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MedicalScience English language edition 2012

Four Swedish issues of Medicinsk Vetenskap 2011

English language edition 2012

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Life in the lab

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Creativity

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Pain


• Bättre resultat med robotkirurgi Sidan 18 • Män ser olika på behandling Sidan 20 • Krönika: Om PSA-screeningen Sidan 22

Editorial Wallberg-Henriksson, President företag Sidan 24 SåHarriet får du ett friskare

Musik – en nyckel till välmående Sidan 26 Därför gör det ont att föda barn Sidan 31 Fler överlever hjärtstopp utanför sjukhus Sidan 32 Fler fettceller hos feta Sidan 36 Psykisk sjukdom vanlig hos kvinnliga sexualbrottsdömda Sidan 42 Östrogen kan skydda mot hörseltrauma Sidan 45 Celltransplantation ny metod mot diabetes Sidan 46 Large areas around Karolinska Institutet of great significance in the fight against God vård ochare nycurrently teknik ger friskare 48 in Stockholm being turneddiabetespatienter into common diseases suchSidan as cancer,

Scandinavia’s leading life science region takes shape

lasse skog

building sites. A vast amount and cardiovascular Aktuellt/Noterat. Sidan 3–5of• construction Publicerat. Sidandiabetes 38 • Boktips. Sidan 50 work is under way – tangible proof that Karo-

or har ordet linska Institutet is off to a flying start in its et Wallberg-Henriksson third century.

diseases.

Omslaget: Skogssork fotograferad av Jörgen Wiklund, Naturfotograferna

All this is part of vid Karolinska Institutet Harriet Wallberg-Henriksson är rektor

One example is the construction of the new university hospital, which will be a regional, national and international hospital tasked with providing highly specialised medical care and re har jag inte trainingvanligare, nämligen sorkfeber. Mediernas and research in collaboration with da mig av gamla rapporter om de fästingburna sjukdomarKarolinska Institutet and various other organett område därisations. jag nas spridningsområden och bristen på ka på beprövad nästan blivit ett lika säkert In theTBE-vaccin same area har Karolinska Institutet is enskaplig evivårtecken som vitsippor. Förra året slog also building one of the world’s largest labon för solbad, trädantalet fall av sorkfeber hos människa ockratories, called Biomedicum. Clinical and r i skog och mark så rekord i vårt land. Vid Karolinska Instiexperimental research will work together in ovälkomna möten tutet bedriver vi framgångsrik forskning this centre. Close cooperation with the new dsugande krypen. I om både TBE och sorkfeber, något som är university hospital also creates an opportunity mött fästingplågan viktigt inte minst med tanke på att vissa for interdisciplinary collaboralick smör och lite forskningsrönresearch tyder på and att ett allt varmare sharedkan resources. addition, within r taget och är tion on klimat bidra tillIn ökad spridning av year Karolinska ut, det vet jagabezoonoser. Institutet will have access to a completely Hall, Ett new annatLecture tema i det här which numretwill är be international meeting place for edicinsk Veten-an important prostatacancer, den cancerform som är researchers, students general public. ngburna sjukdovanligast blandand mänthe i Sverige och som for Life Laboratory – a collabolia och en annan The Science också skördar flest liv. De senaste åren har om som smittarration between debattenfour kringuniversities så kallad PSA-screening in Stockholm som blivit allt and Uppsala och risken för överbehandling that combines advancedi mycket technical know-how and state-of-the-art equipment with a broad knowledge in translational medicine and molecular bioscience – already represents Sweden’s largest investment in large-scale bioscience research. This joint venture will be

the vision to make the Stockholm-Uppsala region an internationally recognised centre, präglat forskningen kring prostatacancer. where world-leading Screening och kunskap research, medical careom anden eventuell sjukdomsutveckling ställer business work in tandem.både läkare och patienter inför svåra val. En operation av There are seven universities prostata kan leda till livslånga biverkningand colleges of higher educaar och sänkt livskvalitet hos den drabbade tion in the region that collabmannen. Samtidigt vet vi idag att operaorate in complementary discition av prostatacancer kan rädda liv. plines. In this area, we are now Läs också om nya spännande studier increating Scandinavia’s leading venue om mitt eget forskningsområde, diabetes. for research and innovation in life Forskare vid Karolinska Institutet harscience. This isannat a development which will place bland visat att transplantation av in- the Stockholm-Uppsala region on the medical sulinproducerande celler från bukspottmap, but all möss will be körteln tillabove ögat hos kanofgegreat en significance to many people’s healthnär and opportunities for mängd olika möjligheter det gäller a healthier lifeoch in kanske the future. ökad kunskap till och med

mna möten med blodsugande kryp

framtida bot.

Editor-in-chief: Christina Bostedt Editor: Cecilia Odlind

Medicinsk Vetenskap 2/08

Karolinska Institutet – A Medical University Karolinska Institutet is one of the world’s leading medical universities. Its mission is to contribute to the improvement of human health through research and education. Karolinska Institutet accounts for over 40 per cent of the medical academic research conducted in Sweden and offers the country’s broadest range of education in medicine and health sciences. Since 1901 the Nobel Assembly at Karolinska Institutet has selected the Nobel laureates in Physiology or Medicine.

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Medical Science is an annual English language edition of the Karolinska Institutet popular science magazine Medicinsk Vetenskap. Here you can read examples of current research at our university.

E-mail: medicinskvetenskap@ki.se Web: ki.se Address:

Information and Public Relations Office, Karolinska Institutet, SE-171 77 Stockholm, Sweden Design & production:

Curt Lundberg Translation:

Semantix Translations Print: Elanders 2012


Contents Medical Science 2012

40–43

Some gut bacteria causes severe diarrhoea, such as this form av E.coli.

Faecal transplantation has been hailed in recent times as the answer for people with diarrhoea caused by a bacterial imbalance. The human gut is home to over 1,000 different species of bacteria, but what are they and what do they do? Read about how researchers at Karolinska Institutet are trying to understand the importance of this myriad of bacteria.

STEPHANIE SCHULLER/SCIENCE PHOTO LIBRARY

Special focus: Pain 9 Managing pain through acceptance. 12 Warning signals that run amok. 13 Illustration: Pain pathways. 18 Martin Ingvar on the need for more research. Regular features 2 Editorial 4 News 26 Top publications 31 The picture 38 Research round-up

’’ johan bergmark

NEWS 6 Condome use among young people Rarely used for casual sex. 8 Allergy vaccines Researchers working on more effective forms. 19 Nobel special The immune system’s scouts and conductors. 22 Researcher profile Bertrand Joseph on life and death of the cell. 25 Expert brain How to train it. 28 Life in the lab Salamanders offer clues on brain regeneration. 32 Creativity and mental illness The mad genius not a myth after all? 35 Dental health Worse in children with ADHD. 36 Cultural competence Means more effective healthcare. 40 Gut flora Patients healed by others’ faeces. 44 Rare diseases Researchers on why we should care.

8

25

Good research can be summed up in three words: collaboration, collaboration and collaboration!

28

Bertrand Joseph, researcher at the Department of OncologyPathology on the key to successful research. Read more on pages 22–24.

m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  3


News

helena wallin

Major investment in cancer research

Cancer is the group of illnesses that causes the highest number of deaths worldwide. In a bid to increase knowledge about cancer and improve the treatment of its various forms, a number of EU-financed Networks of Excellence have been set up at Karolinska Institutet. The idea behind these networks is that leading researchers from different fields and countries will work together and complement each other’s expertise. “Research collaborations can put a stop to the negative effects of the increasing cancer burden,” says Ulrik Ringborg, professor emeritus at the Department of Oncology-Pathology and leader of the EurocanPlatform project. “In the long run, patients, the general public and the health service all stand to gain.”

Prescriptions for physical activity spread beyond Sweden Physical inactivity increases the risk of developing most chronic illnesses, such as diabetes, cancer and cardiovascular disease. To help patients switch to a more active lifestyle, many Swedish doctors these days prescribe physical activity, an approach that is now beginning to spread beyond Sweden. “While poverty is declining in many countries, the problem of chronic illness is rising,” says Carl Johan Sundberg, researcher at Karolinska Institutet’s Department of Physiology and Pharmacology. “This being the case, questions about the role of lifestyle in reducing these illnesses are very relevant in many parts of the world.” Sundberg was one of the researchers who spoke at UN headquarters during the early autumn 2011 when a delegation of Swedish researchers from Karolinska Institutet went to the General Assembly to launch the idea of prescriptions for physical activity. Sundberg is also running a project, funded by the Swedish International Development Cooperation Agency, to introduce the method in Vietnam, and will be training a hundred or more doctors there. Inquiries about similar programmes have also been received from other countries.

Prescribed exercise counteracts illness

The idea of physical activity on prescription (FYSS) was developed in Sweden ten years ago, and has since been used in the health service and assessed as positive on several occasions by researchers at Karolinska Institutet, among others. 2010 saw the FYSS documentation that supports the project being translated into English.

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Aim to find answers to cancer problems EurocanPlatform Aim: To find better ways of preventing, detecting early and treating various forms of cancer. Members: A network of the 28 most research-intensive European institutions in the cancer field.

colin cuthbert/SPL

A morning exercise class at Hoan Kien Lake in Hanoi, Vietnam. Researchers at Karolinska Institutet will now be training Vietnamese doctors in how physical activity can be included as part of a prescription for patients to reduce their risk of developing chronic illnesses.

Systems Microscopy Aim: To create mathematical models of biological cancerrelated events, such as the spread of tumours. Members: Researchers in the fields of biology, medicine and mathematics from seven European universities and one company. SYSCOL Aim: To identify the genes that cause colon and rectal cancer, and what controls the expression of these genes. Members: Researchers from nine European universities, one American university and one company.

80,000

questionnaires are being sent out to parents around Sweden. The aim is to map how environmental factors such as air pollution, noise and interior environments affect the health of children and adolescents, and how this has changed since the previous survey in 2003. Commissioned by the Swedish National Board of Health and Welfare, the survey is being led by researchers from Karolinska Institutet’s Institute of Environmental Medicine.


Louise Olsson, researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet, on her study showing that socioeconomic background affects the treatment of rectal cancer.

stefan zimmerman

’’ The operation ends more frequently in a permanent stoma if you’re not married.

First-ever artificial trachea transplant The world’s first transplant of an artificial trachea seeded with the patient’s own stem cells has been carried out at Karolinska University Hospital, Huddinge. Carried out in June 2011, the operation was performed by Paolo Macchiarini, a professor at Karolinska Institutet, together with a team of international researchers. The patient had severe tracheal cancer and, in the absence of a donor, transplanting the artificial trachea was the last remaining option. The synthetic trachea was made from a nanocomposite material and had been pretreated with stem cells from the patient to avoid the risk of rejection. Artificial tracheas could also be used in children, where access to donated organs is far more limited.

Paolo Macchiarini in the operating room at the Karolinska University Hospital.

Fluoride in toothpaste fundamental for public health istock photo

KI’s research 50 years ago When sweet things are more readily available than effective dental products, the tooth fairy rejoices! After the Second World War dental health hit an all-time low in both Europe and the USA , and it was not uncommon for youngsters to have just as few teeth as the elderly. “It was a dreadful situation,” says Björn Klinge, professor of parodontology. “But they realised that they couldn’t drill their way out of the problem and the focus shifted to preventive dental health instead.” The 1940s brought a major research breakthrough: fluoride can protect tooth enamel from decay. On the back of this,

Fluoride in toothpaste protects our teeth, thanks to research done by Yngve Ericsson.

the late Karolinska Institutet researcher Yngve Ericsson embarked on a famous study in 1961. The aim was to find a form of fluoride that was suitable as an additive to toothpaste, so that the protective properties of the fluoride were not affected by other ingredients such as grinding agents

or detergents. The analysis of the properties of various preparations resulted in extremely valuable core information for the development of toothpastes containing fluoride. Ericsson’s research paid off in the form of very valuable patents. By setting up the Swedish Revenue Patent Fund for Research in Preventive Odontology, he made it possible to donate considerable royalties to “promote scientific research in the field of preventive odontology” – a unique gift from a Swedish researcher to subsequent colleagues in his field. “The results of his research extend beyond a dramatic improvement in dental health, as his successful patents still generate huge sums of money for preventive research,” says Klinge. Olle Bergman

m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  5


Hot topic: Condom use Many young men and women rarely or never use condoms during casual sex. However, only 10 per cent consider themselves at high risk of contracting a sexually transmitted infection, reveals a new study from Karolinska Institutet. text Gustaf Andersson

Risk awareness not always a factor in condom use mats levál

Amy Levál ida czumbel

Inga Velicko

The study is based on a survey distributed to 20,000 people aged between 18 and 30 throughout Sweden, and reveals that condom use is extremely low in this age group. Just over half of the women, and around 40 per cent of the men, stated that they never use a condom with casual partners. There was no link between condom use and perception of the risk of contracting sexually transmitted infections (STIs) among the men, even though more men reported condom use during casual sex. “We thought there’d be a link between condom use and awareness of the risk of contracting an STI,” says Amy Levál, doctoral student at Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics. “But that just wasn’t the case for the men. This indicates that there are probably other factors that determine whether young men use condoms or not, which is something we need to investigate if we want to increase condom use.” Of those who stated that they never used condoms, men did not perceive their risk of contracting STIs as high, while women did see themselves at high risk. “Given that risk perception and the factors associated with condom use are so vastly different for men and women, as we found in this study, we might want to consider making sex education curricula more genderspecific. This way we could motivate condom use for each group of individuals specifically in a manner relevant for them,” says Levál. Although most young people know of the benefits of using condoms, this clearly is not enough to ensure

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their use with casual partners. Levál believes that it is important to increase communication on the subject. “A follow-up study has indicated that these adults find it difficult to talk about condoms and sex with casual partners,” says Levál. “We need to look into the barriers to using condoms so that we can understand how to get young people to overcome them.” Most young people have a high STI awareness. Nevertheless just 10 per cent feel that they themselves are at high risk of contracting one. Meanwhile a clear majority – around 80 per cent – feel that the risk is moderate or low. “We’ve explored this risk gap in more detail and looked into why people put themselves in a situation where they think there’s a risk, but our analysis isn’t ready yet,” says Levál. Another finding from the study was that women with a sexual debut before the age of 15 were twice as likely to have unprotected sex later in life as those with a later debut. “This is extremely interesting as I’m researching human papillomavirus, HPV, which is responsible for cervical cancer, among other things,” says Levál. “An early sexual debut is one of the known risk factors for cervical cancer.” Why this is so is the subject of much debate, but the accepted explanation is that an early sexual debut results in longer exposure to HPV. This study’s results also suggest that these particular women are risking exposure to a higher number of infections than women with a later sexual debut.


i stockphoto

Love is in the air – the summer brings an increase in the number of casual sexual encounters. A new study from Karolinska Institutet shows that condom use among young people is low during intercourse with casual partners.

Syphilis and gonorrhoea on the up again At the same time as condom use among young people is low, the incidence of many STIs is increasing. “This is an obvious risk group that we need to focus prevention efforts on more,” says Levál. Inga Velicko, doctoral student in the same department as Levál, researches another STI – chlamydia. The work of her research group involves a modelling study of different scenarios of infection spread, and measures that can be taken to prevent it. “More than anything, we’re looking at risk factors for reinfection, but also at who gets infected, and where, when and why infection occurs,” says Velicko. Although the number of reported cases of chlamydia has stopped increasing over the last years, it is still high. According to the Swedish Institute for Communicable Disease Control, over 36,800 cases were reported last year, and the disease is easy to transmit without realising one is doing so, as it is often symptom-free. “There’s a high number of unreported cases,” says Velicko. “But people are talking more about chlamydia these days, and there are lots of chlamydia campaigns such as Chlamydia Monday in September to raise people’s awareness about testing. The Swedish Institute for Communicable Disease Control also launched a campaign last autumn to increase condom use.” F

Chlamydia

Going up. Chlamydia is the most common STI in Sweden and is, in many cases, entirely symptom-free, which means that it can be passed on without anyone realising.

Gonorrhoea

Going up. 842 cases were reported in 2010. A strain of the gonorrhoea bacteria that is multiresistant to antibiotics was discovered recently in Japan.

HIV

Going up. 465 cases were reported in Sweden in 2010. These days the majority of people infected are heterosexual, and mostly infected before migrating to Sweden.

Syphilis

Going up. 199 cases were reported last year in Sweden, mostly among homosexual men.

HPV

No statistics yet published, but Levál and her colleagues have just finished tracking condyloma incidence over time throughout the country. Human papillomavirus (HPV) can lead to condyloma or cell changes that can result in cervical cancer. HPV is highly infectious and most people will be infected at some time during their life. There are currently two vaccines which, if given before sexual debut, protect against the most common forms of HPV. Sources: Swedish Institute for Communicable Disease Control and Swedish Association for Sexuality Education (RFSU)

m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  7


Ten questions gustaf andersson

Marianne van Hage is professor of clinical immunology at Karolinska Institutet’s Department of Medicine, and senior consultant at Karolinska University Hospital Solna.

Pollen is a problem for the growing number of allergy sufferers in Sweden. We spoke to Marianne van Hage on the subject. text Gustaf Andersson

Which allergies can you vaccinate against?

1

Which allergies are there vaccines for? “In Sweden it’s primarily grass and birch pollen, cat, dog, bee, wasp and mite allergies. But many allergy sufferers don’t get vaccinated and manage well on normal medication.”

2

How does an allergy vaccine work?

“The same way as normal vaccines – we introduce into the body a preparation that activates the immune system. In this case, the preparation is an allergen. As we want the body to build up tolerance to the allergen, we start with a very low concentration which is then gradually increased.”

3

How are allergy vaccines administered? “Usually by injection. For a few years now it has also been possible to use sub-lingual tablets, but so far this has been available only to people with grass pollen allergy. There’s also been a study where the vaccine was administered on a patch.”

4

What are the disadvantages of allergy vaccination? “Vaccination by injection is currently an extremely protracted process where patients have to be given injections every eight weeks for at least three years in order for the vaccine to be effective. Anyone with an allergy to bee or wasp stings, for example, will generally have to do this for five years. Injected vaccines can also result in hardening of the skin, granuloma formations, and they sometimes cause side effects. Tablets, on the other hand, can be taken at home, but unfortunately need to be taken every day for three years.”

5

You’re trying new ways of designing effective vaccines. How is it going? “We have, among others, produced the main cat allergen, Fel d 1, which is a protein that causes over 90 per cent of cat allergies in Sweden. We have modified it to obtain a molecule that is less allergenic as the IgEantibodies no longer recognise the modified Fel d 1 to the same extent. We have had good results when testing this modified allergen as a vaccine in our mouse model for cat allergy.”

6

What else are you working on? “We’ve also developed a better adjuvant – a substance in the vaccine that facilitates vaccination by stimulating the immune system. Aluminium hydroxide is currently used but it can result in hardening of the skin around the injection site. Instead we’re using carbohydrate-based particles that we’ve tested with Fel d 1 with promising results. These particles didn’t result in any hardening of the skin and kept the allergen at the injection site for up to a week, unlike with aluminium hydroxide where the allergen tends to spread, which is something we want to avoid as it can cause serious allergic reactions. The particles are about to be evaluated in a preliminary study in humans.”

7

You’ve also taken part in a clinical study carried out in Switzerland. What did that involve? “It was an intranodular vaccination where the allergen is injected straight into the lymph nodes in the patient’s groin. The study involved 20 people with cat allergies who were treated with Fel d 1.”

8

What did you find? “The treatment stimulated the immune system favourably and had no side-effects.

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The patients overcame their allergies and were still allergy-free one year on. The greatest benefits of this kind of vaccination are that it requires just three injections over two months and that we can give allergen doses that are a thousand times lower than in a normal injected vaccination. The aim is to go on to test the effect in a larger study with more patients.“

9

How has allergy vaccine research changed since you started out? “In the 1980s we worked with whole allergen extract which contained both allergen and non-allergen components. Since the end of the 1990s we’ve produced several individual allergen components and have therefore been able to improve diagnosis and treatment. We have a completely different knowledge these days to help allergy sufferers.“

10

How do you see vaccination in the future? “We already know which components can cause allergies, and that every allergy sufferer has a unique allergen profile. In the future we will be able to tailor treatments with individual components according to these individual profiles, which will enable us to get very good results.”

Allergies are common • Around 30 per cent of the Swedish population has some form of allergy. The proportion is higher in children than adults. • Why so many people are allergic is still unclear, but there are theories that it could be due to changes in lifestyle, environmental factors or the fact that we live cleaner lives than previous generations. • The most common allergies in Sweden are to cats and grass and birch pollen.


Special: Pain

Today there are no good medications for chronic pain. In the absence of functional medicine, research has taken an interest in how patients can manage their pain in a better way. For Katarina Wellington, suffering from constant pain from her fibromyalgia, the turning point came with behavioural therapy. Read more in the Medical Science special issue on pain.

m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2009  9


Special: Pain Although Katarina Wellington’s fibromyalgia means that she is in constant pain, she thinks that life is great. Thanks to a new type of behavioural therapy developed partly at Karolinska Institutet, she has learnt to accept her pain and built an active and meaningful life once more. text Helena Mayer photo Ylva Sundgren

Managing pain through acceptance 42-year-old Katarina Wellington was finally diagnosed with fibromyalgia two years ago after suffering from constant pain around her body and severe migraines since childhood. As an adult, her work as a teacher became more or less all she could manage. “I’d cut down on everything that was fun and social. I’d hurry home after work so I could do what I had to do before I began to fade. It was a constant battle against time and pain. My partner and my children also found it very difficult with me being so down.” Katarina has undergone countless medical examinations over the years. She has also “tried everything” by way of alternative therapies such as homoeopathy, crystals and healing, as well as intensive exercise and various diets. “Conventional medicine is very much focused on handing out medicines and writing sick notes,” she says. “It feels like nobody’s ever tried to look at the whole, so I’ve had to try to put my pain into context myself.” Eventually the situation was so bad that Katarina was referred to a pain clinic. She was diagnosed with fibromyalgia and prescribed acupuncture and amitriptyline, an early antidepressant commonly used to treat migraine. “It’s working incredibly well. I’ve stopped having those terrible headaches and I’ve begun to sleep properly again.” She also took part in a research study at Karolinska Institutet of a technique called Acceptance and 10   m e d i cal s c i e n c e • e n g li s h lan g uag e e d iti o n 2 012

Commitment Therapy (ACT). This is an extension of cognitive behavioural therapy (CBT) and is used mainly for rehabilitating people whose lives are dominated by long-term, chronic, debilitating pain. ACT gives patients the tools to learn to accept their pain and find ways to lead a more meaningful existence. Two of the five studies underpinning ACT’s acceptance as an evidence-based therapy for long-term pain have been performed at Karolinska Institutet. In the study in which Katarina Wellington was involved, participants learned about the mechanisms behind pain. They also performed various exercises in relating to pain in an accepting way and allowing it to be there without doing anything to take it away or reduce it. Goal formulation and mindfulness training were also included: learning to be in the here and now. The sessions lasted a total of 12 weeks and began and ended with an MRI scan of the brain. At a followup visit after four months, participants said that the pain was still present, but no longer worried them or stopped them from getting on with life. “If you can’t do anything about the pain itself, it makes sense to look at what you actually can change in order to make your life more like you would want it to be. We’re shifting the focus from how the patient feels to what the patient does,” explains one of the researchers behind the study, psychologist Rikard Wicksell from the Department of Clinical Neuroscience at Karolinska Institutet and the Behavioural Medi-


Katarina Wellington feels healthiest when she exercises. She enjoys free dance and dance improvisation, and sometimes takes classes in flamenco.

cine Section at Karolinska University Hospital in Solna. He says that patients often allow their pain to restrict their lives. “Many patients have a clear autopilot which avoids things that cause them pain,” he says. “In the short term, you might think ‘If I don’t go to football, my back won’t hurt as much.’ This works temporarily, and you avoid the risk of the pain growing. However, these short-term gains tend to lead to a downward spiral of avoidance.” Paradoxically, says Wicksell, pain patients often score their pain at the same level today as they did five years ago, even though they have restricted their existence from meaningful to “just” staying home and taking painkillers. “We tend to ask ‘What kind of life do you want to lead, given that you will probably be in pain either way?’, because that takes us onto a very different path. It might sound harsh, but it’s based on facts and is presented sensitively. It’s all about getting the patient

to ask ‘What can I do to stop the pain ruling my life?’” Wicksell also calls this autopilot “the pain monster”. This sends out negative messages such as “I can’t do that, it’ll hurt too much.” There are also, figuratively speaking, anxiety monsters, tiredness monsters and so on, which make it hard for pain patients to return to an active and meaningful life. Some situations can set off a whole chorus of these monsters. The method has completely turned Katarina Wellington’s life around. “I’m strong now and I’ve learnt to live with the pain,” she says. “Now that I’ve identified what’s important to me, it’s easy to steer my thoughts in the right direction when the pain monster rears its ugly head. I’m still in pain the whole time, but I’m no longer frightened and I’ve given up looking for cures. Instead I do what makes me happy and focus on things that I can actually do something about.” F

Rikard Wicksell

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Special: Pain

Pain is a vital warning signal. But when things go wrong, it turns into a fire alarm that will not switch off even when the fire has long since been put out. Researchers are doing all they can to turn down the volume. text Ola Danielsson

Warning signals that run amok

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my hand, as those with arthritis have in their joints, this pain threshold would be lowered, not only in the nerve endings in the hand but also in the relay stations in the spine. This sensitisation is normally a good thing, because the increased tenderness and pain ensure that the person avoids using injured parts of the body, allowing them to heal in peace. But in some patients this inflammation leads to the volume in the pain system being cranked up out of all proportion – the slightest stimulus in a joint can trigger a pain impulse that is amplified many times en route to the brain and is experienced as severe pain. In order to reduce the volume, researchers must first understand what happens when inflammation in a joint leads to sensitisation in the spinal cord, and why this hypersensitivity remains even after the inflammation subsides. By inducing rheumatic inflammation in mice, researchers are investigating how the pain threshold changes before, during and after inflammation – and why. “One hypothesis is that the inflammation damages the nerve in a way that makes it stay hypersensitive, and perhaps no longer responsive to signals that would have normalised the threshold values after a short-term inflammation,” Svensson explains. But it is not just the nerves that are under the microscope in pain research. One of the hottest areas of research right now is the glial cells. These are best known as garbage collectors in the immune system, but recently more and more research groups have confirmed the unexpected discovery that they communicate

ola danielsson

Pain can be a very useful warning signal. Hit your thumb with a hammer and this stimulates pain receptors in the skin, a signal is sent to the brain, and it hurts. The natural reaction is to bandage the thumb, whereupon the pain subsides. But this picture does not tie in well with something like long-term joint pain, which is one of the most common pain conditions. Joint pain often starts when pain receptors are stimulated by inflammation, but even once all signs of the inflammation have gone, something often continues to cause pain – the question is what. “The inflammation activates the pain nerves, and in some cases this eventually leads to something changing in the actual pain system so that the pain persists, and it’s this change that we’re trying to understand,” says Camilla Svensson, a researcher at Karolinska Institutet’s Department of Physiology and Pharmacoclogy. We now know that between the pain receptors and the brain are a number of relay stations which all affect the final perception of pain. Camilla Svensson’s research focuses on the interplay between the inflammation in the joint and activity at the first relay station, where chemical messengers transmit the pain signal from the peripheral nerves to the neural pathways in the spinal cord. She demonstrates this by brushing a thin nylon thread against the top of my hand. I can feel it, but obviously it doesn’t hurt. This is because my pain nerves have a higher activation threshold than my other nerves – a stronger stimulus is needed for them to send signals to the brain. If I had chronic inflammation in

Camilla Svensson

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Pain pathways

Somatosensory cortex Processes the type and location of pain

3

Limbic system Emotional processing

Frontal cerebral cortex Thoughts and expectations

Pain

Thalamus

1

4

Stimulus

Painful stimuli activate pain receptors that send signals along specialised pain nerves to the spinal cord.

PAI N

Ascending pain signal

The pain signals are processed in different parts of the brain and a sensation of pain develops. This is affected by thoughts, feelings and expectations.

Regulation

The brain generates signals that descend along the spine and either inhibit or amplify the pain signals in the spine.

Descending inhibitory signal al Descending amplifying sign

All experience of pain originates in the brain, but it is the pain signal’s route to the brain that determines where in the body it is felt.

rve Pain ne Mo tor ne ur

on

The three types of pain Nociceptive pain The type of pain felt when tissue in the body is damaged. The pain signal starts in the pain receptors, or nociceptors, which are located in the skin and the internal organs, and which register pain.

Neuropathic pain Caused by injury or disease in the nervous system. Both direct damage to the nerve and pressure on the nerve can lead to pain. Can develop as a result of slipped disc, diabetes, stroke etc.

Relay

cle

Synapses in the spinal cord connect the signals to new neural pathways. The signals can be inhibited or amplified during this process. In some cases, the pain signals also lead to the activation of a motor neuron that triggers a muscle reflex.

Mus

Refl ex

Inflammatory pain Inflammation leads to the secretion of substances that lower the pain threshold and amplify pain. Occurs temporarily when tissue is damaged, and can be chronic in illnesses such as rheumatism.

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Spinal cord Interneuron

SVENSKA GRAFIKBYRÅN

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Special: Pain

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Pain consists of different components which are handled in very different parts of the brain before being put together into something that we perceive as a single thing.

ulf sirborn

Eva Kosek ulf sirborn

Predrag Petrovic

with the pain nerves and actively help lower the pain threshold. “This may be one of the reasons it’s so hard to develop good painkillers. Pain research has focused almost entirely on the nerves – it wasn’t known that completely different cells also play an important role,” says Svensson, whose own contribution to glial research has been to show what role they play in long-term inflammation. Eva Kosek, a researcher at the Department of Clinical Neuroscience, is looking into the role of glial cells in the human body. Many of her patients suffer from chronic pain with no known physical cause. With luck, glial cells will offer a new way of turning the volume of pain signals down, if not off. But she explains that even if the pain signals make it through the spinal cord to the brain, it is still not necessarily too late, because signals then immediately rush back in the other direction, which affects the stream of incoming pain signals. In other words, the brain can regulate its own supply of pain. In healthy people this happens all the time without them even noticing, which is the whole point. “There’s a survival benefit in only feeling pain at the right times,” she explains. “For example, normal physical labour generates many pain signals that the body iSTOCKPHOTO

When we see someone else in pain, the same parts of the brain are activated as when we ourselves are in pain.

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neither wants nor needs to acknowledge.” Sometimes, though, the pain regulation system can instead amplify the pain, and even generate pain without any pain receptors in the body’s tissues outside the central nervous system being stimulated. These pain-amplifying mechanisms have turned out to play a major role in long-term pain, and in many cases they are more important than the physical cause that originally triggered the pain – what started as a warning signal becomes a fire alarm that gets stuck on. “In arthritis, for example, there is only a very weak relationship between how inflamed the joints are and how much they hurt,” says Kosek. Despite this, she still hears older colleagues saying “The X-rays are entirely normal, so it can’t hurt” – a reasoning that research has shown to be wholly mistaken and can be expected to be taken as a direct insult by many patients. One patient group that has had to put up with considerable scepticism due to a lack of clear, physical, pathological changes is people with fibromyalgia, a condition characterised by pain and tenderness in large parts of the body. “Studies using fMRI scanners have shown that the parts of the brain that help deal with pain are less active in people with fibromyalgia,” says Kosek. “We believe that the cause of the disease is an imbalance in the body’s pain regulation. The volume control is not working as it should.” Pain is not just problematic in itself but can have many negative side-effects such as sleep disturbances, loss of concentration, impaired memory, anxiety and depression. Patients’ way of dealing with their pain has a major say in how much of a problem it is in their lives. One important part of pain management is learning not to be afraid of pain. Statistics show clearly that those who take time off work for back pain are less likely to recover than those who work on despite the pain. Keeping mobile – within reason – is the best thing for back pain, and physical exercise is now recommended as a treatment for rheumatic pain. Research has shown that the mind plays an important role not only in how we deal with pain but also in how much it actually hurts. The placebo effect is very


istock photo

become incapacitated – for example by breaking bones without noticing. But there is also a kind of pain that has no survival value at all, and which the body struggles to regulate itself. This is neuropathic pain, which arises when the nervous system is damaged or diseased. Per Hansson, professor of clinical pain research at the Department of Molecular Medicine and Surgery, has devoted his career to trying to understand and alleviate neuropathic pain. He explains that this pain can result from an operation or from diseases such as cancer, shingles, diabetes, stroke and spinal injuries. A sixth of all diabetics – around 60,000 people in Sweden – suffer from pain as a result of nerve changes, mainly in the legs and feet. Some also develop allodynia, where they become hypersensitive to touch. “This has a huge impact on their quality of life,” says Hansson. “Even very gentle stimuli such as the blowing of the wind or the pressure of clothes against the body can be painful for these patients.” The most common form of neuropathic pain is probably nerve root pain, where a nerve root in the back is squeezed and damaged, perhaps as a result of a slipped disc or surgery for such an injury. “Ordinary non-neuropathic back pain tends to come and go and is movement-related, but if the cause

The temperature at which the body’s pain receptors are activated varies considerably from person to person. Women tend to have a slightly lower pain threshold than men.

ulf sirborn

powerful when it comes to pain – even a completely inactive sugar pill can provide pain relief if the patient believes it to be an effective medicine. If, on the other hand, a patient expects a treatment to be painful, it generally will be more painful. Predrag Petrovic, a researcher at the Department of Clinical Neuroscience, is trying to understand what happens in the brain when thoughts and emotions impact on depression and pain. He believes that the placebo effect is a logical consequence of the brain’s way of working. “The brain is constantly modelling the future,” he explains. “What we experience is always a mixture of incoming signals from the body right now and the brain’s picture of what will be happening subsequently.” By studying the brains of research subjects with PET scanners, Petrovic and other researchers have also managed to break down the experience of pain into its component parts. “It’s a bit like Lego,” he says. “Pain consists of different components which are handled in very different parts of the brain before being put together into something that we perceive as a single thing.” The sensory perception of pain – that it hurts – is processed in one part of the brain. Another contributes the location of the pain – where it hurts. Finally there is an emotional component – the unpleasantness. Combining these components in different ways results in different types of pain. “With what is known as abstract pain, there are no incoming pain signals from the body to the brain, but the pain system is still partially activated,” says Petrovic. “This occurs, for example, when we see someone else hurting and feel their pain in sympathy,” says Petrovic. Research may eventually lead to new drugs for these different types of pain, but Petrovic believes that this knowledge can be applied more immediately to how we view pain. It is important for doctors to remember that the results of treatment for pain will be affected by the patient’s expectations and confidence in the treatment, and that these in turn are influenced by the doctor’s approach and way of presenting the treatment. “This knowledge about the role of expectations bodes well for CBT-like treatments for pain,” he says. “It’s not a hush-hush thing – we can work quite openly with the patient’s expectations as an important factor in the treatment.” It is easy to forget that pain is ultimately a valuable warning signal that something is wrong. People who lack the ability to feel pain, such as those with a certain hereditary disorder in part of northern Sweden, soon

Per Hansson

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Special: Pain ulf sirborn

Tomas Hökfelt

is damage to a nerve root, the pain is constant,” says Hansson. Neuropathic pain is often felt in a different part of the body to where the cause is actually located. This is because the brain always projects the pain to receptors in the nerve endings, even though the damage itself could be anywhere along the neural pathway, including within the brain itself. Nerve damage following amputation will often therefore result in phantom pains in the missing part of the arm or leg, and nerve root damage in the back can cause pain in the leg rather than in the back. “We need better treatment methods, as we’re unable to help around 60 per cent of patients with their neuropathic pain,” says Hansson. “The problem with the medicines used is that they affect many different systems in the body and can therefore have significant side-effects. It’s unclear to what extent these medicines actually act on the mechanisms specific to neuropathic pain.” Every time a nerve sends a signal, it is the result of small channels opening in the cell wall through which electrically charged ions can flow. Researchers know that the expression of sodium channels is altered in damaged nerves which put out pain signals spontaneously, making them more easily irritated, but it is unclear how this knowledge can be used to attack neuropathic pain. Tomas Hökfelt, professor of histology of the Department of Neuroscience, and his group may, however, be on the trail of the causes of neuropathic pain signalling. Together with Zsusanna Wiesenfeld-Hallin, professor of basic and clinical neurophysiology at the Department of Laboratory Medicine, he discovered many years ago that a chemical messenger called galanin is produced in

Medicines shut down parts of the pain system Medicines can suppress or relieve pain temporarily by acting on different parts of the pain system. Medicines that work around the body. These prevent pain impulses from reaching the brain and/or are anti-inflammatory. Example: Ibuprofen. Medicines that work centrally in the spinal cord or the brain. In addition to suppressing pain, these medicines affect the perception of pain, making it feel less unpleasant. Examples: morphine and morphine-like substances. Medicines that work both centrally and around the body. Some medicines act on pain caused by nerve damage in the body or in the brain and central nervous system. Examples: tricyclic antidepressants and anti-epileptic drugs. Source: Swedish Medical Information Service

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large quantities in damaged nerve cells. The researchers were then able to demonstrate that galanin has a painrelieving effect, while another group showed that it stimulates regrowth of damaged nerves. “We believe that galanin is one of many components of the body’s own defence against neuropathic pain,” Hökfelt explains. “The reason why some people suffer from neuropathic pain may be that this defence has failed.” There was rejoicing in Tomas Hökfelt’s laboratory when, using knowledge from experiments with galanin, researchers managed to block an enzyme in mice with the result that their pain threshold was dramatically increased for two whole days. No medicines have yet been able to achieve such an effect, either in animal models or in patients with severe pain. The next step is to investigate what role the enzyme in question, PLC, plays in the human body and whether something similar could be achieved there. Hökfelt hopes that this research will result in new drugs for neuropathic pain, but stresses that this is easier said than done. “It’s hard having mice as the basis for drug development. Time after time it turns out that the human body is different, and so we’re now performing tests on human tissue to identify any differences and similarities between the pain system in humans and various rodents.” The use of laboratory animals in pain research is particularly problematic from a methodological point of view, as what is being studied is a subjective perception that quite simply cannot be measured. One common method of studying whether a mouse has a reduced pain threshold is to stimulate a paw with a thin filament and see whether the mouse pulls it away. However, Camilla Svensson prefers not to use the word pain when talking about animals. “The only thing we can say for certain is that there is ‘nociception’ – the mouse pulls away its paw as a result of activity in pain nerves,” she says. “We can never know for certain whether there is a perception of pain.” And if there is, she adds, it is not certain that it is the same type of pain that is actually the problem in the conditions that researchers are trying to understand. Sudden pain is easiest to study, whereas low-grade aches and pains are possibly a greater problem for patients. Svensson and many other pain researchers are now developing new experiments based on animals’ natural behaviour and trying to capture the essence of clinical pain. One method is to measure how much mice move around spontaneously under different conditions. Researchers are also using preference tests where mice


The most common forms of chronic pain: Men: Lower back pain Women: Muscular pain and joint pain in the lower back, neck and shoulders The elderly: Joint pain due to osteoarthritis Around 20 percent of the population are affected by chronic pain. Source: Eva Kosek

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... no ‘magic bullet’ for all pain is in sight.

BLUESTONE/SCIENCE PHOTO LIBRARY

make various choices, such as spending more time on a surface of a certain temperature than on another, or whether to drink their pain medicine. With luck, this focus on new methods will reap rewards in the form of new painkilling drugs. But no “magic bullet” for all pain is in sight, and treatments need to be designed collaboratively by teams of doctors, psychologists, social workers and physiotherapists working together. “Unfortunately the healthcare system has moved in the opposite direction, and many of the old pain clinics have closed,” says Eva Kosek. “Many patients have nowhere to go.” This situation is particularly problematic because it is patients with long-term pain who suffer most from their pain. Kosek says that many of her patients live with pain that they describe as the worst imaginable. On a scale of one to 100, they put their pain at 100 – and some even higher.

“If you ask them to draw a comparison with the pain they felt when giving birth, for example, they say that it was different, that it was very intense but also positive, so they didn’t really suffer. Their chronic pain, on the other hand, is harder to deal with because of the level of suffering.” Kosek believes that this is one of the big challenges for pain research. What is it that makes some pain cause great suffering, and how can we reduce this suffering? In a number of pioneering studies, researchers have begun to look at the differences between this long-term pain and more short-term pain in the brain. They have shown that brain activity connected with long-term pain is concentrated in parts of the brain that deal with cognitive functions and emotions, with hardly any activity in the parts involved in short-term pain perception. “With chronic pain there’s so much more going on than when you hit your hand, say, and as yet we understand very little about it,” says Kosek. F m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  17


Comment Martin Ingvar stefan zimmerman

New knowledge about the role of the brain in chronic pain means that we need to reassess how we deal with patients, otherwise they turn to alternative medicine in response to a perceived lack of help. More research is the way to evidencebased care, believes Martin Ingvar.

Research is the only way forward

O

bstinately she heads off in her tracksuit, brandishing her walking poles. It’s a matter of selfrespect. “The doctor said the pain would get better if I went walking, but I’m not so sure. It just feels worse each time.” The doctor is well-informed and has given evidence-based instructions – right now, that means moving, though in the past it was quite the opposite. However, we must remember that pain is always only the patient’s subjective perception, constructed from various measurable signals from the body and the brain. Doctors and researchers can only listen. Chronic pain is more than just an ache. Pain affects our behaviour, psyche and other bodily functions: we remember less, concentrate less, are more easily depressed and find it hard to get motivated. Furthermore, our ability to handle pain is affected by the pain itself. And if that isn’t enough, it affects our stress and inflammation systems. Almost half of all patients who seek medical advice for pain are seeing an alternative practitioner too, although only half will say so. This is sending a clear signal about the need to communicate the values represented by rational, clinical medicine. But patients have already found their own answer. Many feel that their symptoms are not taken seriously and turn, instead, to alternative medicine. This may or may not provide a cure or relief, but it will at least involve extensive contact with someone who is likely to listen and take heed of their symptoms. Both patients and the health service are searching high and low for explanations for chronic pain. As the human brain is designed to give explanations, causal connections are being established everywhere – not only by patients but also by the health service and alternative medicine. The biomedical base model that results in symptoms through illness just isn’t enough when it comes to chronic pain: it is accurate, but doesn’t go far enough. It is rare that one cause or one clearly identified disease 18   m e d i cal s c i e n c e • e n g li s h lan g uag e e d iti o n 2 012

A professor at the Department of Clinical Neuroscience, Martin Ingvar is also Dean of Research.

process can be described. It is generally only the symptom of pain and its associated effects that present. For example, we send all patients with back pain for an X-ray or MRI to rule out anything serious. At the same time we often find things such as wear, calcifications, compressed discs and skewnesses in our examinations. But these rarely explain the amount of pain the patient is in and say even less about the prognosis. Things that look healthy can result in debilitating symptoms – and things that look serious may only give very mild symptoms. Nevertheless, both doctor and patient risk being influenced by X-ray findings before, for example, invasive interventions such as surgery. And then it gets better, or perhaps not. Either way, the brain is designed to configure the situation retrospectively so that the doctor usually got it right. At least in his own eyes. Chronic pain without a known cause is one of the health service’s greatest clinical concerns. This comes through in our approach, knowledge, understanding, treatment and followups. Around 40 per cent of all sick leave is due primarily to chronic pain. There is a real need for a fresh approach for both patients and society, especially when research is providing a better basis for understanding. For example, it has been shown that the brain’s pain-suppression mechanisms can be amplified with exercise and modern psychotherapy. Health care also needs to change if it is to meet patients’ needs. I believe that quality clinical research with randomised studies is the only way forward. In the short term it is difficult, labour-intensive and expensive, but in the long run it is the only way to phase out ineffective treatments and usher in new ones. We clearly need to start delivering when it comes to chronic pain. For both society and the patient. Research methods alone have what it takes to produce accurate knowledge. As Mary Lasker said: “If you think research is expensive, try disease!” F


Focus: Nobel Prize in Physiology or Medicine 2011 Although you may never have heard of Toll-like receptors and dendritic cells, you wouldn’t last long without them! This year’s Nobel laureates discovered the receptors and cells that enable the immune system to swing into action whenever it needs to. text Ola Danielsson interviews Ann-Marie Dock

The immune system’s scouts and conductors You may well be relaxing at home in your armchair, but in actual fact you are under vicious attack. Tiny microorganisms – viruses, bacteria, fungi and parasites – are constantly trying to invade our bodies. But we don’t generally need to get involved as our immune system is an expert when it comes to mounting appropriate counter-attacks, working silently to seek and destroy the invaders. But this year’s three winners of the Nobel Prize in Physiology or Medicine did get involved, so involved that they were able to find out how it all works. Using fruit flies and mice, Jules Hoff-

Nobel Prize in Physiology or Medicine

mann and Bruce Beutler discovered that there are receptors around the body that sense molecules associated with microorganisms and activate the innate immune system. In mammals these are known as Toll-like receptors (TLRs). The innate immune system is the immune response’s first line of defence which includes inflammation among other things. Ralph Steinman discovered dendritic cells and demonstrated that they act as a conductor, directing the adaptive immune system. This is the immune response’s later phase and involves T-cells, antibodies and the formation of an immunological

1

Bruce Beutler

(1941)

(1957)

TLRs Cell membrane

Inflammation that slows down infection

Adaptive immunity The dendritic cells receive signals from the innate immune system and can detect any microorganisms that may have slipped through. The dendritic cells, in turn, activate the T-cells, among others.

Jules Hoffmann

Recognised for their discoveries relating to the activation of innate immunity.

The TLRs activate our innate immunity, and the majority of the atta attacking microorganisms are destroyed.

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SOURCE: Nobel Assembly, KI

Particles

Particles from microorganisms bind to Toll-like receptors (TLRs) on the body’s cells.

Our immune system operates through a two-step process. This year’s Nobel laureates were chosen for their discovery of how these steps are activated and how they work together.

Bacteria, viruses, v viruse uses, fungi and other microorganism microorganisms ms atttack us constantly. attack

Innate immunity

memory that ensures that the body is better equipped to deal with future infections. Unless the TLRs and dendritic cells do their job every time we are exposed to infection, the invader will take over and we will become ill. But they can also be involved when the immune system makes a mistake and attacks the body itself, as is the case with chronic inflammatory disorders. On the following pages, researchers at Karolinska Institutet describe how this knowledge of TLRs and dendritic cells can be used to better understand and fight various illnesses. F

hite The T-cells, a type of white blood cell, trigger a number of defence reactions and develop a memory against infections. Ralph Steinman

(1943–2011) Dendritic cell

Recognised for his discovery of the dendritic cell and its role in adaptive immunity. SVENSKA GRAFIKBYRÅN

m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  19


Focus: Nobel Prize in Physiology or Medicine 2011 We asked researchers whose work builds on that of the Nobel laureates about the importance of TLRs in various illnesses:

professor of clinical microbiology at the Department of Microbiology, Tumor and Cell Biology. Is researching bacterial infections. Could Toll-like receptors be behind the differences in susceptibility to infection?

“Yes. Some TLRs play a greater role than others in how susceptible we are to infections caused by pneumococcal bacteria. We’ve shown that the absence of TLR9 affects the course of infection and the risk of developing septicaemia. Other studies have also shown that TLR9 affects susceptibility to bacterial meningitis. Differences in susceptibility to infection can also depend on genetic mutations in the signalling path from the receptor to other parts of the immune system. But some studies have also shown that people with a specific genetic make-up can have some degree of protection from serious infections caused by pneumococci. Some strains of bacteria are more likely to result in illness than others. This could be because they have characteristics such as surface structures or toxins that activate one or more receptors, of which TLRs are a key group, and trigger an inflammatory reaction, which can affect the symptom picture.”

stefan zimmerman

Ulf Sirborn

Ulf Sirborn

Birgitta Henriques Normark,

Sven Pettersson,

Lars-Olaf Cardell,

Could Toll-like receptors be linked to chronic inflammatory disorders such as inflammatory bowel disease?

Can Toll-like receptors affect the development of asthma and allergies?

professor of host-microbe interactions at the Department of Microbiology, Tumor and Cell Biology. Is researching inflammatory bowel disease and the body’s bacterial flora.

“Inflammatory bowel disease (IBD) involves damage to the intestinal wall which means that the normal bacterial flora activates and maintains chronic inflammation of the intestinal tract. TLRs are found both in the barrier of epithelial cells which line the inside of the intestine, and in other parts of the body. The discovery of TLRs has meant that we now have the key, as it were, to understanding and mapping key signalling paths that could explain how bacteria, both those that normally exist in our body and those that cause disease, can contribute to chronic inflammation of the bowel. However, there isn’t currently any support for the idea that genetic changes to these receptors could cause IBD. TLRs also constitute important signalling paths in other chronic disorders, such as obesity and diabetes, where there is a link with the body’s intestinal flora.”

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professor of ear, nose and throat diseases at the Department of Clinical Science, Intervention and Technology. Is researching asthma and allergic rhinitis.

“Yes. We know that children who grow up on farms with cattle develop fewer allergies than other children. It’s thought that this is down to microbes from the animals and their ability to activate certain TLRs. It’s also widely accepted that respiratory tract infections are a common reason for acute exacerbations in both adults and children with established asthma. There is much to suggest that the ability of TLRs and their other recently-discovered relatives to recognise a huge number of bacteria and viruses triggers an immunological defence reaction that also worsens asthmatic inflammation of the respiratory tract. This is opening up new opportunities for the treatment and prevention of asthma attacks in the future. Our research results also suggest that TLRs are involved when it comes to the origins and development of chronic respiratory disorders such as chronic sinusitis.”

The absence of TLR9 affects the course of infection and the risk of septicaemia.


We also asked about the significance of dendritic cells in various illnesses: Ulf Sirborn

Smittskyddsinstituet

Kerstin Bergh

Liv Eidsmo,

Karin Loré,

Rolf Kiessling,

How are dendritic cells involved in skin inflammation during psoriasis?

What role do dendritic cells play in HIV?

How can dendritic cells be used to treat cancer?

researcher at the Department of Medicine, Solna. Is doing research on skin immunology, focusing on psoriasis.

“Dendritic cells play a key role in psoriasis, an inflammatory disorder in which the skin develops thick red patches and scales. The skin is infiltrated by a number of different cells originating from the immune system, including inflammatory dendritic cells. It is unclear as to why the inflammatory dendritic cells are found in psoriatic skin but these cells secrete many signal substances that drive tissue inflammation, such as TNF-alpha, IL-12 and IL-23. Biological drugs containing antibodies that block TNF-alpha, IL-12 and IL-23 are very effective in treating severe psoriasis. During treatment with biological drugs, the number of inflammatory dendritic cells decreases in the skin as the inflammation is reduced. There are currently many different treatment alternatives that can be used to improve psoriasis, but there is no curative treatment available. When treatment is stopped the disease often returns.”

researcher at the Department of Medicine, Huddinge. Is doing research on HIV vaccine development.

“Dendritic cells may play a couple of different roles in HIV. As they are found in the mucosal membranes, they can be among the first cells to be infected. The number of dendritic cells in the blood is declined in HIV patients, which may mean that they are depleted by the infection. Dendritic cells also have the unique property of being able to take up the virus without breaking it down. They can, therefore, be carriers of HIV without being infected themselves. The virus can then be transported to the lymph nodes and transferred to the T-lymphocytes. So, while activating T-lymphocytes in the process that initiates an immune response, the dendritic cells can also help spread the infection. They are therefore often compared to Trojan horses in HIV. As dendritic cells are so effective at triggering an immune response, researchers are now looking into whether they could be used to improve a vaccine for HIV or for treatment. But HIV is very changeable so there are still many challenges with developing a vaccine.”

professor of experimental oncology at the Department of Oncology-Pathology. Is researching a vaccine for cancer.

“Dendritic cells are used to produce cancer vaccines. Recently the first vaccine for prostate cancer was approved in the USA, and this uses dendritic cells. The vaccine was given to seriously ill patients and extended their survival by several months, which demonstrates that the method works. The next step will be to test it on patients where the disease hasn’t progressed so far. There are also many clinical studies of malignant melanoma under way, a serious type of skin cancer that can activate the immune system. The results to date have been very promising. The cancer vaccine is based on producing dendritic cells from the patient’s white blood cells, allowing them to multiply and then loading them with dead tumour cells or with molecules derived from tumour cells. Thereafter the dendritic cells are given back into the patient as a cancer vaccine. The vaccine trains the immune system’s T-cells to recognise the cancer cells and attack them, and only them. Developing a vaccine is a tricky process that needs labs of the highest standard. At Cancer Center Karolinska we too are working on clinical trials of a cancer vaccine based on dendritic cells.”

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Researcher profile Meet Bertrand Joseph, the ideas man who tells his students to read less and think more, and sees curiosity and collaboration as the key to quality research. text Cecilia Odlind photos Johan Bergmark

“All questions are good questions” Having a scientific article published in the world-renowned journal Nature is considered quite a feat by most researchers, testimony that your research is ground-breaking and of the highest standard. If this is also an “original article” – a longer article that is given extra space – it is nothing short of a sensation. So Bertrand Joseph has had quite a lot on his plate recently. “I’ve had researchers and journalists getting in touch from all over the world, not to mention patients and others,” he says. “I even had an e-mail from an Alzheimer’s patient in Brazil who just wanted to thank us for our work.” In the study in question, Joseph and his colleagues show that a well-known family of enzymes can prevent inflammation in the brain and are therefore a potential new target for drugs to fight neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. But even if their findings do lead to a cure, the road from discovery to licensed medicine is generally a long one. Does he feel under pressure from patients and their families to get rapid results? “No, it’s all positive. Contact with patients means a lot to me because they’re the reason we’re doing the research – it gives us the strength to carry on.” The aim of this particular project is to stop nerve cells from being killed off prematurely, whereas in other projects he and his colleagues are looking at what stops some cells from dying when they ought to, as happens in cancer. In one way or another, though, all of his research is about the death of cells. “I sometimes hear from funding bodies that I lack focus, but that’s simply not true. Our 2 2   m e d i cal s c i e n c e • e n g li s h lan g uag e e d iti o n 2 012

research question is always the same: How does the cell decide whether to die or not? The answer can then lead us to projects in a range of different fields and diseases, but all of them look at the difference between life and death, which is crucial at cellular level too.”

Bertrand Joseph on: Scientific dogma: Question it! I tell my students to read less and think more. It’s all too easy to get bogged down – the best projects generally stem from truly original ideas fuelled by curiosity and an open mind. Daring to ask questions: All questions are good questions. I have new ideas all the time and take them straight to the lab and ask people what they think. The title of his most recent lecture, “Cracking the death code”: Researchers also have a role as storytellers. If you want someone to read what you have written, or listen to what you have to say, it needs to be clear and interesting. Otherwise your research is pointless. Research funding: Should be based more on the research you’re doing now and will be doing in the future, not what you’ve done in the past.

In his research projects he therefore works with researchers in a variety of other fields, including diabetes, genetics, epigenetics and cancer. Joseph says that this is the key to successful research. “There are no good researchers, only good research groups. Good research can be summed up in three words: collaboration, collaboration and collaboration!” This wide-ranging creativity also helps when coming up with new ideas, which Bertrand Joseph does a shade too regularly according to those generally tasked with testing them – his students. “They groan a bit at some of my ideas, but we try to test all hypotheses, even ones that may seem a bit daft.” The project that resulted in the article in Nature began as “hobby research” – a sideproject where the researchers decided out of curiosity to investigate how enzymes called caspases affect microglial cells, a type of brain cell which plays an important role in some brain diseases. The aim was to show how these caspases, which were already known to cause cell death, kill microglial cells. Only it turned out that the cells did not die. “We could have just left it there, but instead we asked a key question: If the caspases don’t kill microglial cells, what do they do?” The answer – that caspases can also act as chemical messengers activating other cells –

p


Name: Bertrand Joseph. Title: Researcher at the Department of Oncology-Pathology. Age: 38. Family: Wife Bettina, children Astrid (8) and Nils (6), and cat Panda. Motto: Focus on the positive. Hero: “Sten Orrenius, gentleman researcher and professor emeritus at Karolinska Institutet. He’s hugely knowledgeable and experienced, and also very generous about sharing his knowledge. Despite his own greatness, he doesn’t look down on others.” Currently working on: Recently had an original article published in the world-renowned scientific journal Nature which was soon high up on the top 10 list of most-downloaded articles. How he winds down: Building stairs, cupboards and the like for his house (which he designed himself), skating, sailing and watching bad TV. m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  2 3


’’

“I’m researching the whole time – on the train, in bed, out shopping, whenever. Research is a true pleasure for me and not something I need to take a break from.” opened the door to a brand-new field. The researchers were able to show that the enzymes activate the microglial cells, and these cells, in turn, trigger an inflammatory reaction. When they gave substances that inhibit caspases to mice, they found that fewer microglial cells were activated, resulting in reduced inflammation and cell death. And when they then contacted clinical researchers in Lund who helped them investigate caspase activity in brain samples from deceased Alzheimer’s and Parkinson’s patients, things got really exciting. “At first we could scarcely believe it – the results were almost too good to be true. These patients had markedly increased levels of activated caspases in their microglial cells.” Now they hope to go one step further and find drugs to inhibit these caspases. According to the people around him, Bertrand Joseph is a person who “delivers”. And he says himself that he works to clear deadlines. “I’m very organised, ticking off task after task. When I was doing my PhD, for example, I developed a system of schedules that required three stopwatches running simultaneously so that I could keep up with all of my experiments! I don’t think I’ve ever started something and not finished it,” he says, acknowledging that back home it is his wife Bettina who is responsible for the to-do lists. Joseph’s predilection for combining people with different backgrounds is clear from the composition of his research group: seven researchers from seven different countries. Team spirit is crucial, he believes: “A good team is not under you but with you.” According to his colleagues, his leadership style is also about empathy, friendliness and understanding. Perhaps his motives for creating a good team spirit in his group stem from his own experience in the early stages of his research career. He was born and grew up in France, and decided while still at school that research 2 4   m e d i cal s c i e n c e • e n g li s h lan g uag e e d iti o n 2 012

was his future. Once safely ensconced in the lab, he worked manically and completely independently. “I’d work seven days a week, 14-16 hours a day. My thesis was ready in less than three years, whereas it would normally take at least four. I met my supervisors only three times during this period.” With this scant supervision, there was nobody to tell him to ease off. So once he gained his PhD, military service provided a much-needed break. “It was a turning point for me. I had time to reflect and began to realise that there was more to life, that maybe research was not everything.” Family is now what matters most to Joseph, something which he also tries to impress upon his students. “I like to tell them not to work too hard!” But does he practise what he preaches? On the day of this interview, he leaves work at 3 pm to take his children to the cinema. But he would not call it a respite from his research, nor feel that he should need one. “I’m researching the whole time – on the train, in bed, out shopping, whenever. Research is a true pleasure for me and not something I need to take a break from.” F

Bertrand Joseph believes that research benefits from good group dynamics. He is French himself, and his group includes researchers from India, Spain, Ireland, Germany, Sweden and the Netherlands.


folio

Music practice can have a positive impact on general intelligence.

Why does music make us feel good?

Five quick questions for Fredrik Ullén, who carries out research into the workings of the brains of experts, in other words people who have got really good at something. text: Ola Danielsson

Music brings us joy, but it also has positive effects on our cognitive abilities and health. We do not know why this is but the project “Humans making music: an interplay between culture and nature” aims to find out. Project leader will be professor Fredrik Ullén in collaboration with colleagues at the Swedish Twin Registry, Stockholm University and Umeå University.

How can you train to be an expert? sara appelgren

Fredrik Ullén

What happens in the brain when you become an expert? “Expertise is all about specialisation, which means training up a high-level but very precise capacity to carry out specific tasks. The key aspects of this process are automation (so that not all elements of a complex task require our full attention), optimised problem-solving strategies and effective teamwork between our working memory and long-term memory. The anatomy of the brain also changes as a result of long-term training, with areas of both the grey and white matter becoming more developed.”

How do I set about becoming an expert in, say, playing the guitar? “The single most important factor underpinning all expertise is focused practice. Practice really does make perfect!”

Can everyone get to be really good at something, or do you need to have a particular type of personality? “I believe that personal variables do play a role in addition to practice. For example, intelligence seems to be important for those types of expertise that require us to manage

new information. Personality, motivation and interest are important, for example, because they affect what you choose to practise and how intensively you go about it. But we need more research in this area as research to date has focused mainly on practice.”

What can your research into expertise be used for? “Understanding the mechanisms behind expertise makes it easier for us make training more effective, stimulating and fun. I’ve seen plenty of interest in this from people in both education and business. We also work with clinical researchers to assess how motor training can help groups of neurological patients with impaired motor function.”

If you practice one thing, will you get better at other things too? “The knock-on effects are generally limited. You get very good at what you spend a lot of time practising, but not at other things. However, some forms of practice, for example music practice, have a positive impact on general intelligence. How this works is a very exciting area of research.” F m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  2 5


Top publications 2011 Editor: Cecilia Odlind

A selection of the most recent publications from Karolinska Institutet in the world’s leading scientific journals. Nature:

A novel study has deepened the understanding of how chromosome replication works. By studying DNA replication in yeast cells, researchers at Karolinska Institutet have discovered that a protein complex (Smc5/6) helps to release torsional stress created in the DNA molecule when chromosomes are replicated in preparation for a coming cell division. “Our study also indicates that the stress can propagate more freely along the DNA in a chromosome than was previously thought,” says KI professor Camilla Sjögren, head of the team that conducted the study. The study therefore sheds more light on the mechanisms behind one of life’s most fundamental processes. Since topoisomerases, enzymes known to remove replication-related stress in the DNA, are common targets for cancer treatments, the finding might eventually lead to new therapies. When a fertilised egg develops into a complete organism, or when old cells are replaced by new ones, it is done through cell division. If human daughter cells are to survive and develop normally, they must each obtain a full set of 46 chromosomes, which are made of double-stranded DNA helices. Since the original mother cell started as a cell with 46 chromosomes, these must be duplicated before division takes place. During this process, the DNA double helix is separated so that the replication machinery can reach the individual DNA strands. This prising apart of the strands creates stress in the form of over-twisted DNA in the vicinity of the replication zone. If this stress is not removed, replication can be slowed down or even stopped, and this, in turn, can lead to mutagenesis and/or cell death. “Several modern cancer treatments attack topoisomerases, but there’s a problem in that some cancers become resistant to such therapies,” says professor Sjögren. “Now that we’ve discovered that also the Smc5/6 complex releases the stress which forms during the replication process, our results might trigger the development of drugs that target Smc5/6. This could create another tool for inhibiting tumour growth.” Chromosome length influences replication-induced topological stress Kegel A, Betts-Lindroos H, Kanno T, Jeppsson K, Ström L, Katou Y, Itoh K, Shirahige K, Sjögren C Nature March 2011

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Follow Popeye’s example: eat spinach and grow strong.

bulls

Research into chromosome replication reveals details of heredity dynamics

Cell Metabolism:

Nitrate improves mitochondrial function The spinach-eating cartoon character Popeye has much to teach us, new research from Karolinska Institutet shows. The muscles’ cellular power plants – the mitochondria – are boosted by nitrate, a substance found in abundance in vegetables such as lettuce, spinach and beetroot. In a new study, researchers at the Karolinska Institutet had healthy people take nitrate equivalent to 200-300g of spinach or lettuce for three days, after which they were given a cycling task to perform. The researchers then analysed samples from their thigh muscles and compared them with similar samples from the same subjects when they had taken a placebo instead. After nitrate ingestion, a significant improvement was seen in the efficiency of the mitochondria, which consumed less oxygen and produced more of the energy-rich substance ATP per consumed oxygen molecule. “The mitochondria play a key role in cellular metabolism,” says professor Eddie Weitzberg, who is heading the study with professor Jon Lundberg. “Improved mitochondrial function probably has many positive effects on the body, and could explain some of the health benefits of vegetables.” The results are of sports-physiological interest, as they show that nitrate reduces oxygen consumption during physical exercise; however, they are also of potential significance to diseases involving mitochondrial dysfunction, such as diabetes and cardiovascular disease. The group has also recently shown that nitrate reduces the blood pressure of healthy individuals and that in laboratory animals it counteracts components of the metabolic syndrome, a pre-stage of diabetes. Dietary inorganic nitrate improves mitochondrial efficiency in humans Larsen FJ, Schiffer TA, Borniquel S, Sahlin K, Ekblom B, Lundberg JO, Weitzberg E Cell Metabolism February 2011


Cell Metabolism:

A selection of the most recent publications from Karolinska Institutet in the world’s leading scientific journals:

New research redraws pancreas anatomy Research from Karolinska Institutet shows that insulin secretion in the pancreas is not under direct neural control, as has previously been thought. Thanks to the secretion of the correct amount of insulin and other hormones, the body is able to maintain an almost constant level of blood sugar. Applying advanced microscopic techniques, researchers at Karolinska Institutet and the University of Miami have now zoomed in on the islets of Langerhans, containing the hormone-secreting cells of the pancreas. They discovered that there are only a few nerves in the human islets of Langerhans, which is in marked contrast to the mouse, where the islets of Langerhans are better studied and found to be rich in nerves. Another difference that they discovered was that most of the nerves in the human islets establish contact with the smooth muscle cells of the blood vessels instead of with the gland cells, as in mice. “This fundamental difference is highly significant and important, since the knowledge could form the basis for new and more specific diabetes drugs”, says professor Per-Olof Berggren, one of the leading researchers in the study. Autonomic axons in the human endocrine pancreas show unique innervation patterns Rodriguez-Diaz R, Abdulreda MH, Formoso AL, Gans I, Ricordi C, Berggren P-O, Caicedo A Cell Metabolism July 2011

Unexpected cell repairs the injured spinal cord

Cell dysfunction linked to obesity and metabolic disorders Dynamics of human adipose lipid turnover in health and metabolic disease Arner P, Bernard S, Salehpour M, Possnert G, Liebl J, Steier P, Buchholz BA, Eriksson M, Arner E, Hauner H, Skurk T, Rydén M, Frayn KN, Spalding KL Nature September 2011

Better result with patent drug in heart failure Association of candesartan vs losartan with all-cause mortality in patients with heart failure Eklind-Cervenka M, Benson L, Dahlström U, Edner M, Rosenqvist M, Lund LH JAMA January 2011

science photo library

A pericyte origin of spinal cord scar tissue Göritz C, Dias D, Tomilin N, Barbacid M, Shupliakov O, Frisén J Science July 2011

Heparin a key role player in allergy and inflammatory reactions Mast cells increase vascular permeability by heparininitiated bradykinin formation in vivo Oschatz C, Maas C, Lecher B, Jansen T, Björkqvist J, Tradler T, Sedlmeier R, Burfeind P, Cichon S, Hammerschmidt S, Müller-Esterl W, Wuillemin WA, Nilsson G, Renné T Immunity February 2011

New method for producing neurons Transcription factor-induced lineage selection of stem-cell-derived neural progenitor cells Panman L, Andersson E, Alekseenko Z, Hedlund E, Kee N, Mong J, Uhde CW, Deng Q, Sandberg R, Stanton LW, Ericsson J, Perlmann T Cell Stem Cell June 2011

Science:

After injury to the central nervous system, CNS, neurons are lost and largely replaced by a scar often referred to as the glial scar based on its abundance of supporting glial cells. In a new study, researchers show that the majority of scar cells in the damaged spinal cord are not glial cells at all, but derive from pericytes, a small group of cells located along blood vessels. They reveal that these pericytes start to divide after an injury, giving rise to a mass of connective tissue cells that migrate towards the lesion to form a large portion of the scar tissue. A pericyte They also show that these cells are needed to regain the tissue integrity, and that in the absence of this reaction, holes appear in the tissue instead of scarring. These new findings indicate a critical and previously unknown mechanism for scar formation following damage to the nerve system, and give reason for further investigation into whether the modulation of pericytes after CNS injury can stimulate functional recovery.

How the stem cell niche never dies EphB signaling controls lineage plasticity of adult neural stem cell niche cells Nomura T, Göritz C, Catchpole T, Henkemeyer M, Frisén J Cell Stem Cell December 2010

Improved survival and treatment for chronic blood disorders The success story of targeted therapy in chronic myeloid leukemia: A population-based study of 3,173 patients diagnosed in Sweden 1973–2008 Björkholm M, Ohm L, Eloranta S, Derolf Å, Hultcrantz M, Sjöberg J, Andersson T, Höglund M, Richter J, Landgren O, Kristinsson SY, Dickman PW Journal of Clinical Oncology May 2011 Smaller surgical procedure sufficient for high-risk melanoma A randomised multicentre trial comparing 2-cm vs 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm Gillgren P, Drzewiecki KT, Niin M, Gullestad HP, Hellborg H, Månsson-Brahme E, Ingvar C, Ringborg U The Lancet October 2011 These are just some of the publications from the last year, where researchers at Karolinska Institutet have contributed to journals with an impact factor of over 15. The impact factor reflects the average number of references during a year to articles published in a journal during the two previous years.

m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  27


Life in the lab While using animals for research purposes is nothing new, using small amphibians which can regenerate limbs has led to unique research results. text Gustaf Andersson photos Ylva Sundgren

Salamanders can heal their own brains Daniel Berg is changing the water for a handful of red-spotted newts, a kind of aquatic salamander. The aquariums lining the walls of the small room are noisy, and preparations are in full swing for the year’s first experiment. As well as changing the water, Berg must also inject BrdU into the 15 amphibians that are divided between four different aquariums. “The substance is a nucleotide analog and will be stored in the salamanders’ stem cells and used to analyse which cells actually divide,” says Berg, doctoral student at Karolinska Institute’s Department of Cell and Molecular Biology. “This allows us to see how quickly the brain produces new cells, and also to monitor them.” The work is part of a research project which started just over four years ago to investigate the regeneration of nerve cells in salamanders’ brains. The team is headed up by Andras Simon, associate professor in the same department. He is also the man behind the introduction of salamanders as an experimental animal in Sweden. “We are currently the only ones in the world to be using this approach to studying the regeneration capacity of the brain,” says Simon. Regeneration is the salamander’s distinguishing contribution to science, and it can regenerate not only many types of tissue but even entire limbs. We have been aware of this unique phenomenon for 2 8   m e d i cal s c i e n c e • e n g li s h lan g uag e e d iti o n 2 012

a couple of hundred years, but it has been hard to study the underlying molecular and cellular mechanisms. The Simon lab is about to change this situation. By injecting a substance, which knocks out some cells in the salamander, they are able to induce a Parkinson’s-like condition in the animals. One month later the salamanders have cured the damage to their brains. “We can’t see any difference in either the tissue or the animals’ behaviour,” says Simon. “The regeneration of the nerve cells is complete. Salamanders p

Research team leader Andras Simon (right) introduced the salamander as an experimental animal for regeneration studies in Sweden. Here we see him talking to doctoral student Daniel Berg in the research team’s lab.


Unique model for the brain’s regeneration Salamanders have the unique ability to regenerate missing limbs as well as nerve cells in the brain. This can help researchers to answer two main questions: how are new cells produced, and how is the process stopped when the normal number of cells has been reached? The research group has recently discovered that the formation of new nerve cells in salamanders under normal conditions is just as limited as that of mammals which cannot regenerate tissue. This means that the salamander’s brain is an excellent model for identifying which mechanisms are needed to reactivate the production of nerve cells after it has stopped.

Experiments on salamanders’ brains, which are no larger than a pin-head, have led to important research results.

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Life in the lab

Left: Team leader Andras Simon shows where the salamanders’ stem cells are cultured. Above: Doctoral student Daniel Berg makes preparations for the year’s first experiment on salamanders with unmodified brains.

’’ Andras Simon

Daniel Berg

Eventually we’ll start testing the results on other animals and hope that our knowledge can lead to new treatment strategies for humans. are very interesting animals and in some respects are easier to work with than, say, mice.” Although just 8 cm from head to tail, aquatic salamanders have clear personalities. “I’ve noticed that one of them loves climbing up the aquarium glass more than the others, and then there’s one that hides the whole time,” says Berg while carefully moving an aquarium into a quiet room nearby where the light is better. Berg’s work varies from week to week. Right now there’s a lot of reading to do, but some days he sits and collects tissue samples all morning and afternoon – a finicky job that takes time. “Although we use the latest technology and draw on all available stem cell expertise, very few other people are conducting research into salamanders’ brains and so we’re pretty much starting from scratch and have a very free hand,” says Berg. The group is currently in a productive phase. An article on nerve cell regeneration was published in December 2010 in the journal Development and another was recently published in Cell Stem Cell.

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Most of the work for these articles was done over the last few years – as ever, you have to be in it for the long haul in research. “We average one article a year, but it can vary a lot from year to year,” says Simon. “We can plan our research, but not the results.” The work has now been under way for almost ten years and Simon would like it to continue for at least ten more. “We’re very excited at the moment about our discovery of a mechanism that controls how nerve cells and stem cells in the animals’ brains communicate with each other.” Simon believes that this communication is fundamental to understanding how the brain regulates the stem cells. The next goal will be to characterise the genes and analyse this communication further. “Eventually we’ll start testing the results on other animals and hope that our knowledge can lead to new treatment strategies for humans.” F


The Picture Photo: John Lock Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet.

Here we see human skeletal cancer cells. Using a series of high-resolution images taken with a confocal microscope, the researchers have managed to create a film showing how the cancer cells move. The film is an example of a research technique used in systems microscopy. “When trying to understand how, for example, cancer cells break free and establish new tumours, we have to get a picture of the entire process,” says Staffan Strömblad, professor of clinical molecular biology at Karolinska Institutet and coordinator

of the Systems Microscopy Network of Excellence (see page 5), a close collaboration between biologists, medical researchers and mathematicians that aims to create mathematical models for biological events. “The new technology is there but needs to be developed further and, more than anything, used.” F Watch the film at http://www.youtube.com/karolinskainstitutet (search on “migrating human skeletal cancer cells”).

m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  31


Hot topic: Creativity It’s official: creativity and mental illness are two sides of the same coin. A new study from Karolinska Institutet reveals that artists, authors and researchers are more likely to have schizophrenia and bipolar disorder in the family than the rest of the nation. text Karin Tideström illustration Anna Ödlund

On the edge of madness Kristoffer lindgren

Simon Kyaga

The myth of the mad genius has been around since Aristotle. As has the notion of the suffering artist and the idea that all artistic creation stems from a tortured soul. It is a fascinating and emotive subject that has led many a researcher to try to substantiate or refute a link between creativity and mental illness. But to date, none has reviewed the subject quite as comprehensively as Simon Kyaga, a medical doctor and doctoral student at Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics, and his colleagues. Their study saw them turning to Sweden’s unique patient registers for help. Kyaga used the Swedish National Inpatient Register to identify everyone who had been admitted for psychosis in Sweden from 1973 onwards, a total of over 300,000 people. Statistics from Sweden’s multi-generation register helped to identify their relatives, while the Population and Housing Census allowed him to find out the jobs, past and present, of both the patients and their relatives. The research group identified a number of jobs that they defined as creative – both artistic, such as artist, musician, designer, actor and author, and scientific, in other words academic researcher.

Defining creativity • The most widely accepted definition of creativity is the ability to generate work that is new and meaningful, as opposed to trivial or bizarre. • Most creativity tests are based on coming up with as many solutions as possible to an open problem. In the study mentioned on page 34, Örjan de Manzano’s research group assessed creativity using the inventiveness battery of the “Berlin model of intelligence structure”, a verbal, figurative and numeric test that measures divergent thoughts and maps the association pathways of test subjects.

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“We tried to choose jobs that are recognised as creative, where the work tied in with the accepted definition of creativity – generating new and meaningful ideas,” says Kyaga. “Previous research has also shown that people with these jobs have specific personalities and score highly on the rating scales for creativity.” The study showed that patients with bipolar disorder were clearly over-represented in creative jobs. As were their healthy relatives. Close relatives of schizophrenics were also over-represented in creative jobs. The same did not, however, apply to the schizophrenic patients themselves. “During the study it became clear that schizophrenia is such a serious and debilitating illness that many who have it cannot cope with working life at all”, says Kyaga. The strongest links were for the healthy relatives of both patient groups. “So, it doesn’t seem to be the illnesses themselves that are linked with creativity, but rather something in the personality type of people at risk of developing them.” Manic depressive patients and their families were slightly over-represented in the group of researchers, while relatives of patients with schizophrenia were more likely to have more artistic jobs. “My feeling is that the bipolar personality type is quite well suited to research,” says Kyaga. “Bipolar patients are, on average, more ambitious than the normal population. This is essential in the academic world, where it’s important not to give up but instead to keep going for long periods. It could also be beneficial to have some periods where you generate more ideas, and others where you’re more structured.” It is too early to say exactly what the link is down p


The study referred to in the article defines scientist as a creative job. Medical Science asked three researchers for their views:

How important is it to be creative to succeed in research? ulf sirborn

Kirsty Spalding, researcher at the Department of Cell and Molecular Biology: “Yes, it’s definitely important! You have to be creative to come up with new ideas and new ways of approaching problems and questions. You also need to be able to interpret data creatively.”

stefan zimmerman

Georg Klein, professor emeritus at the Department of Microbiology, Tumor and Cell Biology: “Unfortunately I can’t give an answer as the question is too general. The word creativity has no precise definition and has also become something of a cliché. Using the word as though it is something fixed that everyone recognises is like looking for a black cat in a dark cellar.”

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stefan zimmerman

Cecilia Söderberg Naucler, professor at the Department of Medicine, Solna: “There are plenty of examples of researchers who generate important research results without being innovative or creative. However, I think that creative people are more likely to solve complex problems and come up with unconventional solutions. This is probably a prime hunting ground for Nobel laureates.”


Last year another study from Karolinska Institutet pointed in a similar direction. For the first time a biological process was identified that seems to be linked to both creativity and schizophrenia. Örjan de Manzano at the Department of Women’s and Children’s Health studied a number of healthy people who had PET scans of their brains and took a creativity test. Örjan de Manzano found a clear link with the dopamine receptor D2 in the thalamus. The fewer D2 receptors in the thalamus, the more points scored in the creativity test. A low number of D2 receptors in the thalamus is also found in schizophrenic patients and their close relatives. The thalamus acts as a kind of hub in the brain – all the information that is fed in from our senses passes through it before being distributed to the various regions of the brain. “Fewer D2 receptors seems to lead to decreased 3 4   m e d i cal s c i e n c e • e n g li s h lan g uag e e d iti o n 2 012

ADHD also linked to creativity There is also talk of links between other diagnoses and creativity, for example ADHD. Lisa Thorell, associate professor at Karolinska Institutet’s Department of Clinical Neuroscience, believes that there could be a clear link. She researches cognitive processes and ADHD in children. “Children with ADHD are creative in ways that sometimes result in problems for them, as they think outside the box, at school for example,” says Thorell. “It’s widely believed that the cause of ADHD is biological, and studies have established the involvement of the dopamine system, as is the case with creativity.”

Lisa Thorell

filtering and autoregulation of the information flow,” says de Manzano. “This could explain the associations and links that other people just don’t make. But it could also mean that these people find it more difficult to focus and sometimes lose control, as is the case in psychosis-like conditions.” It is, above all, the ability to make unusual associations that the researchers are linking with creativity. Kyaga’s study established that patients with unipolar depression, without a manic phase, were not more creative than other people. On the contrary, they and their relatives were under-represented in creative jobs. “It seems to be primarily positive symptoms, such as delusions, changed perception of reality, greater sensitivity to sensual impressions and megalomania, that are linked to creativity,” says de Manzano. “Depression and apathy, on the other hand, appear only to be destructive.” But what about research and creativity – are researchers more creative than other people? Kyaga feels that the issue is more complex: “Researchers are such a heterogeneous group. It’s fairly well accepted that you don’t have to be creative to do research. But you probably do in order to be a successful researcher.” De Manzano believes that a research group as a whole definitely needs to be creative: “The overall aim of research is to generate new ideas and develop them into something that increases our knowledge or understanding of the world. Being creative is, quite simply, what the job’s all about.” There could, after all, be something in the myth of the mad genius – but not of the suffering artist. F

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to. The study shows that there are family patterns and that they could be linked with social factors in the family. But the research group’s theory is that creativity and mental illness are two sides of the same genetic coin. “I think that it’s about the cognitive side of things,” says Kyaga. “That something in the genes makes these people more able to produce ideas and associations than normal.” This theory also provides a potential answer to the riddle of why a mental illness as serious as schizophrenia has not died out through evolution. Schizophrenia affects patients when they are young and leads to significant reductions in fertility, with schizophrenics having far fewer children than their peers. Nevertheless the illness has survived, and around 1 per cent of the population has it. It could be that people with a predisposition towards schizophrenia have more children than average. “For there to be an evolutionary advantage, you have to be more successful than others at spreading your genes. The same genes that result in schizophrenia may well have positive sides too. It’s entirely possible that creative people have more children.”

ulf sirborn

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There could, after all, be something in the myth of the mad genius – but not of the suffering artist.

Örjan de Manzano


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Around 10 per cent of all children sometimes have problems cooperating during trips to the dentist. The reason is often unclear, but both a fear of dentists and a disability such as ADHD or autism could play a role. Here we talk to My Blomqvist who wrote a doctoral thesis on ADHD and dental health.

Clear instructions and praise can help children with ADHD to stay focused during dental work.

text Ola Danielsson

Do children with ADHD have worse dental health? medicinsk bild/HS

My Blomqvist is a dentist and a researcher at the Department of Dental Medicine, Karolinska Institutet.

Why is there a need for research into ADHD and dental health? “Many dentists find it hard to deal with children who don’t cooperate or who behave strangely, and there’s a need for greater understanding that the cause can be a disability such as ADHD. Children with ADHD are also a risk group for developing caries.”

Have you got any advice for dentists? “Children with ADHD generally function best in a calm environment. Dentists need to help children to stay focused on the treatment. Explain in a clear and simple way what will happen and offer encouragement instead of asking too many questions. Praise for appropriate behaviour will help children during treatment.”

One of your studies filmed 11-year-olds on a trip to the dentist. What were your findings? “That children with ADHD found it harder to concentrate. They asked more questions about things that had nothing to do with the check-up, and were less likely to answer the dentist’s questions.”

Do children with ADHD have worse dental health? “Yes, we noted that 11-year-olds with ADHD had worse oral health with a higher prevalence of caries than the control group. The 13-year-olds had also got into unhealthy habits with more snacking and worse brushing.”

New centre of expertise for neurodevelopmental disorders

2010 saw the opening of KIND, a centre of expertise for neurodevelopmental disorders, at Karolinska Institutet. The aim is to serve as a link between different players in the field of ADHD so that research results will be of benefit to society. Part of KIND’s remit is to develop a better working relationship between the health service and academia, and to create better conditions for research. This work will include setting up a register of everyone in Stockholm with a diagnosis of ADHD for use in research. Find out more at www.ki.se/kind.

What are you researching now? “I’m studying dental health in young adults with ADHD. The preliminary results show that a fear of dentists is more common in this group. They’ve had more bad experiences in the dentist’s chair and feel, for example, that they’ve been given treatments they weren’t prepared for.” F m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  3 5


Transcultural care research Culturally competent personnel who understand their patients well will result in cheaper and more effective health care, asserts professor Azita Emami, who leads research into transcultural care in Sweden. text Annika Lund illustration Anna Ödlund

“You can understand others only if you understand yourself ” ulf sirborn

Azita Emami

Professor Azita Emami, a trained nurse, finished her PhD on the care of elderly Iranian patients almost ten years ago. Her supervisor, professor Sirkka-Liisa Ekman, had previously submitted a PhD on the care of elderly Finns in Sweden. These were the first tentative steps in transcultural care – a field of research new to Sweden although it had existed in other countries since the 1960s at the very least, with the USA leading the way. “There’s a tradition over there when it comes to these issues, as their society was multicultural right from the very start,” says Emami. She explains that transcultural care is now an important concept which constitutes a natural part of research in the USA. “It’s hard to get funding for research in the States unless there’s a transcultural perspective.” Emami believes that cultural competence is crucial to good care. The basic idea is that a nurse with high levels of cultural competence can understand patients more easily, even if they do have a different cultural background. The argument is that greater understanding paves the way for better communication as nurses can adapt their message so that it actually gets through to patients. This means that patients grasp information more quickly, have greater confidence in the caregiver and adhere to the treatment.

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And it is this last stage of the process – greater adherence to treatment – that offers major benefits, according to Emami. “These days we have good diagnostics and good treatments in many areas, but we’re still seeing major shortcomings in patients’ treatment adherence. This is a key bit of the puzzle for care – and this is where cultural competence plays a major role.” Emami has a professorship with a specialisation in transcultural care in the division of nursing at Karolinska Institutet’s Department of Neurobiology, Care Sciences and Society. She has also been dean at Seattle University’s College of Nursing for the last few years, which is why she leads her research group from afar. Right now the group is working on around ten projects on transcultural care. “The important question in all of the projects is: what makes us different, and what do we have in common even if we have different backgrounds?” she says. Several of the group’s projects tackle considerations other than ethnicity. One studies the gender perspective in the care of the elderly, while another looks at alienation and the perception of ill health among young Stockholmers. Emami believes that her field has developed and moved on from its previous sharp focus on ethnicity.


Cultural competence is crucial for a hith quality care.

Anyone wishing to improve their cultural competence can start by looking at their own cultural background. Understanding the context that has shaped us as individuals makes it easier to understand how others have been shaped, believes Emami. “In the past, research focused more on understanding others, but I think that this is possible only once you’ve understood yourself,” she says. She sees a future where it will be possible to use instruments developed by the research group to compare the effectiveness and costs of care, and to link these to the cultural competence of care personnel. Emami explains that it is well established

Cultural competence all about listening – and doing A mother, born in Iraq, products from Iraq again. She takes her one-year-old who eventually stops taking her has a cold along to the local child along for check-ups. child health clinic (BVC). She “Although this isn’t a true explains that the child has story, it’s realistic,” says Anita been given the normal Iraqi Berlin, a paediatric nurse who household remedy for childdid her PhD at Karolinska hood colds, a powder that Institutet on cultural compeis mixed with hot water. The tence among BVC staff. Anita Berlin product was purchased in She feels that a culturally Iraq and brought over to competent nurse would have Sweden. handled the situation differently. She shows the product to the nurse, “The most important thing here is who has never seen it before. not to lose the mother’s confidence. The meeting leads to a crisis of confi- The solution could be for the mother dence – for both parties. The nurse to come back for a follow-up visit fairly does not want the child to receive soon. They will then discuss the child’s medication without the health service cold and the treatment again,” says first being consulted. The mother, on Berlin, who is continuing her research the other hand, thinks that the care into cultural encounters in paediatric personnel should be able to answer care at the Swedish Centre for Family questions about medicines. Furtherand Community Medicine at Karolinska more, the mother feels under suspicion Institutet’s Department of Neurobiology, and decides not to say anything about Care Sciences and Society. ulf sirborn

“I’m one of those people who believes that cultural identity goes far beyond ethnicity – it’s everything that forms a person, including age, sex and socioeconomic status,” she says. “I feel that we tend to attach far too much importance to ethnicity when discussing cultural identity.” Maria Jirwe is a senior lecturer in the division of nursing at the Department of Neurobiology, Care Sciences and Society. She is often asked by nursing students how best to care for patients from a different cultural background. “My message is that you can’t learn how to care for Muslims, Jews or Arabs, we simply care for patients as individuals.”

in American studies that higher levels of cultural competence make for more effective and cheaper care, and she believes that the results will be the same in Sweden. “That’s when transcultural care will really take off in Sweden,” she says. F m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  37


Short notes istockphoto

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These figures are so alarming that a new campaign must be launched at once to curb the trend.

Miriam Katz-Salamon, researcher at the Department of Women’s and Children’s Health, on her study showing that the number of cases of sudden infant death syndrome is on the rise again. The reason for the increase is believed to be a lack of information to new parents.

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Cognitive behavioural therapy (CBT) over the Internet has been shown to be effective in the treatment of disorders such as depression and agoraphobia. A new thesis by Erik Hedman, a doctoral student at Karolinska Institutet’s Department of Clinical Neuroscience, reveals that online CBT can also be used to treat social phobia.

Each year more than 100 million people are affected by natural disasters. There is often a shortage of basic information on where the people affected actually are, making it harder to get help out to them.

Mobile phone data improve Online CBT for social phobia response to disaster in Haiti How does online CBT work?

“A 15-week long programme of Internet treatment starts after the patient has had a diagnostic examination with a psychiatrist. The content of the treatment is the same as that of normal CBT, but all the information is relayed as text. Each week patients receive homework tailored to their needs through a system not dissimilar to e-mail. Following the treatment, patients meet a doctor for assessment.” What are the advantages of online CBT for social phobia?

“In many ways it increases the availability of CBT as it can be used over long distances and is

the only way to provide CBT in some sparsely populated areas. The treatment time per patient and week is also reduced from 50 minutes to five so that more people can benefit.”

Are there any disadvantages?

“Treatment depends on patients being able to read and to speak Swedish, so it can be difficult for anyone with reading difficulties or who doesn’t speak the language. To date, online CBT for social phobia has been available primarily in Stockholm, but Internet-based treatment is likely to grow.” Cecilia Groop

Social phobia: a common form of anxiety Around 8 per cent of the Swedish population suffers from social phobia, an exaggerated fear of being scrutinised in social situations. Sufferers are hugely anxious about talking in front of a group and tend to avoid social contexts.

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Population movements following natural disasters make it hard to deliver the right amount of crucial aid to the right places. Researchers at Karolinska Institutet and Columbia University in the US developed a new way of solving this problem during the earthquake disaster and cholera epidemic on Haiti, tracking the movements of two million anonymous mobile phones and reporting directly to forces on the ground. “This work was greatly appreciated by the aid agencies, and we believe that the method could bring about important improvements in disaster response and development cooperation in the future,” says Linus Bengtsson, registered physician and doctoral student at the Department of Public Health Sciences, who led the work on developing the method. “We’re now working on setting up an organisation which can routinely carry out this kind of analysis following future disasters.” PLoS Medicine, August 2011

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children and adolescents with brain tumours were included in the first ever study to investigate links between mobile phone usage and the risk of brain tumours in young people. Their mobile phone habits were compared with those of 646 controls. Although the results showed no increase in the risk, the researchers stress the importance of continuing to monitor the situation.


Boosting immunity to colds through exercise henrik montgomery/scanpix

Exercise reduces the risk of catching a cold, reveals a new thesis from Karolinska Institutet. To increase immunity to colds in people with desk jobs it takes around an hour of demanding physical activity each day (such as cycling to and from work, going up stairs, carrying heavy shopping bags etcetera), or around three hours of moderate physical activity (such as actively playing with the children, going for a brisk walk etcetera) each day. This reduces the risk of catching a cold by 18 per cent, revealed a study that followed over 1,500 people for 15 weeks using an Internet-based questionnaire. Physical activity was also able to counteract infections in people with long-term stress, an effect that was particularly evident in men. What marks the study out from others in the field is that it used normal people instead of elite athletes. “In sports medicine, people are obviously interested in questions such as how hard an elite athlete can train without becoming ill,” says Elinor Fondell at Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics, who recently submitted a thesis presenting the study. “This has meant that most studies investigating the link between infection and physical activity are carried out on elite athletes. But we also need to find out more about how physical activity affects the

health of normal people.” In her thesis, Fondell also studied how taking vitamins C and E prevents colds, and the impact of sleep on the immune system.

But you’ll need to do an hour’s vigorous physical activity a day, or at least three hours of moderate physical activity.

Anders Mutvei

håkan jansson/scanpix

Sense of fairness hardwired in the brain A new study from Karolinska Institutet and the Stockholm School of Economics shows that the brain has inbuilt mechanisms that mean that we automatically react against unfairness. The research subjects’ sense of fairness was challenged by a proposer in the Ultimatum Game (a game to split a fixed sum of money) at the same time as their brain activity was monitored using MRI.

The researchers found that the area of the brain that controls financial decisions is located in the amygdala. In response to unfair proposals, the research subjects punished the proposer, even if it cost them money to do so. A drug that reduces activity in the amygdala also reduced the reaction to unfairness. PLoS Biology, May 2011

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Focus: Gut flora The time has come for pathogenic gut bacteria such as Salmonella, Legionella and E. coli to step aside – the spotlight is now increasingly on the beneficial bacteria in our intestines. With its unique germ-free animals studied since the 1950s, Karolinska Institutet is now a world leader in a field that everyone’s talking about: gut flora. text Jenny Ryltenius

Faecal transplants restore JOHN SENNETT

Elisabeth Norin

Flatulence and defecation are perhaps what most of us associate with the stomach and intestines, which is not so surprising when you consider that the gastrointestinal tract is the body’s largest metabolic organ and gives everyone, sick or healthy, a daily reminder of its function. Less likely to occupy our minds is that the gut is the home to more than a thousand different species of bacteria, together weighing more than a kilo. A growing number of researchers, on the other hand, are now spending their days pondering the significance of this myriad of bacteria. Medical Science met three researchers at Karolinska Institutet who are attempting in different ways to find out what our normal gut flora looks like, how it helps us to stay healthy, and what roles it plays in serious diseases. Elisabeth Norin, associate professor at the Department of Microbiology, Tumour and Cell Biology at Karolinska Institutet, is studying faecal transplantation as a way of restoring gut health in people with diarrhoea caused by a bacterial imbalance. There were anecdotal reports throughout the 20th

Antibiotics sabotage the gut flora • The lumen of the gastrointestinal tract is home to at least a kilo of bacteria of more than a thousand different species. There are ten times more bacteria in the gut than there are cells in the entire body. This is known as our normal gut flora. • It seems that a well-balanced gut flora can protect us against invasion by harmful bacteria. Imbalances in the gut flora arise when some species are favoured at the expense of others. • External factors such as diet, lifestyle and antibiotics can affect the composition of the gut flora. A single course of antibiotics can affect the gut flora for a period of several years. Source: Magen – Bakterier, buller och brak, Karolinska Institutet University Press.

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century of the use of faeces from relatives to cure diarrhoea. One recent case in the US particularly caught the attention of the Swedish media: a woman who had suffered from diarrhoea for several months after repeated courses of antibiotics that knocked out her normal gut flora. Eventually the situation became so desperate that her husband donated his faeces for application into her rectum by means of an enema. Within hours the woman had completely recovered. Elisabeth Norin and her colleagues have gone one step further. In the late 1990s a healthy middle-aged woman donated her faeces to Karolinska Institutet. After careful analysis to check that it contained no pathogenic parasites, viruses or bacteria, the donated material was then treated in a way that allowed the normal gut flora to be cultured under controlled conditions. “This gut flora culture is unique and occurs nowhere else in the world,” says Norin. “More than 100 patients have now been treated with it against diarrhoea, mainly in Sweden and Norway, and around 80 per cent have been cured – and we’ve seen no side-effects.” One crucial resource for her research – and all other gut flora research – has been the unique germfree rats and mice at Karolinska Institutet. Since the 1950s, around 100 generations of rats have been raised in a completely sterile environment, originally delivered by Caesarean section, so that they have never kept any bacterial flora in their intestines or anywhere else in their bodies. “By studying these germ-free animals, we saw that if we gave them faeces from animals raised in a


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In the late 1990s a healthy middle-aged woman donated her faeces to Elisabeth Norin’s research group at Karolinska Institutet. This material has since been used to treat more than 100 people with diarrhoea caused by a bacterial imbalance, and has cured about 80 per cent of them.

gut health

lars clason/folio

normal environment, the normal gut flora became established very quickly,” says Norin. “But without a faecal transplant, the animals sometimes became ill with diarrhoea and could even die.” But which of the bacteria in our faeces are the ones that matter? “The truth is that we don’t know exactly what we’re transplanting, because of the difficulties in analysing the bacteria composition,” says Norin.

To find out what bacteria are to be found in the culture that has already cured 100 people of persistent diarrhoea, she has begun working with, among others, professor Lars Engstrand from the Department of Microbiology, Tumour and Cell Biology at Karolinska Institutet. He is studying the culture using a technique developed at the Swedish Institute for Communicable Disease Control and Karolinska Institutet a few years ago and now employed worldwide.

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Focus on: Gut flora

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It would be wonderful to be able to come back in a hundred years and see what this research has led to. I think that eventually we’ll have a kind of library of gut bacteria genes.

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Joseph Rafter

But it does not end there. Rafter is also interested in how diet, together with bacteria, can activate genes and cause them to produce proteins with particular effects. Studies of germ-free mice given a probiotic bacterium without any other change in diet revealed a decrease in fat deposition. “We saw that many genes in the colon are activated Prehistoric faeces offers answers to today’s questions Professor Lars Engstrand from the Department of Microbiology, Tumour and Cell Biology at Karolinska Institutet is leading work on analysing the faeces of Ötzi the Iceman. Using a technique called massively parallel pyrosequencing (see main article), the aim is to ascertain the normal gut flora of Europe’s oldest natural human mummy, who lived around 5,300 years ago. It is hoped that this will provide an answer as to whether genes with resistance to antibiotics were already in existence before antibiotics began to be used as medicines, which is not that far-fetched a hypothesis given that the yeasts from which penicillin originated were around back then. The results are now finalized and will be published later this year in collaboration with colleagues from Italy and Germany.

magnus pehrsson

Massively parallel pyrosequencing is opening doors which could lead to new medicines in the future. Elisabeth Norin hopes that one day it will be unnecessary to use her special culture to treat long-term diarrhoea. “Our dream is that once we know which bacteria we have in the culture, we can freeze-dry them and put them in a tablet or capsule,” she says. Faecal transplantation also has potential in areas other than the treatment of diarrhoea. For example, research has been conducted in overweight patients. In a Dutch study, it emerged that insulin sensitivity in overweight patients with metabolic syndrome (a precursor to diabetes) increased when they were treated with faeces from slim donors. After six weeks, their blood lipids were also much improved. Patients who were treated with their own faeces, on the other hand, showed no change. This means that gut bacteria not only play a role in local conditions in the intestines, such as diarrhoea, but also seem to affect other diseases. Professor Joseph Rafter from the Department of Biosciences and Nutrition at Karolinska Institutet is trying to find out how. As vice-coordinator of the EU-funded project Tornado, he is involved in several different studies mapping the molecular mechanisms used by gut bacteria to impact the body’s physiology. “We now know that bacteria in the intestines do not just have an effect on one another and the lining

of the intestines,” says Rafter. “They can also ‘talk’ with tissues and organs a long way from the gut, such as the brain, liver and fat tissue. It seems quite clear that the gut flora also plays a role in diseases like diabetes, obesity and even autism in children.” He has seen that gut bacteria release residues – metabolites – which can influence the host. These metabolites can be absorbed through the wall of the gut into the bloodstream, where they come into contact with target molecules in the body’s various organs. Rafter and his colleagues are now attempting to identify these target molecules locally in the lining of the gut and in the liver, intestines and fat tissue. “What’s exciting is that the conversation – or crosstalk as it is known – between the bacteria and the host can be influenced from outside through diet. This means that if we can show how the bacteria’s metabolites affect a signalling pathway in the body which is important for, say, fat deposition, we could influence this pathway from outside with a diet containing probiotic bacteria, for example.”

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“We’ll also be analysing the bacterial flora in the faeces of patients with diarrhoea before and after treatment with the culture,” says Engstrand. The technique is known as massively parallel pyrosequencing and, put simply, analyses the complete DNA of the gut bacteria. In one study, Lars Engstrand looked at the gut flora of identical twins where one was healthy and the other had the inflammatory bowel disorder Crohn’s disease. “The twins’ gut flora differed in that the ones who were ill lacked certain groups of bacteria,” says Engstrand. “As far as our normal gut flora is concerned, it seems to be the case that the more species we have, the better.”


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Eat a varied diet!

iSTOCKPHOTO

How to look after your gut flora – tips from the experts:

Don’t eat more fibre than your stomach can take!

1. Eat a varied diet and your gut flora will thrive. 2. Be careful with antibiotics, because they knock out good bacteria as well as bad ones. iSTOCKPHOTO

3. Don’t eat too much fibre. Some people’s gut flora turns excess fibre into wind – listen to your gut. 4. Don’t be obsessively hygienic or scared of the germs around us. Don’t disinfect your kitchen. 5. Avoid colonic irrigations. They can endanger the whole balance of your gut flora.

by probiotics, and this in turn inhibited an enzyme that is important for the deposition of fat. Whether the results can be replicated in humans remains to be seen, but the genes we’ve looked at are the same as those found in the lining of the human gut.” Another field that Rafter has spent several years studying is the possible preventive effects of probiotic bacteria when it comes to cancer of the colon. “There are very clear indications that probiotics can protect against cancer in animal studies,” he says. “In humans, though, we cannot yet say any more than

A little dirt is good for the tummy, so don’t go overboard when cleaning the kitchen!

that there is a possible protective effect against colon cancer.” Like Elisabeth Norin, Joseph Rafter dreams of new treatments in the future, and his hopes too hang on analysis of the bacteria’s DNA. “It would be wonderful to be able to come back in a hundred years and see what this research has led to,” he says. “I think that eventually we’ll have a kind of library of gut bacteria genes. We’ll then be able to go into this library and pick out a single bacterium that we know releases a metabolite that regulates a particular disease, and use it to treat patients.” F

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Focus on: Rare diseases

Suffering from a rare disease might mean encountering ignorance and a health service that is ill-equipped to help. But trailblazers in the world of research offer hope. text Ola Danielsson illustration Anna Ödlund

The dilemma of rarity Erik Cronberg

Désirée Gavhed

There are around 7,000 known serious diseases that are classified as rare, in other words that affect fewer than five people in every 10,000. Patients with unusual diagnoses are, to say the least, a motley crew, but common to all is what the organisation Rare diseases Sweden refers to as “the dilemma of rarity”, namely the additional handicap that goes with rarity, primarily manifested as widespread ignorance. Many of the rare diagnoses are syndrome diagnoses, which means that they affect several organs and bodily functions and therefore need several specialists to work together. The organisation’s own surveys show that there is considerable dissatisfaction among patients with how the care system works. Rare diseases Sweden would like medical centres of excellence for unusual diagnoses to be set up to avoid patients being pushed from pillar to post between different departments. Désirée Gavhed, a researcher at the Department of Women’s and Children’s Health at Karolinska Institutet, agrees that more centralisation of care and knowledge would be good. She researches the rare disease Langerhans cell histiocytosis and also works more generally to improve conditions for researchers and doctors who work with unusual diseases.

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“You can’t know everything, but information about unusual diagnoses must at the very least be readily accessible to, say, general practitioners who need to refer patients,” says Gavhed. One of the key tools for doctors looking for information is the ICD diagnostic manual, which gives each disease a specific code, making it searchable on the basis of symptoms. However, most rare diseases do not have their own codes, but are instead lumped together as miscellaneous, which means that in practice they do not really exist, explains Gavhed. Although the list of problems is long, there are two accepted solutions in the form of more research and better coordination of the knowledge that already exists. In a bid to achieve the latter, the research group has helped to build up a portal on the Internet for unusual diseases as part of the EU project Orphan. The idea is that this will serve as a natural source of information for both doctors and researchers, as well as for patients. In another EU project, the researchers are working on proposals for national plans setting out how each country should manage rare diseases. A great deal now depends on whether politicians manage to swing into action.


The researcher’s view:

“Nobody cared”

Research funding bodies other than the pharmaceutical companies are often sceptical as well on account of the low number of patients involved. As it is difficult to round up enough patients to carry out studies, the research can also take a long time. “We mustn’t forget that research into rare diseases can lead to groundbreaking results in completely different areas which simply couldn’t have been antici- p

ulf sirborn

On the initiative of professor Jan-Inge Henter, an international collaboration organisation – ICORD – has also been set up for everyone working with rare diseases, including patient associations, the pharmaceutical industry, researchers and the authorities. Pharmaceutical companies have long been unwilling to invest in drugs for rare diseases, known as orphan medical products (OMPs), as development costs are so high relative to revenue. In a move to accelerate research and development into OMPs, the EU decided in 1999 to follow the example of the USA and offer incentives. Pharmaceutical companies that invest in OMPs are encouraged to do so with tax-free assistance from the European Medicines Agency during the development phase and exclusive marketing rights to the end-product for ten years.

“When I started working with FHL, very few people knew what it was and practically nobody cared. In 1982 a little boy with the disease came to St Göran’s paediatric clinic, followed subsequently by his little brother. A couple of years later we had seven patients the same winter, which got us wondering whether the disease was more common than we’d previously realised. The patients had a very high fever, and large quantities of white blood cells had accumulated in the spleen. Without treatment, 100 per cent died, usually in a few months. We didn’t know whether the disease could be cured but we developed a treatment based on chemotherapy and immunotherapy to suppress the immune system followed by bone marrow transplantation to replace the entire immune system. It turned out that the treatment cured half of the patients. When they don’t survive it’s because they don’t make it as far as the transplant or because they die from transplant-related complications. Later we were also able to show that the disease is due to defective apoptosis, with the result that spent cells in the immune system do not die or get broken down. FHL is a very difficult, but often overlooked, disease, which has increased my motivation to work with it. It feels great to be able to make a difference. The treatment we developed has been refined but is still, in principle, the one that is

Name: Jan-Inge Henter, professor of clinical paediatric oncology at the Department of Women’s and Children’s Health. Is researching: Familial haemophagocytic lymphohistiocytosis (FHL). Number affected: 1 in 50,000. Symptoms: High fever, low blood count and an enlarged liver and spleen. used throughout the world for FHL today. I now know that it has saved several hundred lives, which is very motivating! I’m even more delighted to hear that this knowledge has spread all over the world and has found other applications. Similar disease pictures can sometimes arise in bacterial and viral infections, rheumatism and cancer, and then the treatment that was developed for FHL can be lifesaving. Last year, for example, it was used to successfully treat a man who was badly affected by swine flu.”   

Interviewed by Ola Danielsson

m e d i ca l s c i e n c e • e n g li s h la n g uag e e d i t i o n 2012  4 5


Focus on: Rare diseases

The researcher’s view:

“I chose to work with these diseases because it’s an area where you can make a real difference. Many of the diseases can be treated if only we can find the cause. It’s real detective work where we’re looking for biochemical changes, such as accumulations of toxins in the body or a lack of a vital substance, and the gene underlying the problem. Acute forms of a disease can manifest within days of birth, when the mother’s metabolism is no longer protecting the child. Some substance that needs to be broken down accumulates in the body, the child is poisoned and ends up in a coma. Other forms manifest themselves later in life, not uncommonly through mental developmental disorders as the brain is highly sensitive to metabolic disturbances. Treatment can involve introducing a missing enzyme or a substance that helps enzymes to work, or following a special diet to avoid a specific substance

private

Magnus Nordenskjöld

ulf sirborn

“Real detective work” that cannot be broken down. For example, phenylketonuria (PKU) requires patients to adhere to a very strict diet free from normal protein. However, things are worst for patients with a disease with no obvious cause. It’s tedious to undergo examination after examination, and many are worried that the disease will affect siblings or other relatives. It’s important to know what the problem is, even when there isn’t a cure. Diagnostics have improved dramatically in recent years, and we have discovered three brand new diseases on the back of this. In the past we were forced to look for individual genes, but now we can look through an ever larger number of genes in one go. This is what I’ve enjoyed the most during the six years I’ve worked with these diseases, and it makes a real difference to patients.” Interviewed by Ola Danielsson

pated,” says Gavhed. “Some countries have a national fund for research into rare diseases, which I think Sweden would do well to copy.” Given that around 80 per cent of rare diseases are caused by a genetic mutation or chromosome defect, a key driver behind research is to identify the genetic causes of the diseases. This, in turn, is vital for an accurate diagnosis and the right treatment. “The same symptom picture can result from different genetic mechanisms, which can be important for the patient’s family,” says Magnus Nordenskjöld, professor of clinical genetics at Karolinska Institutet’s Department of Molecular Medicine and Surgery. “The risk of other relatives developing the disease, the potential for preventive measures and sometimes the

4 6   m e d i cal s c i e n c e • e n g li s h lan g uag e e d iti o n 2 012

Name: Anna Wedell, professor of medical genetics. Is researching: Congenital metabolic disorders. Around 500 have been discovered to date. Number affected: Around 40 new cases a year in Sweden. Symptoms: Vary considerably, from acute intoxication to mental developmental disorders. Symptoms are often seen in the brain, liver and muscles, although all organs can be affected.

choice of treatment and any antenatal diagnostics are determined by the mechanism.” Genetic diagnostics are in the midst of a technical revolution which will improve the chances of establishing a diagnosis. The latest technology in the new Science for Life research lab at Karolinska Institutet means that researchers can avoid searching gene by gene, and allows them instead to look through a patient’s entire DNA in one go. “Diseases such as hereditary cardiac arrhythmia, which can result in life-threatening irregularities to the heartbeat, can be caused by mutations in any of a large number of different genes, just some of which are known, says Nordenskjöld. “This makes it difficult to come up with a diagnosis, but the new technology will make it much easier.” F


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