous, tired and slow. By January 2013 I was desperate. Through a doctor at the clinic Hötorgskliniken I came into contact with a research project at Karolinska Institutet which studied patients with Irritable Bowel Syndrome, IBS. I got a bacterial culture based on another person’s healthy stool delivered to my duodenum by using gastroscopy. After seven rounds of treatment I recovered. After I got ill, it took one and a half year in total until I recovered completely. The feeling was magical, I still can’t express how happy I am about having the opportunity to receive this treatment”. As told to: Cecilia Odlind

32

Medical Science–2018

Photo: Marco Glijnis/Kola Productions

“I was desperate”


Our friends the bacteria  In depth “You shouldn’t react to your intestinal bacteria. They’re important for us, we need to be able to live with them.”

Photo: Patricia Torregrosa , iStockphoto

ries in the west for hundreds of years, but it was first highlighted for human beings in the west in 1958 in a scientific report and it was only until the end of the 1970s that use of the method on a large scale started. By giving faeces, or gut flora, from a healthy person, it is possible to quickly restore the balance in the gut flora. Nine of ten patients recover in just a few days. Faecal transplants are now performed throughout the world and can be done with real faeces, but in Sweden Elisabeth Norin and her colleagues have produced a bacterial culture from a donor which they are re-cultivating in the laboratory and using. “It’s very complex and contains several hundreds of different strains. It’s controlled and guaranteed free of HIV, salmonella, shigella and the other common pathogenic intestinal bacteria. The benefit of our culture is that you can order it and use it the following day. If you will use a donor then you need to examine the donor´s health status first. So it’s faster and cheaper and we also know that it’s probably a little safer than taking it directly from a donor”, says Elisabeth Norin. THE LEGAL HANDLING of the method varies slightly in different parts of the world. In America the U.S. Food and Drug Administration has reviewed the treatment and concluded that faeces should be classified as a drug. However, at the same time the agency says that officially they will disregard this as they realise the difficulties of imposing the same requirements on faeces as on drugs. This would entail a risk of the treatment being impossible to use. In Europe there is not yet a joint regulation for faecal transplants, but experts in this area claim that faeces fall under the concept “substances of human origin” in the same way as cells, tissue and milk and this is regulated by the European Commission.

Practically the transplant can be performed in two ways. It is either administered with a tube which is inserted through the nose down past the acidic environment in the stomach to the upper small intestine. “Then it trickles down quickly and we think that the largest effect is in the lower part of the small intestine or upper part of the large intestine”, says Elisabeth Norin. Or it is administered with an enema where patients lie on their side and try to retain the fluid for as long as possible. Then it is a benefit to use the bacterial culture which researchers provide where the dose is only 30 millilitres, while a more regular faecal transplant entails four to five decilitres. She cannot say how many faecal transplants are performed every year in Sweden, but estimates that the number is somewhere between 100 and 1,000 transplants, so it is not a routine treatment. One reason for the difficulty in finding out the exact number of trans-

plants is that the interest in using faecal transplants as a treatment is rising with increasing evidence of a problematic gut flora impacting our health in many different ways. Therefore, there are several diseases for which researchers are either already conducting or planning tests. Elisabeth Norin is also involved in a study on patients who are suffering from Irritable Bowel Syndrome (IBS). “But here our results are not as good as for the Clostridium difficile infection where nine of ten recover. Here roughly three of ten patients recover fully or get a lot better”, she says. ONE REASON FOR THIS may be

that there are several underlying reasons for the problems, and it is difficult to find patients who may benefit from the treatment. Eduardo Villablanca is Assistant Professor at the Department of Medicine, Solna, Karolinska Institutet and he is researching inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease. He explains that it has been ascertained

“There are many people who describe an improvement in their inflammatory bowel disease when taking yoghurt and probiotic cures, so one cannot say that this doesn’t work. We do however require more randomised studies to be sure,” says Professor Lars Engstrand.

Medical Science–2018

33


In depth  Our friends the bacteria

34

Medicinsk Medical Science–2018 Vetenskap №2–2016

Even in this context there have been attempts to restore the gut flora through faecal transplant, but the results are difficult to interpret. “Some people have reported good results, while others have not seen any change and the condition of some patients has even deteriorated. So it’s quite contradictory right now and we still have a lot to learn”, says Eduardo Villablanca. HOWEVER, THE GUT FLORA

does not only strengthen the immune system, it also plays a vital role in the brain’s development. In 2011 a study was published which showed that mice who were born and grew up in a completely bacteria-free environment, and thus did not have gut flora at all, had a different sort of brain development and behaviour than regular mice. The bacteria-free mice were less worried but were hyperactive and showed differing social behaviour. Rochellys Diaz Heijtz, Associate Professor at the Department of Neuroscience at Karolinska Institutet was behind the study which was published in the scientific journal PNAS. Shortly afterwards there were several other studies which confirmed the same results and together these articles

How to maintain a balance in the vaginal flora The researcher Juan Du at Karolinska Institutet is studying the relation of bacteria to the human papilloma virus (HPV) and how this impacts the development of cervical cancer. How can vaginal flora protect against illnesses?

“We believe that microbiota is one of the factors which impacts the normal development of the brain.” formed the start of intensive research on the connection between the gut flora and the brain’s development. Thereafter in animal experiments Rochellys Diaz Heijtz illustrated that there is a time window from birth and roughly until sexual maturity in which it is possible to normalise most of the deviating behaviours. “Now we have delved deeper and realised that there is a time window which can vary for different types of behaviours. It’s very early for social behaviours, but it’s a little later for impact on the brain’s anatomy”, says Rochellys Diaz Heijtz. Her hypothesis is that disorders in the gut flora during the first two to three years of the child can have major consequences. “We believe that microbiota is one of the factors which impacts the normal

“Bacteria can, for example, lower the pH-value, which lactobacillus do, and in this way make the environment inhospitable for other microbes which can otherwise cause bacterial vaginosis or fungus infections”. Can microbiota also protect against deadly diseases like cancer? “HPV infection can lead to cervical cancer. We are now studying whether specific bacteria in the vaginal flora, for example, lactobacillus can eliminate the remaining HPV infection. Now most young women are vaccinated against HPV, but only

against certain types of the virus. We’re interested in better understanding how the vaginal flora impacts the ability to cure HPV type infections which are not covered by the vaccine”. What is the ideal way of taking care of your vaginal flora? “You should maintain good hygiene around the vulva, but allow the vaginal flora to clean the vaginal canal, it’s best at doing that. Showering the vaginal canal is not advisable. You should also pay extra attention after completing a course of antibiotics as the vaginal flora may be impacted then”.

Photo: John Sennett , Ulf Sirborn

that inflammatory bowel diseases are the result of the body’s immune system reacting incorrectly and attacking certain bacteria in the gut flora. However, the people who are affected have certain mutations which in some way increase the probability of the immune system reacting incorrectly. “You shouldn’t react to your intestinal bacteria. They’re important for us, we need to be able to live with them. Therefore, we’re trying to understand why our immune system perceives the bacteria as enemies”, he says. His research is still at an early stage. However, he has already seen that the time it takes between an injury occurring in the intestines, for example, from consumption of alcohol, until it is fixed plays a role. “If it happens quickly, the risk of having an immune reaction minimises. Our hypothesis is that those who get inflammatory bowel diseases have mutations which make the repair slower”, he says. However, there are also environmental factors which play a role. For reasons which are not yet known, Scandinavia and North America have a very high incidence of inflammatory bowel diseases and when people from Asia move here then the first generation is not affected. However, their children have a higher risk of contracting inflammatory bowel diseases. “So even if they have the same genetic background, the risk of contracting it increases. This suggests that the environment can play a more important role than genetics”, says Eduardo Villablanca. One of the tasks of the gut flora is to teach the immune system not to react against the friendly bacteria which are a part of the flora and there are now studies to indicate that children born in Scandinavia do not have the same amount of diversity in the gut flora as children from, for example, Russia or Estonia. Consequently the immune system of Scandinavian children is exposed to different bacteria to a lesser degree. According to Eduardo Villablanca, this may be one factor behind inflammatory bowel diseases. “Our aim is to understand how we can retrain the immune system, either through diet or the microbiota in some way”, he says.


nal and presses on the rectum. Nursing continues to contribute to normal flora. After a while children start to develop their own microbiota. If these processes are disrupted, or if our modern lifestyle eliminates contact with certain bacteria, the diversity of microbiota may decrease, which is not ideal. A major threat against microbiota is treatment with antibiotics and now evidence is starting to accumulate to show the link. “We’ve recently conducted an animal study, which has not been published yet, which shows that pregnant mice who are given antibiotics during pregnancy have a higher risk of giving birth to mice which are hyperactive and have different social behaviour”, says Rochellys Diaz Heijtz. She also talks about a recently published study on people from New Zealand which shows that children who get antibiotics during their first year of life have lower cognitive development. “Naturally the results need to be confirmed in more studies by other researchers before we can be sure that this is true”, says Rochellys Diaz Heijtz. She claims that the evidence is still strong enough for the microbiota’s importance for development of health and well-being of human beings that we should act to protect it. “We now have the opportunity to be more careful for the factors which may be devastating for the microbiota. We can try to avoid using antibiotics unnecessarily. We’re not saying that we should stop using them completely, but we should be more careful in terms of how often we give them and why”, she says.

development of the brain and that disorders of the microbiota can partly explain common neuropsychiatric diseases such as autism and ADHD. We’re not saying that it causes the diseases, but it can be a contributory factor”, says Rochellys Diaz Heijtz. Roughly 30 years ago the hygiene hypothesis was launched, which is based on the notion that the higher incidence of allergies among children is the result of them not being exposed to as many bacteria in our too clean homes. Now

we are increasingly starting to consider our microbiota as an important piece of the puzzle for the explanation as the hypothesis is gaining ground. The interplay between us and our bacteria impacts a range of different functions and imbalanced microbiota can lead to disorders of several different areas, not just allergies. In connection with delivery, newborns get a dose of the mother’s gut flora as some stool is pushed out when the child passes through the vaginal ca-

ANOTHER THREAT against the microbiota is C-section. When children do not receive the first dose of stool which normally occurs during vaginal delivery, the microbiota is affected. A number of small studies have also been published to illustrate a link between C-section and lower cognitive development. However, a recently conducted Swedish study which was both significantly larger and performed in a better manner could not see any link. “After reading most of the studies in the area, my conclusion was that there is undoubtedly evidence to support the claim that the delivery method impacts Medical Science–2018

35


In depth  Our friends the bacteria

IT HAS BEEN known for a while that skin flora is quite dependent on the environment in the surroundings, whether it is cold or hot, humid or dry and so on. However, in an article from 2012 published in the scientific journal PNAS, Harri Alenius and his research colleagues have shown that the composition of skin flora is clearly also dependent on the biological diversity of the nature in which we live. They showed that diversity in the skin microbiota was greater among people who lived in an area with a lot of forests and farmland compared to those who lived in densely developed areas and close to water. “It seems as though the surrounding impacts our skin microbiota which then trains the immune system. The findings show that the immune system is not trained properly in an urban 36

Medical Science–2018

environment”, he says. Harri Alenius points out that in cities there are many more people who suffer from allergies and asthma. “Where you live and how much you are in contact with the natural microbiota in nature impacts our microbiota and can have dramatic effects on health”, he says.

“I don’t think that bacteria are smart, but they can develop smart behaviour to survive. It’s like war tactics”

Photo: Ulf Sirborn

which type of microbes the child receives. But more studies on the long-term outcome and cognitive development are required”, says Rochellys Diaz Heijtz. At the same time new research shows that gut flora is impacted easily by the food we eat and that exercise also contributes to increasing diversity in the gut flora. “Therefore it’s important for children that they eat a varied diet and exercise. Actually these are things which we already know we should do, but perhaps don’t do, but now we have more good reasons to do them”, she says. Another collection of microbes which protects us is skin flora. Skin has a set of microbes which live in symbiosis with us, in the same way as the stomach. The composition of skin microbiota varies slightly depending on the moisture and pH-value of the skin. In the same way as for gut flora, researchers have seen that the diversity of microbes is high on healthy skin. Often one or several bacteria take over during various skin diseases. “When one or a few microbes take over then we can see problems, but we don’t really know whether this is a cause of the problem or a symptom of it”, says Harri Alenius, Professor of molecular toxicology at the Institute of Environmental Medicine at Karolinska Institutet.


“In contrast to our human genes, which we can’t do much about, we can actually impact the arrangement of our microorganisms.”

Photo: Gustav Mårtensson

Another relatively modern threat against the protective skin flora is soap which, similar to antibiotics, albeit with a weaker effect, eliminates both enemies and friends in the microbiota. “It depends a bit on which soap you use and how sensitive you are, but we’ve now realised that we remove the good microbes at the same time as we take away the bad microbes. And we’ve got a lot of good friends on the skin which do a terrific job. If you remove them with soap then you may have irritation problems”, says Harri Alenius. THE MOUTH IS another area where we have specific microbiota comprising hundreds of bacterial species which coexist with us and create a protective environment in the oral cavity. Even here researchers have concluded that there are disturbances in the balance between different bacterial species in the oral cavity, which appear to cause oral diseases. Disturbances which we often cause ourselves through our behaviour. “For example, there is a bacterium which is strongly associated with periodontitis, the leading cause of tooth loss. It can also be found in the mouth of healthy people, but to a lower extent. This bacterium requires blood to grow and if you don’t brush your teeth or don’t use dental floss then the gums start to bleed, which then favours its overgrowth”, says Nagihan Bostanci, Professor of inflammation research, specialising in periodontology at the Department of Dental Medicine, Karolinska Institute. She is also researching how the interaction between the microbiota and tissues in the mouth causes inflammation. Bacteria in the mouth are organised in a biofilm, which is similar to complex societies of bacteria which have merged together in a matrix-like structure where they sit together closely and help each other. This makes it quite difficult

to tackle them. Nagihan Bostanci has developed a three-dimensional model of the mouth with living tissue and oral bacteria so that she can study different effects and understand what happens in the inflammation around the teeth. “Hopefully we can bridge the technical problems of other models. Laboratory animals don’t have the same oral microbiota as us and due to ethical reasons we can’t let the illness proceed to the destructive phase in studies on human subjects”, she says. THE EXPERIMENTAL model of the oral cavity is not completely perfect, but it is still one of the most advanced models available. There she has been able to show that bacteria and tissue have a sort of battle with each other where the tissues release hundreds of proteins, trying to kill the bacteria. In turn bacteria release enzymes to neutralise the proteins. There are even bacteria found which hijack host cells and trick the host not to release its most effective

Have you changed your diet? We asked our bacteria researchers whether the new insights on the significance of microbiota have changed their relationship with food. Lars Engstrand “Yes, I eat a more varied diet, less meat and more fruit, vegetables and fish compared to what I ate a few years ago”. Elisabeth Norin “No, I don’t think so. I have a mixed diet and like fish a lot. On the other hand now that I have grandchildren I tend to tell the parents that they shouldn’t give

weapons immediately. This makes the host response weaker. “But when the bacteria have invaded and established a stronghold then they release everything they have. I don’t think that bacteria are smart, but they can develop smart behaviour to survive. It’s like war tactics”, she says. With a delicate balance between the microbes on and inside our body, we need to take care of our microbiota. And even if the new knowledge essentially changes the view of how everything is connected, the advice is still the same. We should eat a varied diet, be out in nature, exercise, brush our teeth and use dental floss. However, soon this advice may become more specific. “Soon we will have more knowledge of this balance and with that also better opportunities to impact this new organ. In contrast to our human genes, which we can’t do much about, we can actually impact the arrangement of our microorganisms and thereby also the substances which their genes code for”, says Lars Engstrand.

yoghurt to the children during the first months but instead allow the gut flora to develop as normally as possible. Research has shown that yoghurt can disrupt the early development and change the gut flora, which may be negative for health”. Rochellys Diaz Heijtz “Yes, absolutely, I’ve changed my diet completely. I avoid junk food, animal fat and refined carbohydrates, such as white bread and regular pasta. I’ve noticed both physical and mental effects. For example, I have more energy and feel more relaxed”. Harri Alenius “No, I haven’t changed my diet habits. On the other

hand I’ve tried to get my family and friends to be out in nature more”. Nagihan Bostanci “Yes, I try to maintain a balanced diet and avoid frequent and large amounts of sugar or fizzy drinks which stimulate the growth of acid-producing bacteria which cause cavities. I would never smoke either”. Eduardo Villablanca “Yes, I try to eat more fibre, food which is good for the microbiota. We also now know that broccoli contains components which are good for the immune system. So every time I eat broccoli I think that I’m doing something good for both my microbiota and my immune system”. Medical Science–2018

37


Curious about  Artificial intelligence

How AI could outsmart disease

The development of artificial intelligence is moving quickly and will change our lives – not least when we go to the doctor. We are taking the temperature of the AI fever within medicine. Text: Ola Danielsson Illustration: Björn Öberg

38

Medical Science–2018


Medical Science–2018

39


Curious about  Artificial intelligence

T IS LIKE a baby who learns something new every day, says Max Gordon, chief physician and researcher in orthopaedics at the Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet. He is talking about an artificial intelligence – a computer program with the human brain as a prototype – which is currently learning to interpret X-ray pictures in his lab. Instead of a doctor identifying fractures and assessing which patients require surgery, the idea is that computers should be able to do this in the future. There would be several benefits of such an artificial helper in hospitals. “An artificial intelligence never gets tired and can work unsocial hours. Doctors will instead get the time to look more closely at the complicated cases and meet patients,” says Max Gordon. Instead of regular DNA the AI baby has algorithms, mathematical instructions which it received from its programmer. The program is not designed to do everything right, like a regular computer program, but to be able to learn a task through practice. “That is the intelligent part. It is similar to the way the human brain learns by processing information in a network of cells,” says Max Gordon. Nobody explains to the program in Max Gordon’s lab how to behave in order to interpret the photos, instead it

40

Medical Science–2018

THE CONCEPT OF creating machines which can think has existed since Antiquity and eventually resulted in the development of the first computers. However, many people thought that it was impossible to teach a computer to think like a human being. Nonetheless, the AI advocates were persistent. In 1948 the mathematical genius John von Neumann said: “If you will tell me precisely what it is that a machine cannot do, then I can always make a machine which will do just that”. “The theories behind artificial intelligence are old but they have been difficult to implement in practise. Just a few years ago computing power reached a level which actually made the programs start to function,” says Max Gordon, who has worked with programing since his younger years.

Facts: 3 famous AI:s Eliza was a basic chat robot developed in 1966. Despite the fact that Eliza was completely unintelligent, many felt that she really showed understanding of psychological problems, among other things. Eliza’s standard phrases were “how are you doing now?” and “tell me more”. AlphaGo is a computer program that plays the strategically advanced board game Go. When AlphaGo defeated the champion Lee Sedol in February 2016, the journal Science considered, as one of nine options, choosing it as Breakthrough of the Year (instead the award went to the discovery of gravitational waves). Watson is a computer system created by IBM. Originally developed to answer questions on the quiz show Jeopardy!, it is currently pursuing a medical career.

THE BREAKTHROUGH OCCURED in 2012 in a competition where computer programs were assigned to classify millions of photos retrieved online. In one corner of the ring there were traditional programs, specifically written for the purpose by experts in computer vision. In the other corner of the ring there were AI programs with no previous knowledge, but with the potential to learn. The competition was won unexpectedly by a significant margin by the AI program AlexNet, created by the researcher Alex Krizhevsky at the University of Toronto, after 5 days of practice. Three years later an AI program won again – but now at a level which not only surpassed other computer programs, but human beings as well. Human beings have also been defeated by computers in games such as chess, the quiz Jeopardy and board game Go. Thus it seems as though AI programs are about to move on from the baby phase and reach a superhuman level in several areas. The successful algorithms are immediately adopted by several developers who customise them to new tasks. For example, the algorithm for AlexNet was downloaded by Max Gordon who started to train it to interpret X-ray pictures. Another promising algorithm was further developed by Mattias Nilsson Benfatto, computational linguist and researcher at the Department of Clinical Neuroscience, Karolinska Institutet. He trained it for a completely different task, namely to detect dyslexia among school pupils. “DYSLEXIA IS NOT located in the eyes, but is the result of the brain being unable to decode text. By measuring how the eyes move, we can get a view of the linguistic processes that go on inside the head when a person reads or writes,” he says.

Photo: Stefan Zimmerman.

I

learns this on its own, he clarifies. However, at the start during the practice period, Max Gordon needs to be available in the background to give the lead, adjust the algorithms slightly and confirm when the program gives the right answer. His research results, which have not been published yet, show that it is currently right for over 90 per cent of the cases, which is in line with a regular radiologist.

”An artificial intelligence never gets tired and can work unsocial hours.”


One way of identifying children who are in the risk zone of dyslexia, so that they can receive assistance and support, is to let entire school classes take language tests. Another way is to measure eye movements. “A strength of measuring eye movements is that it becomes more objective. In traditional paper tests there are several sources of error, as pupils, for example, need to handle papers and a pencil, and the tests need to be marked by someone. It is also faster, the measurement only takes a few minutes,” says Mattias Nilsson Benfatto. The problem is only that the measurements result in very large amounts of data which is difficult to analyse manually. By training the AI algorithm, Mattias Nilsson Benfatto and his colleague Gustaf Öqvist Seimyr have now automated the analysis, which has made eye movement measurements a more useful tool. In a research project, the results of which are currently being analysed, Mattias Nilsson Benfatto and his colleagues have conducted eye movement measurements in school classes in Järfälla and Trosa. They want to find out about the reliability of the automatic analysis and at what age dyslexia can be identified at the earliest. “Our results so far show a high level of conformity, 90 per cent, between the AI program’s assessment and traditional assessments,” says Mattias Nilsson Benfatto. This is good enough for Mattias Nilsson Benfatto and Gustaf Öqvist Seimyr to now use the technology within the framework of their company, Optolexia, which offers dyslexia scanning to schools. The technology which Max Gordon and Mattias Nilsson Benfatto use is referred to as ‘supervised learning,’ as it requires a human being to supervise the learning with solutions being available. ANOTHER, MORE freethinking artificial intelligence, can be found in a computer at SciLifeLab in Solna. “Artificial intelligence may be a good way of automating things which humans can also do. But many hope that artificial intelligence will also be able

to contribute with something completely new, perhaps detect things which no human being has thought about looking for,” says Mikael Huss, researcher in bioinformatics at SciLifeLab. As an example he mentions the computer program Alpha­ Go, which beat one of the world’s best players in the board game Go in 2016. First the computer observed human matches, then it played matches against itself and learnt from its mistakes. The result was a playing style which is not human. “It played in a way which, according to what the Go players have learnt

”Many hope that artificial intelligence will also be able to contribute with something completely new.”

from childhood, ought to be completely wrong. So it had seen something, found a pattern, which humans had completely missed,” says Mikael Huss. If such a system was applied within medicine, it would find previously unknown scientific links, for example between different diseases or, well... something completely unexpected. This type of breakthrough has not occurred yet, but researchers are working on it. Mikael Huss has started little by little by allowing an AI program to analyse data open-mindedly on the content in some cells, without explaining what is right and wrong. The information was obtained from two studies which other researchers conducted with what is referred to as ‘single cell analysis’. The aim was to see whether the program could find a way to screen the information on its own and create a compact description, a type of definition, of what characterises different cell types. “It worked quite well, the program made roughly the same assessment as the researchers,” he says. Medical Science–2018

41


Curious about  Artificial intelligence The experiment was conducted as part of a degree project which Mikael Huss supervised. Even though the results were promising, the reliability of results was unclear. The program needs to become much more proficient in its task in order to reach a level which would make it workable practically. Reaching this level necessitates practise on many more examples first. In this context Mikael Huss sees a challenge for artificial intelligence within the medical area. “An AI program finds it easiest to learn if it can practise on lots of examples, each of which can be described with relatively few parameters. But within medicine often the opposite applies. Researchers often have problems collecting information on an adequate number of patients for their studies, but each case contains a large amount of data which can be interpreted in different ways,” he says. However, in the Internet’s sea of information AI thrives like fish in water. AI programs are currently being fed millions of practice examples, in the form of news articles and posts on social media which are translated automatically. You have probably seen them in your Facebook feed. The computer company IBM is trying to give its computer system Watson similar conditions, but for the scientific area by inundating it with all text-based scientific information the company comes across, in the form of scientific articles, textbooks and journals. ACCORDING TO IBM, 80 per cent of all health data has been unavailable until now as it is unstructured. However, Watson will be able to see the information and has a dizzying reading speed – almost 200 million pages of text in three seconds. Marketing texts portray superb plans for “Dr Watson” which will initially learn everything about cancer research. The computer system has apparently already made several cancer diagnoses where human doctors have failed. Max Gordon says that there is great enthusiasm in Sweden as well, but believes that it will take a while for artificial intelligence to assume a significant role within medical care. At least in Sweden. “I’ve spent a lot of my research time applying for different permits and 42

Medical Science–2018

trying to understand the rules which apply. Everyone is enthusiastic but there are not any good established paths, as a result of which the preparations in Sweden take longer than they do, for example, for research groups in the US which I have been in touch with,” he says. A poor translation will probably not result in anybody’s death, which is why artificial intelligence can be rampant in relatively risk-free environments, such as in your Facebook feed. But an artificial intelligence which will work in medical care must be a fully-fledged pro from day one and consequently it may take a while before it is assigned important duties. However, Max Gordon believes that it is mainly a matter of time – artificial intelligence will change medical care. This does not necessarily mean that artificial intelligence will replace medical care personnel, but it will lead to a division of tasks between things which humans and machines respectively are best at. “I’m convinced that diagnostics will mainly take place with artificial intelligence. I can’t see any reason for why that won’t be the case, as computers will soon be able to do it in a faster, better and safer manner than human beings,” he says. But communicating a diagnosis to the patient with empathetic sensitivity, or making the right choice between two treatments with their subjective advantages and disadvantages – such things are still done best by humans. “Computers can make risk assessments and present different options. But they don’t have any understanding of the subjective experiences of humans. I think that the role of doctors will progress and focus more on the meeting with patients,” predicts Max Gordon.

”Computers can make risk assessments and present different options. But they don’t have any understanding of the subjective experiences of humans.”

According to researchers, artificial intelligence can revolutionise diagnostics.

The artificial intelligence which has been developed until now can solve limited tasks. Whether this now means that machines can think is uncertain. If that is the case then the thinking is very narrow and single-minded, compared to what us humans do when we think. But maybe at one point what is referred to as general artificial intelligence will develop – a computer which can think freely and learn anything. SOME THINKERS warn that the development of artificial intelligence may be the biggest mistake of mankind. What is there to guarantee that a super intelligence, which is superior to human beings in all areas, will be kind towards us? Others believe that artificial intelligence will solve all of humanity´s big problems. Mikael Huss agrees that major changes are underway, but does not believe that we will get to see this artificial intelligence taking over the world. “Artificial intelligence is both overhyped and underhyped. A lot of things in society will be managed by artificial intelligence in the future, I really believe that. Step by step we will accept things which facilitate our life, not least within areas such as research and medical care. But when that happens we will already be used to it, just like with all technology, it won’t feel like science fiction anymore,” he says.


A close look at cancer stem cells  Advances

The root of evil

And?

Text: Mårten Göthlin Illustration: Anders Kjellberg

How? Where?

At Karolinska Institutet, researchers have succeeded in distinguishing cancer stem cells, cells that drive the disease, from ordinary cancer cells in leukaemia patients. This knowledge is now used to attempt to develop drugs that specifically knock out these cells and prevent them from becoming resistant to treatment.

Certain genetic mutations that control cell growth, cell division and cell function can contribute to the formation of cancer cells, but exactly how and why is something that scientists are still attempting to unravel. The ability of cancer stem cells to regenerate into cancer cells with entirely new properties means that the cancer may become more resistant to treatment, and even more aggressive.

The origins of cancer stem cells may vary. Both stem cells and normal cells, wherever they are in the body, can go through mutations that give them the ability for uncontrolled division.

What? They say that no two cancers are alike, and one of the reasons for this is cancer stem cells. Just like normal stem cells, which can develop into many different cell types, cancer stem cells are able to form various types of cancer cells that require different forms of treatment.

Source: Petter Woll, researcher at the Department of Medicine, Huddinge, Karolinska Institutet. Medical Science–2018

43


In focus Tinnitus

“Not enough attention is paid to tinnitus” Tinnitus can dramatically lower the quality of life. Effective treatments are lacking, but new research which shows that, in some specific cases, tinnitus can be hereditary can hopefully lead to new drugs in the future. Text: Maja Lundbäck Photo: Annika af Klercker

T

ODAY, EVERY SIXTH Swede experiences tinnitus, the perception of sound that do not physically exist. Tones are the most commonly perceived sound, but buzzing, peeping, humming, swishing, droning, whooshing, whistling, or beats that follows the heart rhythms can also be heard. For most people the symptoms are mild, but for about ten percent of those affected, tinnitus is extremely troublesome. “Not being able to get away from tinnitus often results in clinically significant stress and anxiety. Some people have problems sleeping, with their social life, and difficulties working; the risk of sick leave and disability pension increases,” comments Christopher Cederroth, a researcher at the Department of Physiology and Pharmacology at the Karolinska Institutet. Every second person with tinnitus also suffers from sound hypersensitivity, which in a mild form makes it more difficult to be present in noisy surroundings or go to a restaurant; in the worst cases each small sound is a nightmare.

44

Medical Science–2018

TINNITUS IS STILL NOT classified as a disease, but as a symptom of other diseases. “This is most probably the reason why tinnitus has not received sufficient attention as an important health issue. But I believe that certain forms can be considered as diseases,” says Christopher Cederroth. Many people have experienced “ringing” in their ears after a loud concert. Often the problem

has disappeared the next morning. But according to Christopher Cederroth, it isn’t that simple. “This ringing is a sign that a damage has occurred, and repeated exposure to noise can result in permanent tinnitus. This even applies to music that you listen to at a moderate volume, because it’s also a question of how often you listen,“ he explains. THE CURRENT THEORY among researchers in the field is that tinnitus occurs when the sensitive nerve cells in the inner ear, generally those that capture the highest frequencies, are damaged. The brain, which is used to receive this sensory input, tries to compensate for the loss of these signals. This results in a type of overactivity in the nerve cells in the brain. Likewise as it is possible to experience sensations from an amputated part of the body, the sensation of sound can be experienced at the same frequency than that at which damage has occurred. “Animal studies have shown an increased activity in the brain’s auditory centre, but the emotional and cognitive areas of the brain can also contribute to reinforcing tinnitus. If we feel stressed, anxious or think about tinnitus, the activity in the brain’s auditory centre increases and the burden accompanying tinnitus is exacerbated,” explains Christopher Cederroth. IN SWEDEN, cognitive behavioural therapy, CBT, is recommended, which can make it easier for people to manage their symptoms; however, psychoth-

Effective treatments are available, but more are needed Treatments with proven effect: CBT: Psychotherapy that can make the symptoms easier to manage. Notch music therapy: An app that filters out sounds that are at the same frequency as the tinnitus tone. Hearing aids: For patients with hearing loss. Cochlea implant: The auditory nerve in the inner ear is stimulated using weak electrical impulses; highly effective for people with hearing loss. Promising treatment: Vagus nerve stimulation: An electrode implanted in the body stimulates a nerve at the same time as the person hears a certain sound. Only a handful of small studies on people. There is also a number of alternative treatments that lack scientifically-evidenced effect. Source: Christopher Cederroth


“This ringing is a sign that a damage has occurred, and repeated exposure to noise can result in permanent tinnitus.” erapy does not actually silence the tinnitus. It is difficult to find good treatments, and only small resources are allocated to research. Moreover, it takes time to introduce effective methods that are available in Sweden. “This is a shame, because several treatment options are supported by evidence,” comments Christopher Cederroth. Cochlear implants, which stimulate the auditory nerve in the inner ear using weak electrical impulses, have been shown to remove tinnitus in people with hearing loss. Another method that is used in Germany is a form of sound therapy, called “Notch music therapy”. This uses special telephone applications or hearing aids which filter out the sounds in the range close to the tone experienced with the tinnitus. Notch music therapy can be used with people who experience a tone in the ear. Unfortunately, as there are so many variants of tinnitus, there are still many people who do not get help. THAT THE ENVIRONMENT has a major effect on the problem, there is no doubt. The risk of being affected by tinnitus is greatest in metropolitan areas and increases with age. In Stockholm, every third person over 60 is affected and, according to Christopher Cederroth, the problem will be increasing in line with our modern lifestyle with a lot of sound and noise pollution. “Many people listen in their earphones in a noisy background at high volume even though the phone alerts you with a red colour if the sound exceeds 85 decibels. This is not good, and even more if you are young,” he says. Whether you develop tinnitus appears to depend on a combination of how high, how often, and for how long you are exposed to sound. There also appear to be differences in how predisposed you are to being affected. Christopher Cederroth and his colleagues recently published a study which showed that genetics can sometimes be

Christopher Cederroth has himself experienced tinnitus since 2002. He was the bass player in a band for 10 years and stood directly next to the drummer without any hearing protection. “That made my ears more vulnerable. During a New Year’s celebrations, a dynamite stick exploded next to my left ear. Directly after the explosion, a tone started in my ear which I still hear every day,” he says.

more important than the environment. Using the Swedish Twin Registry, the researchers could see that tinnitus in both ears, so-called bilateral tinnitus, show high heritability, at least in men. This discovery makes it possible to better understand how tinnitus occurs. “Through our discovery, I hope that we will be able to develop an effec-

tive drug against tinnitus. But we also know that tinnitus is sustained and enhanced by thoughts and emotions. I therefore believe that, in order to provide optimal treatment, we must look at tinnitus from an interdisciplinary perspective, and consider tackling the problem from several angles at the same time,” he concludes. Medical Science–2018

45


Advances  5 questions EMMA FRANS

Researcher in the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet.

Why should we be more critical? She has been described as one of the funniest people in Sweden, but Emma Frans’ message is no joke. “Science is not perfect, but it’s our best option. We should be careful when dealing with it.” Text: Cecilia Odlind Photo: Annika af Klercker Apart from doing research, Emma Frans came out with a book during 2017 and was awarded the Swedish Grand Prize for Journalism in the Voice of the Year category.

You are always promoting a critical way of thinking – why?

“Today more than ever it is easier for individuals to find ‘facts’ on the internet that support a certain argument. Fact checking is increasingly becoming an individual responsibility. As a researcher, you are trained to take a scientific approach. I think it is important for the general public to get better at doing this as well.”

which means the conclusions drawn are not clear-cut.”

What should we pay attention to when we read about new research?

What is the biggest challenge faced when discussing these issues?

“Who is behind the research? If it has been funded by an organisation with a certain agenda, this may affect the results. Another common problem is correlations being presented as causal links. Do we actually become clever from eating fish? Or do clever people eat more fish because they have read that it is good for you? Many also fail to realise that results from cell and animal experiments do not always translate directly to knowledge about people. Likewise, some research is done on too small a scale or is based on unreliable data, 46

Medical Science–2018

“Talking about the shortcomings in the research while at the same time explaining why it is necessary. Science is not perfect, after all. At the same time, it is so much better than the alternatives: pseudoscience, gut instinct or something the bloke down at the gym told you.” What do you research yourself?

“We are nearing the end of a research project at the moment that is indicating that ADHD increases the risk of cardiovascular diseases. There are those who suspect that ADHD drugs are increasing

this risk, but our results are suggesting that those who take the medication cope better.” You also tweet, blog, create podcasts, write books – and so on. Why?

“I felt that scientists’ voices weren’t being heard enough in public debate and wanted to contribute. My efforts have been warmly received: people are very keen to hear about popular science in the field of medicine. It is also possible that bad reporting about research could stop people from believing in science. Taking the scientific approach is the most effective tool we have for finding out the truth though. That’s why it’s important for us to inform people about new research in a credible way.”


Scientific language  Advances

The language of science has become harder to understand It is not always easy to understand a scientific article. And with time it has become even harder, according to a new study from Karolinska Institutet.

Photo: iStockphoto

Text: Ola Danielsson SCIENTIFIC ARTICLES are not known for being easy to read. But is it the research per se that is becoming increasingly impenetrable or the way that researchers describe it? To answer this question, four doctoral students at Karolinska Institutet have examined how readability has changed over time in over 700,000 abstracts published between the years 1881 and 2015 in twelve different disciplines, including medicine, psychology, biology and ecology. “We observed a strong trend showing that scientific texts have become more difficult to read since the 1800s,” says William Hedley Thompson, who carried out the study together with two fellow doctoral students in their spare time from working in the Department of Clinical Neuroscience at Karolinska Institutet. “All twelve research fields displayed this trend, but there were differences in magnitude.” Readability was calculated using two different metrics: Flesch Reading Ease and New Dale Chall. They measure various factors that affect how difficult it is to read a text, such as the number of words per sentence and number of syllables per word. “These metrics have been used to study change in readability in many different fields and media,” says William Hedley Thompson. “One well-

known example is that transcripts of US presidential speeches have become easier to read over time. But in research we see the opposite trend.” A possible reason for the increasing difficulty of scientific texts is that the research has become more niched and complicated. However, the study also shows that “general scientific jargon” – i.e. words that are used often by researchers but that are not technical terms, such as “robust”, “moreover” and “novel” – have gradually become more common. “These findings indicate that science has become harder to understand in purely linguistic terms, and not only because of a more specialized subject matter,” explains William Hedley

Thompson. “One can speculate that new researchers feel that the scientific jargon used by earlier generations sounds serious and scientific, which reinforces these aspects of their own writing.” ”Clear communication is an important part of the scientific process, as it allows results not only to be replicated by other researchers, but also to be better understood by the wider public,” William Hedley Thompson points out. “Researchers should try to write as clearly and comprehensibly as possible, in order to maximise accessibility. This allows research findings to be spread and understood by more people and thus have a greater impact on society.” eLife September 2017 Medical Science–2018

47


Top publications  Many years of fieldwork have facilitated research into the prevalence of cerebral palsy among children in Uganda.

Major survey of cerebral palsy in Uganda reduces knowledge gap STUDIES FROM high-income countries show that about ten per cent of all children have some type of neurodevelopmental disorder and that approximately two in every thousand have cerebral palsy. The corresponding information has been lacking for low and middleincome countries. Since 2005, field workers have annually collected infor48

Medical Science–2018

mation in a health and demographic surveillance system that Karolinska Institutet helped to devise. The data gathered includes birth, death and migration for all people living in a rural part of eastern Uganda. In a 2015 survey, over 30,000 children were screened for cerebral palsy. The results show that cerebral palsy

in 2-17 year-olds is approximately 50 per cent more common in Uganda than in high-income countries, and that, in Uganda, the prevalence of cerebral palsy was twice as high in the younger 2-7 age group than in the 8-17 age group. “In many countries, children with disabilities are neglected and discriminated against and live under difficult circumstances. A first step towards changing this is to show that these children exist and to demonstrate how common various neurodevelopmental disorders are,” says Professor Hans Forssberg of the Department of Women’s and Children’s Health at Karolinska Institutet, who led the study. The survey, conducted in collaboration with Angelina Kakooza-Mwesige and her colleagues at Makerere University in Kampala, Uganda, also shows that the reasons why children develop cerebral palsy differs to that in high income countries, where approximately 40 per cent of sufferers are premature births. In Uganda, only 2 per cent of children with cerebral palsy were premature births, possible because children born prematurely do not survive. A quarter of the children surveyed in Uganda acquired their brain damage after the first month of life, compared to only 5 per cent in high income countries. In interviews, guardians witnessed that their children were born and developed normally until suddenly falling sick with fever and convulsions. According to the researchers, the likely cause of the brain damage is cerebral malaria, which can be tackled with preventive measures against infection or early treatment. Prevalence of cerebral palsy in Uganda: a population-based study Kakooza-Mwesige A, Andrews C, Peterson S, Wabwire Mangen F, Eliasson AC, Forssberg H Lancet Global Health, October 2017

Photo: Istockphoto.

A selection of recent publications from Karolinska Institutet in the world´s leading scientific journals


Shared genes behind asthma, hay fever and eczema

Photo: Istockphoto, Gustav Mårtensson, Camilla Svensk.

IN A NEW STUDY, international researchers have used data from the Swedish Twin Registry, to map where in the genome the common genes for asthma, hay fever and eczema are located. By comparing genetic variations across the entire genome in approximately 360,000 individuals, researchers succeeded in identifying 136 different positions in the genome that can each be linked to an increased risk for all three conditions; asthma, hay fever and eczema. The identified genetic variations affect whether nearby genes are turned on or off, and researchers believe that these genes in their turn affect the function of cells in the immune system. “The mapping of genetic risk factors helps us understand why asthma, hay fever and eczema often coexist and provides new clues on how these conditions can be prevented or treated” says one of the study’s main authors, Professor Catarina Almqvist Malmros of the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.

Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology Ferreira MA, Vonk JM, Baurecht H et al. Participating researchers from KI: Tillander A, Ullemar V, Lu Y, Magnusson PKE, Karlsson R, Almqvist C Nature Genetics October 2017

Asthma, hay fever and eczema are often found together.

Researchers have created cells missing in Parkinson’s patients.

Converted cells attenuated Parkinson’s in mice IN PARKINSON’S DISEASE, dopamine-producing brain cells genenerate and die. In a mouse model of the disease, researchers succeeded in converting glial cells, a type of support cell in the brain, into new dopamine neurons. The type of glial cells used were astrocytes, named for their star shape, which are highly abundant in the brains of both mice and humans. To aid the conversion of cells, various transcription factors – proteins with the ability to alter gene activity – were introduced. This resulted in measurable markers for dopamine signalling in the mouse’s brain, as well as a considerable reduction in symptoms. Researchers also succeeded in converting human astrocytes to functional dopamine neurons in a laboratory environment. “We think that in the future, it may be possible to deliver genes and small molecules, rather than cells, to replace the dopamine neurons lost in Parkinson’s disease” says Professor Ernest Arenas at Department of Medical Biochemistry and Biophysics, Karolinska Institutet.

Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model Rivetti di Val Cervo P, Romanov RA, Spigolon G, Masini D, Martín-Montañez E, Toledo EM, La Manno G, Feyder M, Pifl C, Ng Y-H, Padrell Sánchez S, Linnarsson S, Wernig M, Harkany T, Fisone G, Arenas E Nature Biotechnology April 2017

LIST

Additional top publications Preterm birth linked to higher risk of heart failure Preterm birth and risk of heart failure up to early adulthood Carr H, Cnattingius S, Granath F, Ludvigsson JF and Edstedt Bonamy A-K JACC May 2017 Fewer infections in mechanical heart valves Prosthetic valve endocarditis after surgical aortic valve replacement Glaser N, Jackson V, Holzmann MJ, Franco-Cereceda A and Sartipy U Circulation July 2017 Inflammatory bowel disease in childhood associated with increased risk of cancer Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014 Olén O, Askling J, Sachs ML, Frumento P, Neovius M, Smedby KE, Ekbom A, Malmborg P and Ludvigsson JF BMJ September 2017 Relapse rare in young men after antireflux surgery Association between laparoscopic antireflux surgery and recurrence of gastroesophageal reflux Maret-Ouda J, Wahlin K, El-Serag HB and Lagergren J JAMA September 2017 Breast cancer recurrence risk lingers longer than expected 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years Pan H, Gray R, Braybrooke J, Davies C, Taylor C, McGale P, Peto R, Pritchard KI, Bergh J, Dowsett M and Hayes DF. The New England Journal of Medicine November 2017 Medical Science–2018

49


The moment

As told to : Cecilia Odlind Photo: Mattias Ahlm

“I often wonder what her leg looks like today” Helena Nordenstedt wanted to help her young patient – but her act of kindness went wrong. “When I was working as a doctor in Democratic Republic of Congo a few years ago, I was responsible for the patients we sent to the larger hospital four hours away. There was a six-year-old girl there who had her leg in plaster after being hit by a vehicle. She was to stay at the hospital with her mother for six weeks when the cast was to be removed. I felt sorry for them having to be so far away from their family, so I offered to drive them home early and then drive them back when it was time to remove the plaster cast. But they never showed up when it was time to go back to the larger hospital. I found out indirectly that the plaster cast had been removed as soon as the child got home to her village, since they thought that she didn’t need the cast any longer. What had I done with my ignorant kindness? I have often wondered what her leg looks like now. The lesson I learnt is that people cannot always be relied on to act as I, with my Swedish background, might imagine. Everything from linguistic to cultural differences to lack of resources can cause unexpected situations. Now I am better at listening carefully to people who are more familiar with the local conditions than I am. In our research we are investigating, among other things, cardiac health in HIV patients in Uganda. We also have a project in Sierra Leone about how knowledge and behaviour in the local population influenced the spread of Ebola during the major outbreak in 2014-2015. Without collaboration with my African colleagues, it would not be possible for this research to be conducted at all.” 50

Medical Science–2018

Name: Helena Nordenstedt Works as: Researcher and teacher in global health at the Department of Public Health Sciences, Karolinska Institutet. Currently: One of eight researchers nationwide accepted onto a Fellowship programme at SIGHT, a global health institute at the Royal Academy of Sciences which aims to contribute to the UN’s sustainable development goals.


Improve human health Study one of our 10 Global Programmes in health and life sciences, all in English and with an international focus. A degree at Karolinska Institutet can be the first step towards a PhD here or at a renowned university anywhere in the world. It can open doors to a global future. Bioentrepreneurship Biomedicine (Bachelor and Master’s level) Global Health Health Economics, Policy and Management Health Informatics Molecular Techniques in Life Science Nutrition Science Public Health Sciences – Epidemiology Toxicology

’I choose Karolinska Institutet for its world class reputation and prestige in medical sciences.’ Aman Sakhuja, 2nd year student from Austria

ki.se/masterstudies

Sign up for one of Karolinska Institutet’s Massive Open Online Courses in 2018 Learn from some of Karolinska Institutet’s top teachers – our MOOCs are open to everybody

• From Brain to Symptom. Learn about functional neuroanatomy in relation to psychiatric conditions and their treatment. – April 2018

Keep updated at: ki.se/en/education/mooc-courses

Sign up: edx.org/school/kix

Photo: Erik Cronberg

• Introduction to Physical Examination. This course provides health professionals with the fundamental skills of examining a patient. – Date to be announced


Karolinska Institutet is one of the world’s leading medical universities. Its vision is to significantly contribute to the improvement of human health. Karolinska Institutet accounts for the single largest share of all academic medical research conducted in Sweden and offers the country’s broadest range of education in medicine and health sciences. The Nobel Assembly at Karolinska Institutet selects the Nobel laureates in Physiology or Medicine.

For more information, please visit us at ki.se

the nobel Prize medal® is a registered trademark of the nobel Foundation. Photos: erik cronberg.

KarolinsKa institutet – a medical university

Medical Science 2018 - Karolinska Institutet  
Medical Science 2018 - Karolinska Institutet