Medical science 2017, Karolinska Institutet by Karolinska Institutet

A magazine from Karolinska Institutet

English Language Edition

2017

Awake? Not so dangerous, say researchers. Read their best sleeping tips!

ALSO: FA FATHERS’ F ATHERS’ WORRIES / DEADLY L RUST RUST / ROAD SAFETY

Contents—2017 4

Meet the acting Vice-Chancellor

Advances 5

New research center in Hong Kong 6 Fathers’ worries 7 A close look at Juno 9 Around the body: this is how old you are 10 Research in brief 16 Blood – a red line through history 45 Having surgery? Better outcomes early in the week

Focus 8 Finally, nickel free coins 18 Obesity during pregnancy 20 New genetic technique raises ethical questions 38 Curious about lack of sleep 44 Medication against paedophilia is tested

Meet the reseachers 12 24

46 50

Three researchers talk about road safety Anna Mia Ekström : “Few people know that non-infectious HIV now is a reality” The moment: “The rust doesn’t take anyone anymore” In memory of Hans Rosling In memory of Lennart Nilsson

Doer. Curiosity is not HIV-researcher Anna-Mia Ekströms main driving force, rather she wants to help the world with its problems.

Encounter. A fundamental fertility process has been deﬁned.

7 8

Heads up. She researches the importance of cycle helmets.

Huvudsak.Hon forskar om cykelhjälmens betydelse.

Life saving. Swedes donate 200,000 liters of blood per year.

In depth 28 Multiple sclerosis – a disease with new interpretation

Nickel free. Progress in the ﬁght against allergies.

Medical Science–2017

Acting Vice-Chancellor of Karolinska Institutet

EAR READERS, In this issue of Medical Science there are several articles on Multiple Sclerosis (MS) illustrating how medical research in the last decades has really pushed the boundaries of our knowledge and explored this new knowledge for improved treatment of MS patients. During this time, there has been a remarkable transition from treatment for symptom relief to the roll out of drugs that slow the course of disease. Novel technologies in combination with Sweden’s unique quality register has provided insights into the complex genetic contributions to this disease. The same quality register has been explored to reveal the role of the environment and lifestyle in disease development. This successful example, shows how medical research, in close collaboration with the health care sector, really bring beneﬁt to patients and society at large. Karolinska Institutet works in close collaboration with the health care sector to address increasingly urgent global challenges to health and disease. We also seek strategic alliances with other internationally leading universities and companies, to further enhance our ability to carry out large-scale, ambitious and resource-intensive research. In the beginning of 2017, two individuals who have made outstanding contributions to Karolinska Institutet, medical research and the world passed away. The photographer Lennart Nilsson and the professor in global health Hans Rosling illustrated fundamental aspects of life itself and the world we live in. Lennart Nilsson used his cameras to explore the human body down to its cells. Hans Rosling used pedagogic tools in an unprecedented way to disseminate new knowledge and to question existing prejudices about the state of health in the world. I hope that many will follow in their footsteps. Research at Karolinska Institutet spans the entire medical ﬁeld, from basic experimental research to patient-oriented and care sciences. This year’s edition of Medical Science, will give you a glimpse of some of the many exciting examples of research projects being conducted at our university in the interest of improving human health.

Medical Science–2017

Medical Science is an annual English language edition of the Karolinska Institutet popular science magazine Medicinsk Vetenskap. Here you can read selected examples of current research at our university. Editor-in-chief Camilla Magnusson Acting Director of Communications Karolinska Institutet Editors Ola Danielsson Cecilia Odlind medicinskvetenskap@ki.se Art Direction Lisa Sigebrand, Content Innovation Contributors Anders Kjellberg, Annika Lund, Jenny Ryltenius, Karin Söderlund Leiﬂer, Sara Nilsson, Mårten Göthlin, Maja Lundbäck, Christopher Hunt, Martin Stenmark, Mattias Ahlm, Fredrik Hedlund, Linda Forsell, Annika Af Klerker, Viktor Karlsson Cover: Getty images Print E-print Translation Språkservice Web ki.se Communications and Public Relations Office, Karolinska Institutet, SE-171 77 Stockholm, Sweden ISSN 1104-3822 Follow us on Facebook! Facebook.com/ karolinskainstitutet

Photography: Gustav Mårtensson

Karin Dahlman-Wright:

The e llatest atest in medical research

Two nodes The centre consists of a node in Hong Kong Science Park (the picture) and a node at Karolinska Institutet in Sweden.

Photo: HKSP

Hong Kong Centre – a hub for new knowledge In October 2016, Karolinska Institutet inaugurated a new centre for reparative medicine in Hong Kong. The centre represents a solid reinforcement of Karolinska Institutet’s research in the ﬁeld and is expected to open doors for collaborations in Hong Kong and other parts of Asia. The goal of reparative medicine is to develop new knowledge and tools for repairing damaged or lost tissue in the

body. The activities at the centre will primarily be focused on basic research, but it is hoped that the results will lead to new treatments in the long term. The Ming Wai Lau Centre for Reparative Medicine is Karolinska Institutet’s first overseas establishment and its activities are being funded entirely by a donation from businessman Ming Wai Lau for the first five years. Sara Nilsson Medical Science–2017

Advances 3 × fathers’ worries

What fathers worry about Money and the upbringing and health of their child are three storm clouds hanging over the heads of new fathers in Sweden. An increase in support for fathers would promote equality, says the researcher behind the study. Text: Ola Danielsson

25 %

25 per cent of parental leave days are taken by fathers. Source: Försäkringskassan.se 6

Medical Science–2017

ONE THIRD OF FAT H E R S F E LT WO R R I E D A H E A D O F PA R E N T H O O D

bringing up the child responsibly, meeting financial demands and their child’s health. The fathers who were the least positive about having a child and who rated their own mental health as poor were the ones who were most worried. “It’s important to encourage men to talk about their thoughts on fatherhood,” says Margareta Johansson. “Initiatives focussed solely on fathers can also be of value, especially for those who feel less positive about becoming a parent. Not only is that of benefit to fathers, it is also of benefit to the children and mothers and to equality as a whole.” In line with earlier studies, the first-

time fathers expressed worry about how parenthood would aﬀect their relationship with their partner and how they would manage with less free time, and a fear that they would not be able to provide a good upbringing. What was more surprising was that this applied to more experienced fathers too. “Having a child always brings changes to a family and achieving a good work-life balance just seems to get more complicated with the arrival of each new child,” says Johansson, who says that even fathers who have had children previously may need support in their role as a parent. Sexual and Reproductive Healthcare June 2016

Fathers feel excluded The healthcare provided in conjunction with pregnancy and childbirth in Sweden is for both parents. But this ambition is not completely realised, according to Michael Wells, researcher at the Department of Public Health Sciences, Karolinska Institutet, who has analysed 62 studies in this ﬁeld, conducted between 2000 and 2015. The fathers in these studies describe a feeling of being excluded in many situations, from not being permitted to spend the night with their newborn baby in the maternity ward, to the attitude of healthcare personnel. By and large, the fathers in these studies were involved in the pregnancy and had great trust in the health service, but they often felt that they were only included on a symbolic level. Acta Paediatrica, June 2016

Illustartion: Istock Photos.

FATHERS IN SWEDEN are encouraged to share parental responsibility. For example, 60 of the 480 parental leave days are reserved solely for fathers, and fathers are invited to be present at midwife visits and to take part in parenting classes and the birth of their child. At the same time, studies indicate that it is mostly the mothers who are the focus of care during childbirth, and that fathers feel that support for them is lacking. To ﬁnd out more, Margareta Johansson, a midwife and researcher at the Department of Women’s and Children’s Health, has on four occasions asked fathers to complete questionnaires about their experiences during pregnancy, birth and their ﬁrst year as a parent. The responses showed that a third of the 827 fathers felt worried about parenthood two months after the birth of their child. Their concerns were about

A close look at Juno Advances

This is how the two are united Text: Mårten Göthlin Illustration: Anders Kjellberg

Where? What? Successful fertilisation of the egg cell requires the sperm to fuse with the egg’s cell membrane. This process is controlled by proteins on the surface of both the egg cell and the sperm. Researchers have now charted the three-dimensional structure of one of the vital proteins, which has been named after the Roman goddess of fertility Juno.

How? A pocket has been identiﬁed on Juno to which the sperm protein Izumo1 can bind. The binding between these proteins sets off the fusion of the egg and sperm membranes.

Outside of the cell membrane, the egg is surrounded by protective cells and various proteins. The protein Juno is anchored in the cell membrane.

And? This discovery means that researchers are able to understand in detail one of the fundamental processes of our reproductive capability. This knowledge provides new opportunities to ﬁnd hormone-free contraceptives and could explain some infertility.

Source: Luca Jovine, professor at the Department of Bioscience and Nutrition and the Centre for Innovative Medicine, Karolinska Institutet. Medical Science–2017

Advances 7 questions to CAROLA LIDÉN

professor emerita at the Institute of Environmental Medicine.

Finally, nickel-free coins! Sweden is introducing nickel-free coins and thus improving the health of people with allergies. This is something for which Carola Lidén is chieﬂy responsible. Text: Maja Lundbäck Photography: Christopher Hunt

Why was it so important that the new coins be nickel-free?

“Nickel is one of the most common causes of contact allergy. Hand eczema is a common symptom. As the risk is dependent on the exposure of skin to nickel, it is important to reduce the sources of nickel exposure. Coins are a major source of this exposure for checkout assistants, but also for consumers who are walking around with coins in their pockets.” How did you work together with the Riksbank (Swedens central bank) when the new coins were decided?

“The Riksbank was tasked with conducting a review and producing new notes and coins. When they were going to conduct a health risk assessment, I was contacted as an expert on nickel allergy. The Riksbank understood that they could do something about this and now all new coins are nickel-free.” What rules are there?

“The EU’s chemicals regulation REACH restricts the amount of nickel that is released from jewellery, watches and other objects that come into prolonged contact with skin. This restriction came into force in 2000 and is based largely on our research. How8

Medical Science–2017

ever, the European Chemicals Agency has decided that coins are exempted.” How signiﬁcant is the problem of nickel allergy?

“Nickel allergy has not decreased at the rate we had hoped, despite the EU restriction. One problem is that contact allergies are persistent. If you have become allergic, you remain so for the rest of your life. “ What else should become nickel-free?

“There is a notion that short-term contact with objects that release nickel does not involve any risk, but our research shows that repeated contact for seconds or minutes is suﬃcient to obtain a substantial dose. My proposal is that no objects intended to come into contact with skin should release nickel. This means tools, door handles, keys, sewing needles, bags, pens, mobile phones and laptops.”

Why are the changes taking so long?

“This is because the health interests are in conflict with the financial interests of the nickel industry. When the United Kingdom introduced new coins a few years ago, I was contacted by a British dermatologist. We conducted a study of the new coins, which showed that they were releasing more nickel. But this time we were not able to influence the decision. However, ahead of the launch of the Euro, we were able to have an impact and at least the lower value coins became nickel-free.” How big a difference will the new coins make to the prevalence of nickel allergy?

“I am certain that they will mean a great deal to those people who handle a lot of coins at work. But it will be diﬃcult to measure the eﬀect in the population. Exposure studies would need to be conducted.”

This is how old you are Around the body Renewal is good right? This is how long you have to put up with the cells in different body parts. Text: Ola Danielsson

The cerebral cortex – your entire life THE BRAIN

The nerve cells that make you, you – many of your thoughts and memories are found here – are always the same old gang. It is an open question as to whether new nerve cells can be added under certain circumstances, for example in order to repair an injury.

Hippocampus – 20 to 30 years THE BRAIN

Tooth enamel – your entire life (almost) TEETH

Together with an area of the brain called the striatum, this is the only part of the human brain where the formation of new nerve cells has been detected. Around 1 400 new nerve cells are born here every day and these help to create new memories.

The protective enamel on your teeth is formed once, at various points prior to the age of 12, and never again. It is therefore important to brush your teeth carefully.

T H E D I G E ST I V E T R ACT

Photography: Istock Photos, Getty Images.

Surface of the guts – 5 days The epithelial cells that form the surface of the guts are, like skin cells, part of a vulnerable group and have short lives. This week one generation of cells absorb nutrients and next week another.

THE FLESH

Fat cells – 10 years

We gain about ten per cent new fat cells each year and about the same quantity die. When we gain weight, our fat cells have been given lots of food and have become fat. In childhood, the number of fat cells can also increase in conjunction with weight gain, but during adult life, the number is constant, as far as researchers are aware.

Sources: Retrospective Birth Dating of Cells in Humans, Cell, July 2005, Age written in teeth by nuclear tests, Nature, September 2005, Dynamics of fat cell turnover in humans, Nature, June 2008. Neurogenesis in the Striatum of the Adult Human Brain, Cell, February 2014. Jonas Frisén. Medical Science–2017

Advances In brief Research news from Karolinska Institutet, downloaded from ki.se

“I emailed everyone I could ﬁnd who was interested in spiders” Anna Rising talks about the time when, as a PhD student, she was hunting for a certain species of spider that spins the very strongest silk. When she returned home from South Africa, she had over 100 spiders with her. She is now trying to get bacteria to manufacture a silk of equal strength that is intended for use in medical treatments. Source: The Swedish podcast Radio science/Anna’s spider hunt

How more people can gain better protection against cervical cancer Prevention. The risk of contracting cervical cancer following an uncommon diagnosis, referred to as atypical glandular cells, has been investigated by researchers from the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. They used data from over 3 million Swedish women who had participated in cervical smear tests. The study showed that close to three per cent of the women with atypical glandular cells had developed invasive cervical cancer after fifteen years, which the researchers say is high. The risk of cancer was elevated in both the short and the long term, compared with women whose smear tests were normal and women with other types of highgrade cell changes. This was especially true for women aged 30 to 39. Only just over half of the women with atypical glandular cells were followed up using a tissue sample, compared with almost ninety per cent of the women with high-grade cell changes. This could explain the differences in risk of subsequently developing cancer. According to the researchers, what is needed is for further tissue samples to be taken within one year and an active long-term follow-up programme for high-risk patients. Another study recently showed that the effect of a vaccine against human papilloma virus to prevent cervical cancer is greatest if vaccination takes place prior to the age of 16. BMJ and International Journal of Cancer February 2016 10

Medical Science–2017

Decrease. Researchers have

studied the prevalence of Down syndrome and congenital heart defects amongst 2.1 million babies born between 1992 and 2012. Even though half the babies with Down syndrome had some sort of congenital heart defect, the risk of complicated heart defects dropped sharply during the study period. The group speculates that the result might be attributable to fetal diagnostics. If routine ultrasound reveals a heart defect, the parents usually opt to have the fetus checked for chromosome abnormalities. If Down syndrome is diagnosed, it is not uncommon for the pregnancy to be terminated, which could explain the drop in the number of babies born with severe heart defects. “We plan to examine if other common diseases associated with the condition, such as infection sensitivity and hypothyroidism, have also become less common, says Stefan Johansson, researcher at Karolinska Institutet’s Department of Medicine in Solna. Pediatrics June 2016

Photography: Istock Photos.

Early vaccination and more frequent check-ups for high-risk individuals may further reduce the number of cases of cervical cancer.

Babies with Down syndrome have healthier hearts

Women’s sexual desire can be affected by contraceptive pills Side effect. The eﬀect of

contraceptive pills on sexuality was investigated in a study of 340 young women who were randomly assigned either treatment or a placebo. The results showed that the ability to achieve orgasm was not generally affected by Lust combined contraceptiContraceptive pills ve pills (which contain can lead to a decrease both ethinylestradiol in sexual desire and and levonorgestrel). arousal for some However, sexual desire, women. satisfaction and arousal decreased significantly. ”The effect was rather small and was hardly universal, but for individual women, our results may be of significance to their choice the development of more tarof contraception. For those women for whom these pills geted drugs, where existing have been working well thus immune-modulating drugs can also be of interest,” says far, there is no reason to Mikael Landén, researcher at stop,” says Angelica Lindén the Department of Medical Hirschberg, professor at the Department of Women’s and Epidemiology and Biostatistics. Molecular Psychiatry Children’s Health. The Journal of Clinical Endocrinology and Metabolism February 2016

Illustration: Istock Photos.

Possible mechanism for bipolar disorder discovered Target. Researchers at Karolinska Institutet and Gothenburg University have identified a gene variant linked to psychotic symptoms and cognitive impairment in people with bipolar disorder. The study describes a possible mechanism for how the gene variant produces clinical symptoms by affecting levels of specific proteins in the brain. “There are no treatments currently available to improve problems with attention, memory and concentration, which impact heavily on functional outcome and recoverability. What we’re hoping is that the new mechanisms we’ve discovered will help in

December 2015

Changes in the brain twenty years before Alzheimer onset Early signs. By studying families with known Alzheimer’s mutations researchers were able to examine changes that appear at a very early stage of the disease. “Inﬂammatory changes in the form of higher levels of brain astrocytes are thought to be a very early indicator of

disease onset. Astrocyte activation peaks roughly twenty years before the expected symptoms and then goes into decline, in contrast to the accumulation of amyloid plaques, which increases constantly over time until clinical symptoms show,” explains principal investigator Professor Agneta Nordberg at the Department of Neurobiology, Care Sciences and Society. The results demonstrate that the pathological processes that lead ultimately to Alzheimer’s disease commence many years before symptoms start to show, and that it should be possible to provide early prophylactic or disease modifying treatment. Brain January 2016

1000 Swedes’ genomes were presented in October 2016 by researchers from SciLifeLab. This genetic map is the ﬁrst of its kind in Sweden. The data is now available for researchers and healthcare personnel to assist in researching and diagnosing genetic diseases. swefreq.nbis.se

Chronic kidney disease often goes unnoticed Hidden. In the long term, chronic kidney disease is associated with cardiovascular disease and death. But if it is caught early enough there are good treatment options available. A new study found that around six per cent of 1.3 million examined Stockholmers had chronic kidney disease, roughly as many as those suﬀering from type 2 diabetes. Most of them had not received a diagnosis and were unaware of their problem. Only one in four people with chronic kidney disease had seen a kidney specialist. “Caregivers need such knowledge to be able to treat and prevent serious, lifethreatening kidney failure and to give the correct drug doses. There’s much room for improvement in the health services when it comes to detecting and treating the disease,” says Juan-Jesus Carrero, researcher at the Department of Clinical Sciences, Intervention and Technology. Nephrology Dialysis and Transplantation October 2016 Medical Science–2017

Three researchers about road safety

Foot the MARIE HASSELBERG Occupation: Senior Lecturer at the Department of Public Health Sciences Researches: Injury epidemiology and prevention in a global perspective, including a focus on road traffic injuries.

Medical Scienceâ&#x20AC;&#x201C;2017

Each year, around 250 people die in road accidents in Sweden and thousands are badly injured. How can that be prevented? Text: Maja Lundbäck Photo: Christopher Hunt

“Children must be able to go to school by themselves” “I think it’s important that there’s a balance between a child’s development and their safety. Children need to be protected against serious and fatal injuries, but must also have the right to a stimulating environment and not to be overprotected. So we do a lot of work looking at how we can adapt the environment to children and not the other way round. It’s important for children to be able to get themselves to school on footpaths or cycle paths. Unfortunately a lot of people give their children a lift and that’s not good because you then have too many cars around the school. In Tanzania, where I am also doing work on ways to reduce road traffic injuries, slow vehicles, pedestrians and cars all circulate together. The cars are often old and you can’t always strap yourself in. I am working alongside researchers there on mapping the most dangerous roads, and sometimes if I need to take a taxi in Dar es Salaam I have to travel without a safety belt. Unfortunately, unless something is done, there will be more road traffic injuries as incomes rise and more people get a car. But it’s good to see inexpensive interventions that work, such as the rumble strips that have been introduced in places such as Ghana. In Sweden, over 30 children die on the roads each year. There has been a marked reduction in recent decades, and it is mainly due to safer traffic environments and improvements in children’s car seats. But even though children these days are less exposed as road users, road trafﬁc accidents are still the main cause of child fatalities.” Medical Science–2017

Three researchers about road safety

“I have been bumped into myself”

ANDERS KULLGREN Occupation: Head of Traffic Safety Research at Folksam insurance, Adjunct Professor at Chalmers University of Technology and an associate of Karolinska Institutet. Researches: Risk factors in relation to road traffic injuries

Medical Science–2017

“Each year, around 3,000 Swedes acquire a medical disability as a result of their injuries in a road traffic accident. Common injuries include concussion and damage to the back, arms and legs. I had started research into whiplash injuries, the most common injury, when someone ran into my car from behind. The other vehicle was only travelling at 20 km/12 miles per hour, but when I started to get a sore neck half a day later I began to worry. I knew that the majority of people affected by this get better quickly. In my case, I got better within three days, but for 16 per cent of people the neck pain does not go away. They acquire a disability that affects their lives. The whiplash protection we have today varies in effectiveness. A car that gets several stars in a collision test does not necessarily have the most effective protection – and especially not for both sexes. Some protection systems work much less well for women. I think that’s wrong, and I try to influence car manufacturers by disseminating information about new research findings. Unfortunately, car manufacturers do not put significant resources into developing more effective whiplash protection. Most of their resources instead goes into the development of new automated cars and security systems. It’s thought that the driverless cars of the future will reduce the number of deaths on the road by at least half, which is good, but technology alone will not totally eradicate accidents. Fullyautomated cars will probably also be involved in crashes, but they will be less serious. I hope that in the future we will be able to develop more effective protection against whiplash injuries in minor collisions.”

“I do not believe in compulsory cycle helmets” “It was a normal day at work when I decided to start researching cycling injuries. As a doctor, it wasn’t the ﬁrst time I’d had a patient who had been cycling without a helmet. I looked at the X-rays, which showed a severe head injury, and started to wonder how he might have fared if he had had protection for his head. EVELYNE Studies from other countries ZIBUNG indicate that a helmet law would HOFMANN work – helmets provide protecOccupation: PhD student at tion for the most common head the Department of Molecular injuries. But I don’t believe in Medicine and Surgery at Karolinska University Hospital. compulsion, I believe in informaResearches: Cycling accition. Over 70 per cent of cyclists dents and how they affect in Stockholm already wear a quality of life. helmet. Unfortunately some of them wear their helmet too far back on their head. It should sit two ﬁngerwidths above the bridge of the nose so that it also protects the face if there’s an accident. Around 20 cyclists die each year, down from about 70 in the 1990s. This improvement can be explained not only by increased use of cycle helmets but also by better traffic arrangements for cyclists, with separate cycle paths and marked cycle routes. We don’t know exactly how many cycling accidents there are, but about 8,000 cyclists are taken to hospital each year. Most of them have minor or moderate injuries and can be discharged after less than a day. Despite that, my research shows that even minor injuries, such as a fractured collar bone or broken nose, can affect people’s lives for a long time afterwards. More than two out of three people state that they experience pain or physical discomfort over half a year after their accident, so it’s important that we keep a check on how patients are doing.” Medical Science–2017

The red line of history Life-giving blood has been regarded as somewhat mystical throughout human history. But thanks to research, we are now able to save lives by transfusing blood.

c. 1000 years BCE Bleed yourself healthy The method of treating disease by draining blood, blood letting, originated in Egypt and has been used for 3 000 years. Leeches are also used. This method reached its peak in the 19th century.

Text: Karin Söderlund Leifler

1000 f. Kr.

100 Second century Two blood systems At this time, it is believed that the arteries are ﬁlled with air, but the Greek doctor Galen discovers that, like the veins, they contain blood. He believes that there are two separate blood systems, with blood being created in the liver and heart, which supply blood with a spirit.

1818 From human to human The obstetrician James Blundell is responsible for the ﬁst successful transfusion of human blood. This is provided to a woman who is bleeding heavily following labour. She improves initially, but then dies. Blundell performs further transfusions between humans, which often help the patient.

1650

1665 Between dogs The ﬁrst successful blood transfusion was performed by the English doctor Richard Lower. He keeps dogs alive by transfusing them with blood from other dogs. In the years that follow, humans also receive blood from animals. This is banned in England in 1677. 16

Medical Science–2017

1800

Source: Blodgivning i Sverige, geblod.nu

Facts: Each year, around 100 000 people in Sweden receive blood transfusions. At least one third of these people are in life-threatening situations. Swedish blood donors donate almost 200,000 litres of blood each year.

1900

1917 Blood stores in wartime The British Army collects and stores type O blood to give to soldiers who are injured in the First World War. The year before, it became possible to store blood for several days in a nutrient solution developed by researchers.

1901 The ABO system is discovered Karl Landsteiner lays the foundations of the system that explains how individuals with the blood groups A, B, AB and O can donate and receive blood. This knowledge markedly increases survival in the event of a transfusion. In 1930, he is given the Nobel Prize for his discovery.

Photography: Istock Photos. Illustartion: Istock Photos.

Timeline Blood transfusions

The 1980s Artiﬁcial blood Fear of blood-borne infections gives renewed stimulus to research into artiﬁcial blood. Problems involving severe side effects have so far prevented large-scale use.

1939 The Rh factor is discovered A series of discoveries reveal that the Rh factor in red blood cells is responsible for severe immune responses in cases of blood transfusion. Almost 30 years later, it becomes possible to prevent immune responses to the foetus in pregnant RhD negative women.

1980

2010 Agneta Wikman. T O D AY

2011 Blood from stem cells French researchers successfully culture two millilitres of blood from blood stem cells from bone marrow. The cultured blood is given back to the same individual. A major challenge is culturing sufficient quantities.

1950

The 1950s Technological development Progress in open heart surgery and intensive care signiﬁcantly increases the need for transfusions. Blood starts being stored in plastic bags instead of glass bottles. Separation of the various blood components paves the way for the treatment of haemophilia.

Future challenges

Photography: Istock Photos, Stefan Zimmerman.

Manufacturing blood Researchers want to be able to produce artiﬁcial blood in order to allow better control of the blood’s content and ensure its availability. Identifying risks As new viruses are discovered, there is a constant challenge to develop tests in order to prevent these infections being transmitted in donated blood. There also needs to be more research into whether other diseases can be transmitted in blood. Eliminating the risk of infection Donated blood is currently screened for a number of known infectious agents. The hope is that in the future we will be able to knock out all potential viruses and bacteria in all blood. This is currently undertaken for some blood components.

2016

Sources: The history of bloodletting, Gerry Greenstone, BCMJ 2010; History of Medicine Timeline, Rachel Hajar, Heart Views 2015; Proof of principle for transfusion of in vitro-generated red blood cells, Giarrantana MC et al., Blood 2011; Advancing Transfusion and Cellular Therapies Worldwide – Highlights of Transfusion Medicine History: www.aabb.org/tm/Pages/highlights.aspx.

Preventing foetal brain damage When our immune system comes across blood cells that are perceived as foreign, antibodies are formed against the foreign antigen. One of the strongest antigens is RhD, which is found on red blood cells, but is absent in 15 per cent of the population. This means that an RhD-negative woman may form antibodies against her child’s blood during pregnancy or labour. These can break down the child’s red blood cells. Aside from the child suffering from a lack of blood, the break-down products can cause brain damage. ”Our research has led to a new method for finding the RhD gene in the foetal DNA, which is refined from the mother’s blood. We are now able to find those women who are carrying RhD-positive foetuses and provide preventive treatment during pregnancy,” says Agneta Wikman, senior research fellow at the Department of Laboratory Medicine and consultant at the Division of Clinical Immunology and Transfusion Medicine at Karolinska University Hospital. The mother can form antibodies to the child’s platelets, which are needed to enable the blood to coagulate, in the same way. If the platelets are destroyed, the foetus can suffer from cerebral haemorrhages in the womb. There is currently no routine screening for this. ”We think that approximately ten children are born with these cerebral haemorrhages in Sweden each year. We are conducting research into how best to find those at risk and how to treat them,” says Agneta Wikman. Medical Science–2017

In focus Obesity during pregnancy

“We must have the courage to talk about the risks” Being obese increases the risk of complications during pregnancy and labour, which can aﬀect both the mother and her unborn child. This is a sensitive subject, but Olof Stephansson hopes to turn things around through new research and by having the courage to talk about the problem. Text: Karin Söderlund Leiﬂer Photo: Mattias Ahlm

”W

E KNOW THAT OVERWEIGHT and obesity make pregnancy and labour more difficult. So we have to talk about this. When it comes to smoking, we’ve been able to get the message across that it harms the baby. The figure for the number of women who smoke during pregnancy has decreased from one in three in the 1980s to one in twenty today. Even though obesity is a sensitive subject, it is an issue that we must highlight,” says Olof Stephansson, researcher at the Department of Medicine, Solna. In his job as a consultant obstetrician, he meets many overweight and obese women who have difficulty

Medical Science–2017

during pregnancy and labour. As the population becomes heavier, the number of pregnant women in this group also increases. In 1993 about 25 per cent of pregnant women were overweight (BMI over 25 ) or obese (BMI over 30 ) at the time of their ﬁrst appointment at the antenatal clinic. Twenty years later, in 2013, the proportion had risen to 38 per cent.

What many people do not realise is that the risk of the baby being born very prematurely or dying in the womb is higher when the mother is obese than when she is a normal weight. The mother’s health can also be affected through an increased risk of gestational diabetes and pre-eclampsia. ”The majority of things we work with in labour and pregnancy are affected negatively if the mother is obese. The risk of preterm birth is three times higher for obese women. With regard to hypertension and pre-eclampsia, the incidence is five times higher among women in the category with the highest BMI than among those of a normal weight, which is a substantially increased risk,” says Olof Stephansson. THERE IS SOME difference between maternity care in the different county councils in Sweden, but for women with a BMI over 30, additional interventions are put in place, for example diabetes checks, appointments with the nutritionist and extra blood pressure measurements. According to Olof Stephansson, when a woman is already pregnant, this is not the time for her to try and lose weight. ”We don’t know if it is safe for a mother to lose weight during pregnancy. There are not yet enough studies. Instead, for the majority of people who are obese and overweight, it’s a matter of helping them find the motivation to make lifestyle changes before they become pregnant or between two pregnancies,” says Olof Stephansson. How much weight a woman gains during pregnancy varies greatly. The heavier a woman is beforehand, the less desirable it is from a medical perspective for her to gain more weight. Since last autumn, Olof Stephansson has been a visiting researcher at the University of California, Berkeley. He is conducting research there with his colleagues into weight gain among

Many pregnant women weigh too much More than one in three pregnant women in Sweden is overweight or obese. Obesity, and to a lesser extent overweight, increase the risk of blood pressure diseases, gestational diabetes, pre-eclampsia, very preterm birth, protracted labour, labour complications, large babies, stillbirth and malformations of the child. A body mass index (BMI) over 30 is classiﬁed as obesity. Weight loss between two pregnancies reduces the risks.

”The majority of things we work with in labour and pregnancy are affected negatively if the mother is obese”

Olof Stephansson wants to ﬁnd clever ways to help pregnant women monitor their weight gain and maintain a good weight.

pregnant women. Their study partly uses data about pregnant women in the US, where the problem of obesity is more widespread than in Sweden, and partly material covering 175,000 pregnancies in the Stockholm area and Gotland. ”We will analyse how all these risks are affected by weight gain and what this is like for different BMI groups. What is particularly exciting is that we have new methods that allow us to more effectively compare the different groups and monitor week by week how much weight the women are gaining. In the Swedish healthcare system we currently use guidelines that are published by the American Institute of Medicine. The goal is to revise and improve these guidelines in order to adapt them to the circumstances in Sweden,” says Olof Stephansson. HIS RESEARCH has also involved him and his colleagues monitoring women who have undergone weight-loss surgery before becoming pregnant. Surgery reduced the risk of gestational diabetes and pre-eclampsia, but increased the risk of preterm birth. The babies were also smaller. Weight-loss surgery can be effective for some people, but it is not suitable for everyone. Other ways to try and affect weight are, of course, through diet and exercise, something that has recently been tested on patients in a British study. To many people’s surprise, it appeared that diet and exercise advice was not sufficient to affect obese women’s weight gain during pregnancy. In another study, a diabetes drug, metformin, was given to women who have a BMI over 35 but who did not have gestational diabetes. This drug increases insulin sensitivity and decreases the blood sugar level and is used increasingly during pregnancy. The women who received metformin gained less weight than the control group. ”Of course, we would have wanted diet and exercise advice to work. But there’s maybe something that can be taken from the drug side of things, if

Read more Find out more about obesity research in our previous theme at ki.se.

studies show that this is safe,” says Olof Stephansson. Olof Stephansson is in charge of the new National Pregnancy Register, the aim of which is to increase quality and facilitate improvement and research within the ﬁeld of pregnancy and labour. He argues that the next step is to use “big data”, i.e. large quantities of data that can be used to facilitate better risk assessments for individual women.

He sees there is a potential to use this research to help women become motivated and check their weight. ”Collecting a load of data is easy, but we also have to do something with what we discover. I believe that we have to give something back to women. I want to ﬁnd clever ways to help pregnant women monitor their weight gain and maintain a good weight, perhaps using a mobile app.” Medical Science–2017

Perspective Gene modiﬁcation

Which genetic changes should be permitted? This question is being brought to the fore by the rapid development of genetic technology in recent years. The new genetic tool CRISPR may lead to improved treatments for severe diseases in the future – but is also a topic of debate. Text: Anders Nilsson Illustration: Curtis Parker/The Ispot

T HAS BEEN possible to change the genetic code since the 1970s. Researchers have learned to cut and paste DNA into bacteria, plants, animals and even human cells. But a revolution is now taking place in this ﬁeld. A new powerful genetic tool, CRISPR-Cas9, often shortened to just CRISPR, has become one of the hottest areas of life sciences in the past three years. Researchers all

Medical Science–2017

over the world are competing with each other to become the ﬁrst to use this new tool for various applications within medicine, as well as other applications such as the development of new crops. Compared to earlier gene-modiﬁcation techniques, CRISPR is cheaper, faster, more easily available and simpler to use. The discovery that kick-started this was published in 2012 and as early as the following year, the journal Science declared there was a CRISPR

IT WILL SOON BE THREE years since she began her preparations for using CRISPR and two years since her experiments began. “It didn’t start well. The type of cells I would prefer to use do not do well as single cells, which is required here. Now I’ve introduced CRISPR in other cell lines that are easier to deal with, at the same time as I’m continuing to try to get the first experiment to work”. While she has been working with CRISPR, she has seen how quickly the interest has increased - first within the research community, then outside of this as well. “Three years ago, a search for the term largely only returned academic articles. Now you get a huge number of hits. A lot is being written, even in the normal media. The benefits of CRISPR are that it is easy for anyone with biochemistry or molecular biology training to use and that it does not require any special equipment either,” she says. “You buy the preparation online for thirty dollars. The only difficult aspect I am struggling with is to get it to work

Photo:Ulf Sirbom.

New genetic technology raises ethical questions

craze sweeping the world of science. The fervour has not been doused since then. In December 2015, this technology was named as the breakthrough of the year in the scientific journal Science. But the rapid development is also causing worries: What boundaries should there be for genetic technology and is there a risk of them being set to one side in the hurry. Giulia Gaudenzi is a PhD student in the Department of Neuroscience at Karolinska Institutet and is researching brain development – primarily the cerebral cortex. She is attempting to understand fundamental mechanisms of brain development from a few stem cells to a structure with millions of cells of a thousand different types. “One common way of researching questions like this is to block the effect of a gene in cells and see what the difference is. This has been possible for a long time, but with CRISPR, I can do it better. It means that I can study a purer system,” says Giulia Gaudenzi.

“Of course we are aware that this is a charged issue. But we also feel that we have a great deal of support from patients.”

Photo:Ulf Sirbom.

in the special cells we have chosen”. What does she think the long-term benefit of CRISPR will be? “Alongside research, I am involved in an organisation that works with public health in East Africa and I think about what this technology can mean for lowincome countries. A cheap and easily available tool such as CRISPR provides more opportunities for these countries’ researchers to conduct good research. And in discussions about CRISPR, both improved crops and the opportunity to fight malaria have been mentioned. It would be fantastic if CRISPR is able to save people from dying of hunger and tropical diseases”. IN ANOTHER PART OF Karolinska Institutet, the Department of Clinical Sciences, Intervention and Technology, Division of Obstetrics and Gynaecology, Fredrik Lanner and his research group have just begun to use CRISPR. Their research involves the first few days of human embryo development. At this stage the embryo is called a blastocyst and is a microscopic clump of cells. The aim of the research is basic science: understanding more about what regulates the embryo’s development. Fredrik Lanner hopes that this knowledge will contribute to improved infertility treatment in future. “Fifteen per cent of all couples who want to have children have some form of fertility problem. So the more we know about normal embryonic development, the better we will be able to understand the causes of various fertility problems,” he says. Fredrik Lanner is planning to use CRISPR in the same way as Giulia Gaudenzi and many other researchers; in order to disable the function of a gene and see what difference this makes. But the fact that his research involves human embryos makes this a special case. “Embryonic stem cells and altering the genome are each individually research areas that are subject to ethical discussion – and we combine them. Of course we are aware that this is a charged issue. But we also feel that we

have a great deal of support from the patients. Close to 80 percent of patients who have undergone IVF treatment that we ask choose to donate their left over embryos to this research, embryos that would otherwise be destroyed,” he says. One benefit of conducting embryorelated research in Sweden is that the legislation is straightforward and clear, says Fredrik Lanner. “In Sweden, following strict ethical scrutiny, it is possible to conduct research on human embryos up until the fourteenth day. They must then be destroyed.We conduct research up to day seven, before the embryo would normally have attached to the wall of the uterus. At this stage it is no larger than a grain of sand and consists of about 200 cells.” In April 2015, a Chinese research group became the first in the world to report CRISPRmodified human embryos. This experiment was performed on defective IVF embryos that would not otherwise have developed into

Background: Major interest in the world 2127 of research Number of academic articles in which CRISPR is mentioned. Source: PubMed

CRISPR IS PREDICTED TO BECOME

1 266

602 281 126 2012

2013

children, but it was still much discussed. “Their study led to much debate, and to people pushing for a general ban on all CRISPR research on human embryos. It is good that this is being discussed, but a ban would be very unfortunate,” says Fredrik Lanner. The argument in favour of a general ban is to prevent genetic changes being made that would be inherited by future generations. Such interventions are already banned in Sweden and many other countries, but not all. Fredrik Lanner himself thinks that development of CRISPR will not go venture that way in any case. The most likely reason for daring to make genetic changes to your child would be to prevent the child from developing a genetic disease that you yourself have”. There is already a much simpler and safer method that is used for this purpose: PGD, preimplantation genetic diagnosis. PGD involves the testing of IVF embryos prior to implantation so as to avoid implanting embryos that are predisposed to a disease. “It is thus currently technically possible to choose embryos on the basis of any characteristic we known the genetics of,” Fredrik Lanner points out. “Nevertheless, PGD is only used for avoiding serious diseases, not to choose gender or eye colour or anything else. Society has put in place rules for this activity and they work. I think that society will be able to deal with the issue of how CRISPR should be used just as well”.

2014

2015

2016

In August 2012, the researchers Emmanuelle Charpentier, Umeå University, and Jennifer Doudna, University of California, published the idea that the CRISPR-Cas9 complex could be used as a genetic technology. There has been rapid development since then and CRISPR-Cas9 has been adapted to work in ever more organisms – eventually even people.

significant within a range of areas: Regenerative medicine and for the development of gene therapies for genetic diseases, as well as for medical treatments within other areas such as infectious diseases and cancer. On top of this there are applications outside of biomedicine: The production of crops that provide greater harvests and are more resistant to drought and pests, modified microorganisms for everything from bioenergy to the purification of emissions, genetically modified mosquitoes that stop spreading diseases. The expectations linked to this new genetic tool are quite simply enormous. “The only limit is your imagination”, as one researcher put it when interviewed by Radio Sweden. Medical Science–2017

Perspective Gene modiﬁcation Facts: How do the genetic scissors work?

Researchers have modiﬁed CRISPR-Cas9 so that it is now able not only to cut up, but also to act as a search-and-replace function, which can both remove and add DNA.

CRISPR, which stands for clustered regularly-interspaced short palindromic repeats, is a type of DNA sequencer that is naturally present in the immune defence of bacteria.

Together with small pieces of RNA and the protein Cas9, CRISPR forms a complex that searches for and neutralises viral DNA in the bacterium. Cas9 cuts up the harmful DNA.

However, it is not uncommon for new scientific innovations to attract exaggerated expectations that gradually come to nothing. That CRISPR should be counted as one of the most important events in the history of genetics is already clear, but it is not yet possible to say exactly how revolutionary it will become. “It is difficult to predict what problems may arise when a new promising technology appears,” says Fredrik Lanner. ”Minor details that complicate matters. We have already seen that making new mouse models using CRISPR is not actually as simple as it first appeared.” The problem with CRISPR that has gained the most attention is the risk of what are known as “off-target effects”, i.e. that the small genetic scissors mix up two similar places on the DNA so that the genetic change ends up in the wrong place. Consequently, it is probably that treatments using CRISPR will, to the greatest possible extent, take place in cell cultures in which the result can be checked before the cells are returned to the patient. BUT IF CRISPR can still live up to the extremely high expectations – how can humanity deal with such a powerful genetic tool? There are differing opini22

Medical Science–2017

ons. At one end of the scale: those who argue that CRISPR is so dangerous that it should not be permitted at all. At the other end: the transhumanist philosophy, which sees scientiﬁc advances as suitable tools for remoulding Homo sapiens into something better and more noble – from humans to posthumans. This movement even has a term for its opponents: biofundamentalists. Niklas Juth, who researches medical ethics at the Centre for Healthcare Ethics, Karolinska Institutet, thinks that there are grounds to criticise the arguments of both these groups. “Some arguments return again and again when talking about new medical technologies. One such is the argument that it is unnatural or that we are playing God – that people would be crossing the boundaries that nature or God have given us. Another is the slippery slope argument: that if we take this step now, we are going down a path that inexorably leads to dystopia. In the past, both artiﬁcial insemination and antibiotics have been criticised using the argument that they are unnatural,” observes Juth. And active euthanasia was perceived as a slippery

slope to a murder state 30 years ago. “I don’t set much store by this type of argument. If you scratch the surface of the argument that it is unnatural, you find that is mostly because of personal antipathy”. But giving people full freedom to use CRISPR to edit their genes and become posthumans – it is at this point that Niklas Juth has objections. “If it were to be possible to improve the entire human race, for example increase our sense of justice, I have difficulty seeing what would be bad about that. That’s as far as I’m prepared to agree with the transhumanists. But should a powerful genetic tool be released freely into the marketplace, there is a risk that the economic upper class would in the long term become a genetic upper class. Maybe cognitively superior to the rest of us. They could turn us into slaves!” Niklas Juth places himself somewhere in the less spectacular middle ground, where the use of CRISPR is permitted but carefully regulated. “Against the risk of using CRISPR, you have to balance the consequences of not using this method: That we refrain from eliminating disease and suffering,” he concludes.

Photo:Science Photo, Stefan Zimmerman

It is the piece of RNA that determines where in the DNA the complex will cut. By producing and introducing different RNA, CRISPRCas9 can be controlled to edit anywhere at all in the genome.

GIVING TO KAROLINSKA INSTITUTET

Photo: Erik Cronberg

Our vision, to contribute signiﬁcantly to improving human health, is what drives research and education at Karolinska Institutet. Thanks to generous gifts from Swedish and international friends, we are continuously breaking new ground. If you share our vision and wish to join us in creating a future with better health and quality of life for everyone, then we welcome your support. Please contact us and let us know how you would like to become involved in helping us achieve tomorrow’s medical breakthroughs. Professor Martin Ingvar Deputy Vice-Chancellor Development E-mail: martin.ingvar@ki.se Mobile: +46 (0) 704 84 12 47 ki.se/donations

Donate online: ki.se/donate

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

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

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

Interview erview Anna Mia Ekström

She wants justice It makes no difference whether it is orphaned children in Africa who are not receiving HIV medicine or a young Swedish person who has not dared to tell anyone they are HIV positive – Professor Anna Mia Ekström is on their side. Meet a researcher with a passion for justice who focuses on results and thinks it is time to destigmatise HIV. Text: Cecilia Odlind Photography: Text Photography Martin Stenmark

Medical Science–2017

SHE CARES Professor Anna Mia Ekström looks out for the quality of life and future of people infected with HIV.

Medical Science–2017

Interview Anna Mia Ekström

HEN VISITING a camp for young people with HIV, Anna Mia Ekström met a woman from a small town in Sweden. She had not told either her family or her friends about the infection. Instead, she thought about moving away. Constantly having to wonder whether your boyfriend or family would still be on your side if they knew is a heavy burden for a teenager. You end up in a very disadvantageous position, says Anna Mia Ekström. The fact is, about one in five people with HIV in Sweden have not told anyone else that they are infected. This was one of the conclusions of a study conducted last year on behalf of the Public Health Agency of Sweden that was led by Anna Mia Ekström’s research group. This was the first time the quality of life of people living with HIV in Sweden had been investigated. The results also indicated that one in four stopped having sex entirely following the HIV diagnosis, most of whom received 10–20 years ago, and that the same number felt that the infection had a detrimental impact on their chances of enjoying sex. “These are depressing figures and demonstrate that there is still a significant lack of knowledge about HIV that, in turn, has a detrimental impact on many people,” says Anna Mia Ekström. At the same time, those participating in the study estimated their quality of life as generally good. “It is not that long since HIV infection was equated with a painful and premature death. With this in mind,

Medical Science–2017

many current patients are really happy that they live in Sweden and are healthy thanks to one or two pills a day,” says Anna Mia Ekström. More people than ever, about 7 000, in Sweden live with HIV. Research shows that the drugs that started to appear as early as the 1990s are now so effective that the level of infectiousness becomes very low. In 2013, the Public Health Agency of Sweden reported that the risk of being infected during vaginal and anal intercourse with a person who is well-treated is minimal, provided a condom is used. “We now know that people can live with non-infectious HIV. But this has not been sufficiently demonstrated and been known for that long, which is why many people, including many of those who have HIV, are still under the impression that a person with HIV is a risk to others. Other people’s views of them and their own self-image naturally have a detrimental impact on them, not least in conjunction with new sexual relationships. That is why it is extremely important to put this knowledge out there”. AMONG THOSE WITH known HIV infection in Sweden, about 95 per cent are being treated and undergo regular check-ups to carefully monitor the effects of the medication by checking that the virus level in the body is kept down to unmeasurable levels. But this is a somewhat unique situation globally. Anna Mia Ekström recently travelled to Rakai in Uganda, where she visited a home for children who have lost their parents to HIV and who often have the disease themselves. It was home to 250 children who are looked after by one single doctor without any

Name: Anna Mia Ekström. Title: Clinical professor in infectious disease epidemiology focusing on HIV at the Department of Public Health Sciences. Age: 46. Family: Husband and two children, 8 and 13 years old, and two stepchildren, 21 and 27 years old. When it feels like you are up against it: I try to see the bigger picture. Relaxes by: Running, hanging out with family and running a book club with the theme power, class and gender.

resources. The children’s home is only an hour’s drive from one of the world’s most modern HIV research sites. “There is extremely effective HIV medication just a few miles away, but it doesn’t get there. Injustices like this make me very angry; this is not how the world should be in 2016. It is so obvious that more is needed than just good medication,” she says. Hope for the future, for example. “Unfortunately, these children have, quite naturally, very low expectations about their lives. They usually also have low expectations of a long and good life,” she says. Anna Mia Ekström thinks that trips to Africa make it easier to understand the complexity of the situation. “It can be difficult for us in Sweden to understand that the disease spreads so easily and why people do not better protect themselves against such a serious illness. But if people think they will be dying soon anyway, it does not really make the slightest difference”. A SIMILAR EXPLANATION may be the reason why pregnant women with HIV in many African countries are not able to protect their unborn children from the infection. This is in spite of the fact that, with simple means such as drug treatment during pregnancy and breast-feeding, this is entirely possible. In her research, Anna Mia Ekström has highlighted the factors that are required if prevention is to actually work in practice. “Aside from the fact that the healthcare system has to function, everything from drug distribution being in place and relevant decision makers being informed, there also has to be an understanding of the women’s social environment, for example their opportunity to make decisions about their own lives, inform their partner and basic factors such as having money for food and somewhere to keep their medication in secret,” she says. “This type of understanding is important and people want to work to stop the spread of HIV, with is still progressing at a high rate in many countries and increasing in some,” contends Anna Mia Ekström. ANOTHER EXAMPLE comes from the research group’s work in a slum area in Nairobi, where many people are li-

ving with HIV. Despite the fact that aid organisations on site were offering free HIV drugs via a clinic within walking distance, it was difficult to reach out with medication. “What we in the research community call ’real life effectiveROLE MODEL ness’, that is to say the measure’s “Sweden is best in the effectiveness in practice, was world at talking about sex and LGBTQ issues. No-one therefore very low. We want to else is pushing these issues, find out why,” she says. which is why it is so imThey were able to reveal a portant that we do so.” range of causes: For example, written information worked badly in one area where there are few people who can read advanced text. The advice to take the medication in conjunction with meals also had the wrong effect as many of these people barely had food for the day and then did not take the medicine. The social stigma also had a major impact, many avoided coming to the clinic as they wanted to keep their illness private as they otherwise risked becoming outcasts. Consequently, the requirement for someone who begins receiving medication to list a close relative, which was introduced in order to ensure the patient has the support of those around them, had the opposite effect. “By identifying and listing the tangible causes, we were able to suggest effective remedies. Minor changes that could make a big difference. This is also what is so great about being a researcher. By finding things out, it is actually possible to drive through changes that have a real impact,” she says. So Anna Mia Ekström’s motto is managed so well that 90 per cent of “Just do it”. And according to the UN’s those who are treated have undetectaAIDS body, it is possible to eradicate ble virus levels by 2020. HIV within 30–40 years. In order to “This is how good the situation is in achieve this, the targets have been set Sweden already, so we are demonstrafor 90 per cent being aware they are ting that it is possible”. infected, 90 per cent of those who THAT SHE INSTINCTIVELY watches are aware they are infected receive out for those who are weak, marginalitreatment and that this treatment is

Anna Mia Ekström on …

…the duty to inform The majority who are infected with HIV catch the virus from someone who has HIV without knowing it. Placing the responsibility solely on the HIV-positive individual creates a false sense of security and will not stop the epidemic.

…curiosity No, that’s not my main driving force. There are so many basic problems in this world that need to be solved before I’ll have time to be curious. Instead, I feel a great responsibility for ensuring that my research makes a difference.

sed and vulnerable was surely one of the reasons why Anna Mia Ekström ended up researching global health and HIV, a field in which she has been working since the beginning of the 2000s. That she is also focused on results can certainly be of assistance when she comes up against apparently hopeless situations, like at the children’s home in Rakai. But there was also hope there, believes Anna Mia Ekström. “I saw the significance of an enthusiastic driving force. The manager, Ida, acts as both the children’s teacher and their mother. She really does mean everything to these children, who would otherwise be completely alone. If she wasn’t doing it – who would? I think about research in kind of the same way – if we were not identifying problems and finding solutions – who would do it? No, exactly. Just do it”. Medical Science–2017

In depth Multiple sclerosis

Newly interpreted disease Multiple sclerosis is a disease which doctors have partially misunderstood for 200 years. But now there is new information that will change the view of both the course of the disease and the treatment. At the same time, the researchers have found protective factors that are surprising â&#x20AC;&#x201C; sun, moist snuff, coffee and alcohol. Photo: Science Photo Library

Text: Fredrik Hedlund

Medical Scienceâ&#x20AC;&#x201C;2017

ATTACK The disease MS is caused by the patient’s immune cells (yellow) attacking the body’s own oligodendrocytes (purple); cells that protect the nerve cells in the brain and spinal cord.

Medical Science–2017

29 2

In depth Multiple sclerosis

NOWLEDGE REGARDING the neurological disease multiple sclerosis, MS, has exploded in the last 20 years. Prior to this, MS was something that doctors could only diagnose and provide some symptom relief for, but now there is a plethora of drugs that can slow the course of the disease. “I have been involved in MS research for 30 years. The ﬁrst year I went to an MS conference, 75 people turned up, whereas this year 10,000 neurologists were in attendance. It has been an incredible journey, especially during the last 20 years,” says Tomas Olsson, Professor of Clinical Neuroscience at Karolinska Institutet.

THE FIRST disease-modifying therapy was approved in 1995, but it is really in the last ten years that big developments have happened. Since 2006, seven new drugs for MS have been approved by the authorities in Europe. At the same time, knowledge of the underlying factors relating to the disease has increased dramatically, both on the genetic factors involved and the lifestyle factors that increase the risk of MS. And researchers at Karolinska Institutet have greatly contributed to the development of this knowledge. Thus far, over 200 genes have been identiﬁed whose variants have greater or lesser signiﬁcance in terms of the risk of developing MS. The most important are the genes in the socalled HLA region, which is involved in the manifestation of “human leukocyte antigen”, antigen-presenting molecules found on the cell surface. “There are a number of important 30

Medical Science–2017

THE FACT that so many genes are involved means that it becomes a complicated pattern with regard to how large a role the individual genes actually play; in many cases, it is very small, according to Ingrid Kockum. “Many of us are walking around with a whole bunch of MS risk variants but don’t get MS,” she says. This is also why the heritability of the disease is not so pronounced. Children of a parent with MS admittedly are ten times more likely to get the disease, but as the baseline risk is only two per thousand, this means that only one out of ﬁfty children of a parent with MS inherits the disease. “If there are a wide range of genetic factors that inﬂuence the risk level, it’s not so likely for someone to have them all. It’s not a monogenic disease, such as

Facts: Identified scars in the brain The symptoms suffered by MS patients were first described nearly 200 years ago, and 150 years ago a French neurologist found during autopsies that the patients had hard scars in the brain and spinal cord, an aspect which gave rise to his naming of the condition multiple sclerosis, which means “many scars”. The disease was described for the first time in a Swedish medical textbook exactly 100 years ago, and aside from rest, baths and massages, the recommendations included X-rays, arsenic and mercury ointment.

cystic fibrosis, where mutation in a gene leads to disease emergence,” says Ingrid Kockum. The fact that so many genes are involved will also make the interpretation of individual sets of genes difficult, but this is not the purpose of the mapping either. “We will most likely not be able to predict who will or will not develop MS. However, I believe that genetic knowledge is very important in order to understand the biological processes involved in the disease. But then it is not enough to find where the mutation is located. We also need to understand what it does, what affect it has,” she says. And in this respect, the researchers are still on the starting blocks. What they can say is that very many of the interesting genes they have found are involved in the immune system. This is something that further strengthens the prevailing hypothesis that MS is an autoimmune disease. With a deeper understanding of the biological processes involved in MS, it will be easier to find new targets for treatment. It is not certain that it is necessary to understand everything, suggests Ingrid Kockum. “I think that many different things have to go wrong in order to get MS, and perhaps it is enough if we can stop some of these to prevent the disease from emerging or to cure it,” she says. ALTHOUGH RESEARCHERS have now found more than 200 gene variants that affect the risk of MS, they have not found all of them. “We can now explain about 30 per cent of the heritability with these upwards of 200 gene variants. And this is partly because we have not identified all the genes, but it could also be because we have wrongly estimated the risk. The issue is that we have assumed that each gene is acting by itself, and it is quite obvious that this is not the case. There are combinations of different genes and combinations of environmental factors that lead to a much higher risk when compared with the risk entailed by each one individually,” says Ingrid Kockum. The research on environmental factors – environment and lifestyle – has also resulted in a significant increase in knowledge over the past decade. Smo-

Photo: Privat

genes, and the most important gene variant goes by the simplified name HLA DRB15. If you have this gene variant, the risk of getting MS increases by two and a half to four times,” says Ingrid Kockum, Professor of Genetic Epidemiology specialising in Multiple sclerosis, at Karolinska Institutet. The other gene variants contribute to a much lesser degree in terms of risk increase; between five and twenty per cent, researchers estimate. “This is a much lower risk when viewed individually, but together it becomes significant,” says Ingrid Kockum.

Photo: Linda Forsell

”To be diagnosed was liberating” “Before I was diagnosed, I felt that there was something wrong with my body. I had gone to a physiotherapist for some time because I had knee problems, but despite doing my exercises there was no improvement. When I was told I had MS, it was quite liberating, especially since I had been worried that it was something worse. You can actually do something about MS, even if it felt strange to be affected. When my doctor asked me if I wanted to try a new treatment that was being SOFIA developed, I said yes. The ARKELSTEN medicine I‘m taking is not Age: 40 yet approved speciﬁcally for Diagnosis: MS Received her diagnosis: 2014 MS, but it works great! I think Works as: Member of it’s important that medicine Parliament (M) which proves effective in contexts other than those intended should also be able to be used for just precisely that. I’m put on a drip once every six months. At these times I feel like a patient. Otherwise I work away as normal, as a member of the Swedish Parliament for the Moderate Party. If I’m going to be on an external debate, I have a stool or chair. There is a great acceptance within politics that people have different requirements. It is an unexpectedly favourable industry for the symptoms that I have. For me it is important to exercise and eat properly. If we’re in a long meeting and haven’t eaten in a long time, I speak up. It’s good for everyone; politicians who have eaten work much better! Since being diagnosed with MS, I have a low tolerance for unscientiﬁc advice. I think that there are no easy answers and I don’t want to take courses in all the exciting symptoms; I can simply rely on my doctor to tell me what is important. I’m pretty optimistic, there is a lot of research going on after all.” As told to: Maja Lundbäck Medical Science–2017

“One morning when I was in the shower waiting for the water to reach a comfortable temperature, I saw that the steam was surrounding my leg, but I felt no heat. When I poured the water on my other leg, I burned myself properly. I thought it was probably a pinched nerve, but after a few days I started to have trouble walking and went into the emergency ward. The first hospital couldn’t help me, but I stood my ground and then they sent me on to a bigger hospital. 72 hours later I was diagnosed with MS. It was like a blow straight to the chest. The shock lasted several years and it took eight years before I talked openly about my diagnosis. I was terrified that people would look down on me and think I couldn’t handle things. When I finally opened up about it, I didn’t get that reaction. I haven’t had any serious flare-ups 32

Medical Science–2017

since my first, but sometimes my legs give way, I experience tingling, poor balance and fatigue. But if I feel tired, I often find another explanation for myself and those around me. It often happens DANIEL that I play down various symptoms. HÄGGKVIST The first medication didn’t work Age: 32 Diagnosis: MS so well so I had to switch. Since Received his diagnosis: 2006 then the treatment has worked. Works as: Training Still, I prepare myself every day instructor at Balance. for the eventuality that I won’t be able to walk when I wake up. I’ve also had problems with self-confidence and often wonder if I’m up to the task. At the same time I’ve been lucky; it was good that the diagnosis was discovered early. My approach is to not put limits on myself. I had “Never let it win” tattooed on my arm, which has helped me a lot when I doubt myself.” As told to: Maja Lundbäck

Illustartion: Photo: Linda Björn Forsell Öberg

“It took eight years before I talked about it”

Multiple sclerosis In depth “We can see very clearly that moist snuff users have a protection. There are many indications that it is the nicotine that is the protective element.” king, low levels of vitamin D and obesity are three factors that we have observed contribute to an increased risk of MS. Getting glandular fever in adolescence rather than as a child also seems to increase the risk, as does shift work and organic solvents. What actually happens when these factors increase the risk is something we do not know for sure, but there are hypotheses. It is clear in any case that you have to be exposed to the risk factors before the disease onset, and since MS manifests fairly early on, there is a rather short period of life involved. “Many of the risk factors that we have identiﬁed, such as low vitamin D, shift work and high BMI, seem to act from puberty until the age of twenty; then they have less eﬀect. It appears that you run the risk of MS in your late teens depending on genetic predisposition and trigger factors. The same applies to the Epstein-Barr virus (glandular fever). If you get it in adolescence, it’s worse than if you get it as a child,” says Tomas Olsson.

Photo: Karl Nordlund, Getty images

AMONG THE lifestyle factors, there

is one that stands out as particularly risky, and that is smoking. Anna Karin Hedström is a postdoctoral researcher at Karolinska Institutet and she wrote her dissertation in 2015 on tobacco and its eﬀects on the development of MS. “We have looked at smoking in the context of the various forms of MS and we can clearly see that smoking is not limited to a window in youth. If you look at smoking before the disease onset you can see that it has as much impact even if you started smoking later in life. Smoking seems to be as inﬂuential a risk factor at any time,” she says. In her dissertation, Anna Karin Hedström could also show that smoking had a clear dose-response relationship,

meaning that the more you smoke, the greater the risk increase. In addition, the patients who continue to smoke have a worse prognosis than those who quit. “Smoking is not only a risk factor for MS, it also has a negative impact on the entire course of the disease,” she says. If you also have the prominent risk gene variant, HLA DRB15, smoking increases the risk tenfold, making it the most serious combination identified. The risks of smoking also apply to passive smoking. “If you look at those who have never smoked, you can identify a clear increase in risk for those exposed to passive smoking. What can also be seen here is that the longer you have been exposed to passive smoking, the greater the risk increases,” she says. But it is not the nicotine in cigarettes that is the culprit as you might expect; in fact, it is probably the opposite. “In the beginning we isolated the group of moist snuff users, and then we saw that they had a reduced risk of MS. Over the years we have amassed material and repeated the study, and we can see very clearly that moist snuff users have a protection. There are many indications that it is the nicotine that is the protective element as we know that nicotine has an anti-inflammatory effect,” she says.

Facts: MS is increasing among women New cases of MS are slowly increasing in number in most parts of the world, as well as in Sweden. But the increase seems to be prevalent exclusively among women. In the early 1900s, the gender distribution of the disease was even, and an equal number of men and women were affected. In most older textbooks it says that the ratio is 2: 1, meaning twice as common among women as among men. But the latest research ﬁndings instead indicate the ratio to be 3:1. No one knows why the disease is increasing among women. It is hypothesised that the increase in smoking among women is the cause, but in that case the incidence should instead decrease in a country like Sweden, where the proportion of smokers has decreased over time.

Smoking is clearly linked to an increased risk of MS.

In the case of moist snuff there is also a dose-response relationship entailing that the more you use moist snuff, the greater the decrease in risk. Smokers who also use moist snuff run a lower risk than those who only smoke. “It is therefore the moist snuff that reduces the risk,” she says. Anna Karin Hedström has a theory about how it could be connected. “Our hypothesis is that it is a lung irritation from the smoke that could trigger an autoimmune reaction. If autoimmune cells are activated in the lungs, they automatically take on properties which enable them to enter the brain,” she says. This would also sync up well with one of her latest findings, that organic solvents seem to have a similar risk profile as smoking, including the gene-environment interaction with the HLA DRB15 gene. This is something she intends to pursue further. ASIDE FROM moist snuff, Anna Karin Hedström and her research colleagues have also found other protective factors which are, to a layperson, about as unexpected as moist snuff. What about the protective factors coffee and alcohol? In quite high quantities too. “When it comes to coffee, there is no real effect until you get up to four or five cups a day. And with alcohol, you also need to reach a certain level of consumption before effects are noted,” she says. She points out, however, that the Medical Science–2017

In depth Multiple sclerosis findings regarding coffee are brand new and need to be verified in several studies in order to be assured. Admittedly she compared two very different groups of patients, one in Sweden and one in the US, and saw the same thing in both – the large consumers ran a lower risk. As lifestyle factors affect the risk of developing MS, an individual can personally alter their risk level, but Anna Karin Hedström stresses that MS is a fairly rare disease and that most people will never contract it. However, given that the disease is partly hereditary, people with MS in the family may need to think about reducing their risk, or rather not increasing it. “In which case you should definitely not start smoking and you should also ensure that your child is not exposed to passive smoking. You should also try to avoid your children becoming obese as child and adolescent obesity is a significant risk factor,” she says. Spending time outdoors is also important since sunlight releases vitamin D in the body. The protective factors are of course a bit trickier to manage with prevention in mind, she admits. They have more of an academic interest. “Naturally, you can’t recommend that children start using moist snuff and drinking coffee or alcohol, but the findings can help us understand the mechanisms behind the disease,” she says. THE FACT THAT a lot of new knowledge regarding risk factors for MS is currently emerging, and that Sweden in many cases is a world leader with regard to this knowledge building, is in large part due to the Swedish MS Registry. The registry started in 2000 and now contains approximately 17,500 MS patients, which is over 80 per cent of all patients in Sweden. That makes it one of the world’s most comprehensive MS registries. One of the reasons why it has become so successful is that the registry is not an administrative burden for the attending physicians, but rather a useful tool. Therefore almost all MS doctors in Sweden contribute information to the registry. “When a doctor is going to meet a patient they need to update themselves, and electronic medical records can often be difficult to browse through. 34

Medicinsk Medical Science–2017 Vetenskap №2–2016

In the MS Registry you can just press a button and you get the whole patient history on one screen. Moreover, by pressing another button you can see the patient in question compared with all other patients in the registry who have had the disease as long. You can then get an idea of whether the patient is where they should be, purely from a treatment perspective,” says Jan Hillert, Professor of Neurology at Karolinska Institutet and registry manager for the MS Registry. The registry also enables research that cannot otherwise be pursued and which therefore complements the clinical studies that must be done before a drug can be approved. “There is a lot that we can’t study in clinical trials. If we want to know whether these drugs are safe and effective over a 10-20-year period, we can’t do a clinical study. It would be unethical and is just not an option. This was one of the reasons why we produced this registry; we wanted to know what the long-term effects were,” says Jan Hillert. In addition, the registry contains the majority of all patients and is thus more representative of the actual treatment, while the patients in clinical trials are always a narrower sample of patients. Jan Hillert says that he initially researched the genetics behind MS, but that he has gradually crossed over to epidemiological research using data from the MS Registry. “In Sweden as a whole, we have published about 120 scientific reports from the registry to date. That’s quite a lot,” he says. SINCE JAN HILLERT and his colleagues were interested in genetics from the beginning, they also did something very prudent. “We have collected DNA samples from as many patients as we could. This means that we now have DNA samples from up to 12,000 of our patients. Because we have the registry, we can now also study gene importance for clinical parameters over time. We have also asked the patients about their lifestyle. Therefore, we can study both genes and environment, not only in terms of risk but also with regard to how the disease develops. This is something that is completely unique,” says Jan Hillert.

“Naturally, you can’t recommend that children start using moist snuff and drinking coffee or alcohol, but the findings can help us understand the mechanisms behind the disease.” The MS researchers at Karolinska Institutet are actually the only researchers in the world who have from an early stage focused on both genetics and environmental factors for MS. All the others specialised in either one or the other, which now seems unwise as it appears there are many gene-environment interactions. Many research groups are now trying to supplement their profile, but the Swedish researchers are fifteen years ahead of the pack. THIS IS ALSO thanks to the new knowledge that the researchers have established, the conclusion that the course of the disease was most likely misunderstood previously. Doctors have always understood the initial relapsing form to be a milder prelude to the more active, progressive phase that comes about 20 years after the onset of symptoms, when the physical functions begin to deteriorate more and more. Now we are starting to understand that in all likelihood it is just the opposite. “When we look at markers for ongoing nerve damage we can see a very clear age correlation; it is highest among younger patients and then it drops. Many patients in the progressive phase have no specific ongoing nerve damage at all. The progressive phase is therefore not nearly as active as previously thought,” says Fredrik Piehl, Professor of Neurology at Karolinska Institutet. He ascertains that the increasing loss of function that one sees in the progressive phase is probably mostly related to natural ageing and can be explained by the inflammation that has been going on for twenty years, already breaking down the reserve capacity that existed in the nervous system. “It’s a faster nerve-damaging process early on in the course of the disease that

Usual initial symptom Impaired vision in one eye due to optic neuritis.

Facts: Disease under revaluation

The protective myelin around nerve ﬁbres is attacked and destroyed by the body’s own defence cells.

The prevailing hypothesis is that multiple sclerosis, MS, is an autoimmune disease where the body’s immune system attacks the nerve ﬁbres in the brain and spinal cord and destroys their “protective shield” of myelin. The symptoms depend on where in the brain and spinal cord neuronal death occurs. MS often manifests between the age of 20 and 40. Other symptoms Reduced muscle strength, dizziness and coordination issues, walking problems.

Usual initial symptom Numbness or altered sensation in the arm or leg.

Two phases of the disease: Manifests often in a ﬂare-up 1 The majority of the patients, 80–90 per cent, initially experience a relapsing form of the illness, which means alternating periods of having symptoms and being asymptomatic.

During the first 15–20 years, the inflammatory activity is high and the nerves are attacked and destroyed. The inflammation then reduces while more and more symptoms appear, caused by a combination of the destroyed nerves and natural ageing.

MS can be active many years without symptoms.

This relapsing form often transitions after 15–20 years to the second form which is called secondary-progressive MS, which means an increasing loss of physical functions with age. 2

2 1

3 There is a third form called primaryprogressive MS which is similar to secondary-progressive MS except that patients do not present with the relapsing form beforehand. It is likely that the disease has progressed but without showing symptoms.

3 0

90 years

The damage occurs early on: The symptoms come later Damaged nerves early in life...

Inﬂammatory activity

...result in great loss of function in later life.

Loss of physical functions

Medical Science–2017

In depth Multiple sclerosis

In MS, the myelin sheaths around the nerves in the brain are destroyed and scar tissue forms. This is shown as the white area on this MRI image.

is not noticed, and which is insidious. A young individual has a high resistance to this and can potentially lose half of the nerve ﬁbres running from the cerebral cortex to the spinal cord without displaying permanent symptoms. The problem is that this reserve is something you need when you get older, but then you’ve kind of missed the train,” he says. His view is also supported by the fact that the newer immunological drugs that have been developed in the past decade clearly have better eﬃcacy in younger patients compared with older patients. But these are fairly new insights and the current guidelines for MS treatment still indicate that one 36

Medical Science–2017

should start with milder treatments that have fewer side eﬀects. This is something that Fredrik Piehl believes is a mistake.

“The entire process of MS treatment so far has focused on the wrong things. We under-treat patients in the early stage and over-treat to some extent later on during the course of the disease.”

ONE PROBLEM with an early, aggressive treatment is however that some highly effective drugs are associated with risks of serious side effects. A good example of this is the treatment that is considered to have the best effect, natalizumab (Tysabri), which can cause progressive multifocal leukoencephalopathy, PML – a rare and at worst deadly viral infection in the central nervous system. More than half of the Swedish population carry the JC virus, which causes PML, something that is normally not a problem. But the immunosuppressive drug natalizumab increases the risk of an outbreak and several deaths have occurred, even in Sweden. Among those not infected by the JC virus, the risk of PML is low, but virus-free individuals can become infected, which means that everyone who is treated with the agent must be tested for the virus twice a year. Many patients must stop treatment over time and it causes an unpleasant “rebound” effect where the disease can flare up dramatically and lead to permanent loss of function. However, last spring Fredrik Piehl and research colleagues in Göteborg and Umeå published an observational study in which they had looked at all patients in the MS Registry who had stopped taking natalizumab and started with either fingolimod (Gilenya) or rituximab (Mabthera). The latter treatment is approved for the treatment of, for example, lymphoma and rheumatoid arthritis, but not for MS, but has begun to be used by MS doctors outside of its approved indication, something that can be done within the scope of the doctor’s responsibility in that doctors in Sweden have free right to prescribe medication. A year and a half after the switch, fewer than two out of a hundred patients who had switched to rituximab suffered a relapse while ten times the number

Foto: Science Photo library

“The entire process of MS treatment so far has focused on the wrong things. Often it’s the case that you treat patients who have an increasing degree of neurological disability in their later years with more eﬀective, but potentially more dangerous therapies. We under-treat patients in the early stage and over-treat to some extent later on during the course of the disease. The biggest problem, however, is the under-treatment of younger patients,” he says.

“This study will address several key issues, not who had switched to ﬁngolimod had succumbed to such. This has already afleast the importance fected the prescription of treatments. of administering highly “If it is now working so well on individuals with the JC virus, then it effective treatment should have an equally positive eﬀect on those who don’t carry the virus. This has at an early stage to resulted in a gradual increase in the use younger patients.” of rituximab in more and more patients

Foto: Istockphoto

who have high inflammatory activity,” says Fredrik Piehl. He has continued to study the effects, and at the European MS Conference in September 2016 he was able to present new data on several thousand patients from the MS Registry, where the outcome for those who were prescribed rituximab was better than for those who received the other two treatments. “I think we now have enough evidence to conclude that rituximab has a comparable effect to natalizumab, but where the risk of PML is very small. This we know from the treatment of rheumatism where a lot of treatment data is available,” says Fredrik Piehl. In addition, treatment with rituximab is less cumbersome, indicates Fredrik Piehl, as it is given as an infusion every six months. Aside from this, patients do not need to think about their medication. And finally, the treatment is much cheaper than any other MS treatment. Compared with fingolimod and natalizumab, which cost around SEK 200,000 per year and patient, rituximab costs SEK 25,000 per year per patient. OVERALL, EVERYTHING seems to be close to perfect. After 200 years, a treatment has been found that is effective, safe and easy to take. All this, and at a very reasonable cost to health care. However, there is one problem. Rituximab’s patent has expired and the company behind it has stopped the costly clinical development aimed at getting it approved for MS. Instead, they are developing a new, patentable drug with the same mechanism and similar effect – ocrelizumab – which, however, is not yet approved. But what happens when/if it does get approved? “Will the pharmaceutical company then be able to force Swedish health care to switch treatment, even though the experience of ocrelizumab, and therein the degree of safety, is less known? This question is hard to answer,” says Fredrik Piehl.

It is clear, however, that the pharmaceutical industry is concerned about the developments they see in Sweden. They have been in contact with authorities such as the Swedish Medical Products Agency, the National Board of Health and Welfare and the Health and Social Care Inspectorate regarding the issue of whether it is permissible to systematically treat patients with a drug that is not approved for these patients, and they have also contacted the Ministry of Health and Social Affairs to ask them to investigate the rules that apply to the free right of prescription. The authorities have announced that they do not see any problems and no response from the Ministry has been forthcoming. The question of using rituximab against MS is of fundamental importance for the entire pharmaceutical sector, and not just in Sweden. The system of free prescription right is established in many countries across the world, and the USA is very interested in developments in Sweden, explains Fredrik Piehl. This interest has resulted in him and his research colleagues recently receiving eight million US dollars from an American national research institute to conduct a new study called COMBATMS to compare how things are going for Swedish MS patients in real life, a study that encompasses a longer period than that normally covered in clinical studies. “We are starting now and we will include registry data from 2011 combined with a follow-up over five years, which means that, over a five-year period, we can gradually provide increasingly better outcome data,” he says. One feature of the somewhat unclear situation surrounding rituximab is that there is a very large geographical difference in Sweden in how it is used. “You can interpret the evidence situation in different ways. There are those who say that rituximab is better than all other preparations and should be used

MS often ﬁrst appears at a relatively young age and there is a lot to indicate that it is important to begin treatment early.

for all MS patients. Then there are those who say that rituximab is not approved for MS and therefore should not be used at all. You could say that both views in any way are right,” says Fredrik Piehl. The consequence has been that nine out of ten MS patients in Umeå are given rituximab, four out of ten in Stockholm, and only one of of ten are prescribed it in Skåne. Normally it is not preferable with large geographical differences in treatment, but for the COMBAT-MS study, this means that it will be possible to compare the results of different strategies in large patient groups. “This study will address several key issues, not least the importance of administering highly effective treatment at an early stage to younger patients,” he says. In other words, the future looks quite bright for MS patients. The researchers understand much more about the causes of the disease, there are plenty of new medicines and the doctors are beginning to learn how to use them. There is a new understanding of the disease process which at best will lead to highly effective treatment being administered early on and stopping inflammatory neuronal death, so that the patients can maybe avoid losing their nerve cells and thus never have to enter into the progressive phase. That at least is the plan according to the researchers at Karolinska Institutet. Time will tell how successful the journey will be. Medical Science–2017

Curious about Lack of sleep

On the one hand, sleep is vitally important. On the other hand, we donâ&#x20AC;&#x2122;t need to sleep as much as we think. Here we question researchers about sleep, the activity that single-handedly eats up the greater part of our lives.

Photo: Getty Images

Text: Annika Lund

Medical Scienceâ&#x20AC;&#x201C;2017

TIRED? It is not possible to ascertain from research how many hours’ sleep we need to be healthy – it is more the feeling of being rested that is the determining factor.

Medical Science–2017

Curious about Lack of sleep

Medical Science–2017

THE NINE-POINT self-assessment tool used in the study was developed by his research group and is now used in sleep research internationally. A nine on the scale means a person is ‘fighting sleep’. A car driver who gives themself a nine runs a 25 per cent risk of driving their car off the road within five minutes. Anyone driving a car between four and five in the morning is eight to ten times more likely to be involved in an accident than someone driving during the day. ‘Sleep-related accidents on the road are as common as alcohol-related accidents,’ says Åkerstedt. ‘We have been trying to get this message out for many years, but it is difficult to reach the general public. An awareness campaign would save lives.’ The effects of sleepiness are also reflected in daytime traffic statistics, as the number of accidents increases at around four o’clock in the afternoon, just before the rush hour. This is because the body’s biological clock has set another sleep window just at that point. This is known as a result

of studies of the circadian rhythm of test subjects isolated for several days without daylight or clocks. The subjects fell into a circadian rhythm that involved sleep several times a day. The time it took to fall asleep was shortest at night and at around four o’clock in the afternoon. The body clock that governs the circadian rhythm is in the hypothalamus in the brain. This is where the clock genes are found, which influence sleepiness, amongst other things, by secreting hormones. ‘Our circadian rhythm is probably related to the fact that we have poor night vision and a poor sense of smell,’ says Åkerstedt. ‘It is not practical for us to be awake at night. The reason for the dip in the afternoon is not so obvious, but it is there; it is not to do with blood sugar levels, it’s linked to our biological rhythms.’ Similar experiments, in which test subjects were kept in isolation without daylight or clocks, showed that an hour’s nap seemed to reduce the need for night-time sleep by about four hours. So it is possible to feel just as rested whether you sleep between 11 o’clock at night and seven in the morning or sleep between two and six at night with an additional hour’s nap during the afternoon. This is because the biggest chunk of deep sleep happens in our first four hours of sleep. A four-hour sleep can keep us going until the afternoon, but by then we will need another sleep. This need for sleep means that the hour-long nap has more deep sleep and greater restorative value than another three or four hours of night-time sleep would have had. ‘But that’s not how society’s circadian rhythm is,’ says Åkerstedt. ‘We can’t take ourselves off to have a sleep in the afternoon, so this rhythm no longer works for us in practical terms.’ BUT – HOW LITTLE sleep do you actually have to have to put yourself at risk of injury or illness in the longer term? This is something we don’t know. According to Åkerstedt, one of the major trends in international sleep research is to identify the points at which a lack of sleep becomes harmful. But the issue is a tricky one, and we

Photo: Bildmakarna.

T IS VITAL that we sleep – and not being able to sleep at all results in death. If we have not slept for a long time, we inevitably fall asleep however hard we ﬁght against it. But testing on animals has shown that a complete lack of sleep is fatal. There is also a human illness that completely prevents sleep: the very unusual, hereditary illness fatal familial insomnia which occurs in a small number of families across the world. In those with the illness, an insoluble protein accumulates in the thalamus, which is involved in regulating wakefulness and sleep. When the illness is at its height, the patient cannot sleep at all. The resulting symptoms include loss of weight, hallucinations and confusion, and the patient eventually dies, usually within 18 months. So, while we are asleep, which we are for much of our lives, there are a number of vital bodily processes at work.One of these processes is related to energy balance, whereby cells in our brain ﬁll up with energy while we sleep so that we feel alert and rested when we wake up. But sleep is also important for the plasticity of the brain, because we process memories and learning during our sleep. Everything we do when we are awake creates new synapses in the brain. When we sleep, unused synapses are purged, which means that the brain is continually being reshaped. Debris and waste products are also cleared out, for example betaamyloid, clumps of protein closely associated with Alzheimer’s disease. In addition, recovery and developmental processes are boosted by hormones such as growth hormone. In the longer

term, a lack of sleep increases the risk of a range of illnesses such as diabetes, anxiety, depression, addiction and cardiovascular disease. It also brings a greater risk of premature death. In the short term, it affects our ability to function. When we are really sleepy, we function as poorly as if we were under the influence of alcohol. Torbjörn Åkerstedt, Professor of Psychology at the Department of Clinical Neuroscience at Karolinska Institutet, has been researching sleep for over 40 years. He considers a study that took place in 2013 one of his most enjoyable. Test subjects were asked to drive the 60 miles between Linköping and Gränna at four o’clock in the morning. Åkerstedt drove that stretch of road himself just before dawn, with EEG sensors in place and the test director sitting next to him. ‘It was an extremely unpleasant and transformative experience! My brain literally lowered my eyelids however hard I tried to fight it. People do not realise how strong the connection is between perceived sleepiness and road traffic accidents.’

“Sleep-rela ated accidents on the road are as common as alcoholmay not be asking the right question. A lack of sleep is not just about counrelated accidents. An ting up how many hours we have slept, awareness campaign as the need for sleep varies from person to person and changes over time. would save lives.” At the same time, in studies, people

Photo: Istock Photos, Ulf Sirborn. Illustration: Istock Photos.

who slept between six and eight and a half hours per night were not generally at greater risk of illness or death. However, those who slept five and a half hours or less per night or more than eight and a half hours were at greater risk. But some ‘short sleepers’ get a perfectly adequate amount of sleep. This is evident from information that Åkerstedt and his colleagues have gathered about sleeping habits and health from a sample of the population. Some of them slept less than six hours a day but still felt rested. And none of this group had an increased risk of illness or death. ‘It seems sensible to work on the basis of how rested people feel, particularly a little way into the day,’ says Åkerstedt. ‘Not feeling rested when you wake up is a doubtful criterion as it is influenced by the sleep stage you were in when you woke.’ It is not known why short sleepers do not suffer from a lack of sleep. They probably have a genetic profile that is favourable. And it is likely that

they are simply good at sleeping, with longer periods of desirable deep sleep. Processes beneficial to health mainly take place during deep sleep, and so for scientists the amount of deep sleep is a measure of sleep quality. But why ‘long sleepers’ are at increased risk of illness and death is a mystery. One theory is that individuals who need additional sleep more often have some ongoing, low-grade inflammation that causes both tiredness and other illnesses. The inflammation may, in turn, actually be caused by a lack of sleep, so by that argument a lack of sleep could also be the starting point for the health problems of some long sleepers. One person who has taken a particular interest in the effects of sleep on the immune system is John Axelsson, leader of a research group at the Department of Clinical Neuroscience at Karolinska Institutet. In a study in which he was

Facts: Three myths about lack of sleep 1. MYTH: ‘It’s dangerous to sleep less than seven hours a night.’ False! The need for sleep is individual and changes during our lifetime. 2. MYTH: ‘I can’t function if I don’t sleep.’ False! A lack of sleep is incapacitating, but it needn’t mean that a person is completely out of action. A slight lack of sleep can be compensated for. 3. MYTH: ‘I have to rest because I can’t sleep at night.’ False! Insomnia is not cured by rest, it’s cured by activity. We should keep active and ideally spend time outdoors in spite of feeling tired. That ensures we are really tired when we go to bed. Source: Kerstin Blom

involved, 36 healthy test subjects provided a blood sample three mornings in a row and also answered questions about how they had slept the previous night, how physically active they had been and how stressed they felt. The study revealed changes in the immune systems of those who had slept less than seven hours. Their NK (natural killer) cells, which can kill cancer cells, functioned 30 per cent less well than in those who had slept for a longer time. At the same time, T cell function was almost 50 per cent better. Even in those who described themselves as stressed, T cells – which have a number of roles in the immune system – functioned better. The study is in line with an American experiment, in which over 150 study participants were asked to describe their sleep over a two-week period. They were also asked to take nose drops containing a cold virus. Those who had slept less than seven hours per night got a cold three times as often as those who had slept eight hours or more. In Axelsson’s view, this suggests that the immune system is very sensitive to a lack of sleep and that many people need at least eight hours of sleep for recovery. ‘It seems that we can top up the energy levels in our brain quite quickly,’ he says. ‘We can do it by having a nap, which is presumably why people feel more alert after a nap. But we don’t actually know how we should be sleeping to ensure our immune system recovers.’ He would like lack of sleep seen as a general public health risk somewhere at the top of the list of other well-known dangers to health such as smoking and a sedentary lifestyle. ‘Absolutely. It’s obvious that an immune system less able to fight off infections is a significant health issue. Most of us have between one and five infections per year and many people develop secondary infections, which can be serious for high-risk groups. There are also theories that infections may be associated with the development of allergies and other illnesses. There is good evidence to support the view that sleep provides good protection against infections.’ Medical Science–2017

Curious about Lack of sleep

A DIAGNOSIS OF INSOMNIA is more precise. It means that someone wakes up a lot or wakes very early in the morning, or has difficulty getting to sleep, to such a degree that it affects how a person functions when they are awake. So the diagnosis is not related to length of sleep, it’s more about poor quality sleep. ‘In my line of work we try to help people to worry less about their sleep,’ says Blom. ‘Any worry has a detrimental effect on patients’ sleep. According to public health surveys, a third of all Swedes consider themselves poor sleepers. One in ten Swedes have such serious problems that they can be said to have insomnia. But there are effective treatments. About three quarters of sufferers

“In my line of work we try to help p people to worry less about their sle eep. Any worry has a detrim mental effect on patients’ sleep.” 42

Medical Science–2017

A third of all swedes consider themselves poor sleepers. CBT can often help, mainly by improving sleep quality..

are cured of their sleep problem by cognitive behavioural therapy (CBT). Approximately the same proportion is helped by sleeping tablets, but once treatment has finished there is no further effect from the medication, whereas CBT continues to work because people have learned new behaviours. Those who feel that CBT has helped them only increase the amount of time they sleep by an average of half an hour – so it is principally the quality of the sleep that changes rather than the length of it. CBT can be arranged on a group basis, individually or via the internet. One important element is a diary in which the patient records how they actually sleep in order to build up an accurate picture of their sleeping behaviour. Another important aspect of the treatment is that the patient must develop a significant level of sleepiness before they go to bed by keeping themself awake for a long time. That makes them tired the following day, but they must not rest during the

daytime – they must keep awake until late at night, abiding by a precise, individual schedule in which the permitted period of night-time sleeping is gradually extended. Susanna Jernelöv, who also undertakes research at the Department of Clinical Neuroscience, believes that tiredness is an obvious side effect of the treatment. ‘For many years, psychological treatment has generally been viewed as being free of side effects,’ she says. ‘But that isn’t actually the case. The intense tiredness or sleepiness you often experience when you work with CBT for sleep problems is unpleasant and a definite side effect of the treatment.’ One in four people who receive CBT for insomnia do not benefit from it. A possible reason is that they lack the energy to complete the treatment. Jernelöv is currently undertaking a comparative study of different variants of CBT for insomnia. The aim is to compare the extent of the side effects, so as to identify the variant that is both effective and mild.

Photo: Psykiatri Sydväst, Stefan Zimmerman, Getty Images.

His dream project would be to study the extent to which we can sleep ourselves into health, for example when we have a cold. ‘No-one knows that yet. I have applied for research funds for it but have been turned down everywhere. It is a high-risk project, but the idea is a reasonable one and it would have huge beneﬁts. There is some data to suggest that we automatically sleep more when we are ill. Sleeping more is part of our general response to illness.’ Kerstin Blom, a psychologist and researcher at the Department of Clinical Neuroscience, is in two minds about what is said about the dangers of not sleeping. On the one hand, it is quite true that there is a link between a lack of sleep and an increased risk of illness and premature death. On the other hand, the concept of ‘lack of sleep’ is a bit hazy, so there is potential for the general public to misinterpret and worry unnecessarily.

The moment As told to: Anders Nilsson Photo: Annika af Klerker

“The rust doesn’t take anyone any more” An unknown blood disease was tormenting several of Eva Hellström’s patients. Thirty years later, she knows more and is signiﬁcantly better able to help suﬀerers.

Name: Eva Hellström Lindberg Occupation: Professor of haematology at the Department of Medicine, Huddinge, and consultant at the Haematology Centre, Karolinska University Hospital, Huddinge.

“I was the youngest registrar and under normal circumstances, would not have been free to conduct research independently. But the consultants at the clinic were working mainly with real leukaemia, which was a prestige area. My older colleagues were not so interested in the patients with the unusual blood values that I was pondering over. So they left me alone. It was in the Haematology Department at Huddinge Hospital in the mid-1980s that I met these patients and began wondering about their unknown blood disease. We knew very little about it, only that it was evidently some sort of defect in the bone marrow. This piqued my curiosity – and ended up being decisive for my entire research career. More than thirty years later, I am still researching this disease. One of the patients was a very friendly and patient old man – I remember him as being very old, although he was probably not much older than I am now. He came to us for a blood transfusion every ten days and I saw him slowly become increasingly more tired and grey. The transfusions kept him alive, but were also lifethreatening as they led to an enormous iron surplus over time. Many patients, this man included, eventually died of iron poisoning. I remember the consultant’s harsh words: ‘The rust took him’. I discovered that I was not entirely alone in my interest. In other parts of the world, other researchers had also opened their eyes to the same disease. Gradually it was given the name myelodysplastic syndrome and is actually a whole group of diseases. Thanks to collective effort, we have both charted their causes and developed treatments. My research group has introduced a treatment with hormonal erythropoeitin that slows down the disease and can delay the need for blood transfusions by several years. We are also now able to treat the iron surplus so that patients are not harmed by frequent transfusions. The rust doesn’t take anyone any more.”

Medical Science–2017

Advances 5 questions to CHRISTOFFER RAHM is a specialist doctor in psychiatry and a researcher at the Department of Medicine, Huddinge.

Wants to take action before it is too late Can medication prevent a person with a sexual attraction to children from oﬀending? This will be investigated by Christoﬀer Rahm. Text: Viktor Karlsson Photography: Christopher Hunt

Why did you begin this study?

“While I was training to become a psychiatrist, I worked at a clinic for children and adolescents where I met the victims of sexual assaults. Later on, I worked at the Centre for Andrology and Sexual Medicine, where I got to meet the perpetrators. This made me more motivated to ﬁnd a preventative treatment that helps both victims and perpetrators.” How will the treatment be carried out?

“Our study, Priotab, involves 60 adult men with paedophilia. Half of these people will receive medication and half will receive a placebo. The medication is given in the form of an injection that has an immediate effect and reduces the testosterone level in the whole body, including the brain. The effect then lasts for almost three months. By reducing the testosterone level, we hope to reduce several risk factors for offending such as hypersexuality, low impulse control and reduced empathic capability.” 44

Medical Science–2017

How many Swedish people are sexually attracted to children and what are the current treatments options?

“It is estimated that about three per cent of the population, both men and women, have sexual fantasies about children, but there is most probably a large number of unrecorded cases. In Sweden, we have a opportunity to help them, thanks to a national helpline called Preventell. Around 100 people with this background call this service to seek help each year. They are oﬀered interventions such as psychotherapy and medication.” Is the research able to answer the question of what leads to a person offending?

“There are several reasons, not just paedophilia, but also, for example, that they have a sexual addiction or poor impulse control. According to the

patients themselves, many people with paedophilia believe that they are born with this attraction to children. The studies that have been conducted in this area actually supports the patients’ stories.” You meet these people every day. What are your thoughts about this?

“A large proportion of these men know that their feelings are not accepted by society and seek help for it. They feel really bad and have realised that if they act out their fantasies, people will be harmed. Some of them have also done horrible things to children. But I have to look past the moral aspects in these cases. My principal duty as a doctor is to help people with problems. A preventative approach, preventing men from committing sexual oﬀences, helps both the men and the children.”

Advances 2 × days of the week

Worse having surgery at the end of the week Many people feel exhausted at the end of the week. But new research show that if this fatigue aﬀects a surgeon, there is a risk of this having far-reaching consequences. T H E C LO S E R TO

Photography: Istockphoto. Illustration: Istockphoto.

Text: Mårten Göthlin

RESEARCH FROM THE UK has previously shown that survival 30 days following surgical procedures is affected by the day of the week on which the operation took place. Jesper Lagergren, professor of surgery at Karolinska Institutet, together with colleagues, has compiled 1 748 cases of oesophageal cancer in Sweden and studied the effect of the day of the week on which the surgery took place. They found that mortality after five years was 13 per cent higher if the patients had surgery on Wednesday to Friday, compared with Monday and Tuesday, and mortality increased by 7 per cent for each day later in the week. The results bring to mind what had previously been seen in the UK. The difference is that it has now been shown that the day of the week also has an impact on long-term postsurgical mortality, primarily through an increased incidence of the recurrence of

THE WEEKEND THE SURGERY TO O K P L AC E , THE HIGHER T H E M O R TA L I T Y

H I G H E R M O R TA L I T Y

M O N DAY

T U E S DAY

W E D N E S DAY

T H U R S DAY

oesophageal cancer within ﬁve years. According to Jesper Lagergren, this result may potentially be due to surgeons becoming more tired towards the end of the week and that the surgeon’s precision may suﬀer. This would also explain why this association is most distinct for those surgeons who perform a large number of these operations. ”Operating on oesophageal cancer is one of the most extensive surgicalprocedures that can be performed. The operation takes an average of six and

F R I DAY

a half hours, sometimes signiﬁcantly longer. This places great demands on us surgeons in many ways, not least that we need to remain alert for a long period,” says Jesper Lagergren. However, he points out that it is too early to issue any clinical recommendations. ”More studies need to be conducted in order to conﬁrm the results and we need to gain a clearer picture of the underlying causes. Only then will we be able to rectify this in the best way. ” Annals of Surgery, 2015

Strokes and heart attacks deadlier at the weekend The short-term mortality from strokes and heart attacks can be higher if you are admitted at the weekend, compared with a weekday, as indicated by the results of two previous studies. Rickard Ljung, doctor and researcher at the Institute of Environmental Medicine, has previously compiled data covering around half a million stroke and heart attack patients over the period 1968–2005 and was able to see an increase in mortality of between 10 and 15 per cent one week after falling ill for those patients who were admitted over the weekend. ”The studies were published back in 2007, but the cause is not yet clear and a follow-up of this research would therefore be of interest,” says Rickard Ljung. Medical Science–2017

In memory Hans Rosling

He could explain the world Hans Rosling worked tirelessly to explain the world to in simple terms. Although he has left us now, his message and positive energy live on. HANS ROSLING was a notable Professor of International Health at Karolinska Institutet for many years. However, it was his work as a lecturer and educator that made him world-famous. His mission was to improve

Typical Hans Rosling

CREDIBLE

FACTUAL He was intolerant of platitudes, and would often say “That’s where you’re wrong! Think about it!”

COMMITED

RATIONAL

Statistics were a serious matter to him, and he was passionate about communicating them.

“Feelings are for the bedroom”, he would say.

demonstrate that the world is in constant change. He gained enormous media exposure following a TED talk in 2007 which marked the beginning of his world tour as an “edutainer” and fact-teller. Since then, he has been a speaker in great demand. “I don’t know how he found the time to do everything he did. When it was suggested he should rest, he’d always say ‘I can rest when I’m dead’. I ﬁnd it unlikely that he would be resting now, it just doesn’t suit him,” says Helena Nordenstedt, researcher at the same department. Hans Rosling died of pancreatic cancer on 7 February 2017.

health and living conditions, especially for the world’s poorest. “He was a master of simplifying complex matters, and often did so on a basis of right and wrong, but he could also reconsider his opinions. He was unpretentious like that,” says Anna Mia Ekström, Professor at the Department of Public Health Sciences. When Hans Rosling, along with his son and daughter-in-law, developed a computer program with a new type of visual statistics in the 2000s, he ﬁnally had the means to effectively dispel long-held truths. With this new tool in hand and statistics from every country, Hans Rosling was able to clearly

FUNNY He often made us laugh, think and be dismayed, all at the same time – like when he pointed out that professors are more wrong than right about the world, thereby proving them less knowledgeable than a chimpanzee.

HOPEINSPIRING

He told it like it was, no matter if it was politically correct or not.

WORLDFAMOUS He gave more TED talks than anyone else in the world.

A GOOD TEACHER

Lego, IKEA boxes or apples. He could use whatever was at hand to explain the world.

He showed us that the world is becoming a better place. He called himself a “possibilist”, a person who believes that things are possible.

DYSLEXIC “Is it spelled profesor or professor?”

1940

27 July 1948 Born.

Medical Science–2017

1950

1972 Married paediatrician and researcher Agneta Thordeman.

1960

1970

1967 Began studying at Uppsala University. First statistics, then medicine.

1981 Discovered a previously unknown paralytic disease: Konzo.

1980

1999 Appointed Professor at Karolinska Institutet

1990

1993 Co-founded the Swedish section of Doctors Without Borders.

2012 Named Swede of the Year Abroad

2000

2005 Co-founded the Gapminder foundation.

2010

2017 Hans Rosling passed away on 7 February.

Photo: TT/ Mattias Barda.

LEARN FROM HANS ROSLING Watch his educational videos at gapminder.org or youtube.com

Medical Scienceâ&#x20AC;&#x201C;2017

Top publications

Many sufferers of body dysmorphic disorder have undergone plastic surgery. Now there is alternative help in the form of internet-based CBT.

Imagined ugliness can often be cured PEOPLE SUFFERING from body dysmorphic disorder (BDD) have a preoccupation with perceived flaws in one’s physical appearance, despite looking normal. However, even though the diagnosis is associated with an elevated risk of suicide, higher rate of sick leave and considerable distress, BDD has long been neglected by the care services, leaving sufferers struggling to find the help they need. 48

Medical Science–2017

In order to increase access to therapy, a new type of internet-based cognitive behavioural therapy (CBT) has been developed and tested in the largest treatment study to date. After twelve weeks’ of treatment, one in every three patients no longer met criteria for a diagnosis of BDD. “Our results show that internetbased CBT outperformed supportive therapy, and that its therapeutic eﬀect

is fully comparable with that achieved by conventional CBT,” says Jesper Enander, researcher at Karolinska Institutet’s Department of Clinical Neuroscience. A majority of the 94 patients included in the study had been suffering from BDD for many years and had had previous contact with the healthcare services. One in five had undergone plastic surgery trying to “fix” perceived flaws in their appearance. For the study, the group was randomly assigned to two forms of therapy: internet-based CBT or supportive therapy. Those assigned to this latter control group were later offered CBT. Immediately after the therapy programme ended, half of the people in the CBT group showed greatly reduced symptoms. One third were completely cured. CBT also improved the participants’ quality of life and reduced depressive symptoms. Of the participants who had major depressive disorder at the start of the study, half were no longer depressed. The researchers hope that the treatment will eventually be made generally available. “Many BDD sufferers receive no treatment at all, partly because the condition is relatively unknown within the healthcare services but also because people with the disorder tend not to seek treatment out of fear that they’ll be dismissed as superficial or not be taken seriously. Most of the study participants also said it was the possibility to do the therapy online that made them seek any help at all in the first place,” says principal investigator Christian Rück at the same Department. Therapist-guided Internet-based cognitive behavioural therapy for body dysmorphic disorder: A single-blind randomised controlled trial Enander J, Andersson E, Mataix-Cols D, Lichtenstein L, Alström K, Andersson G, Ljótsson B, Rück C BMJ February 2016

Illsutration: Lisa Henderling/The Ispot. Foto: Christian Rück, Niels Eék.

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

Migraine linked to new genes AROUND ONE IN SEVEN people all

over the world suffer from migraines. The symptoms consist of moderate to severe headaches in recurring attacks. The greatest risk factor is heredity. So far, 13 loci in the human genome have been found to be linked to migraine. In order to identify more such loci, the researchers behind a new study has carried out the largest genetic study of migraines to date. Genetic analyses of material from nearly 60,000 migraine patients and a little over 300,000 control subjects identified 28 loci in the human genome linked to migraine, which had not previously been reported. One of these loci was the first to be identified in the X chromosome. “This identification can contribute to greater insight into the disease mechanisms of migraine, which in turn may provide a support in the development of new and more effective drugs,” says researcher Andrea Carmine Belin at the Department of Neuroscience at Karolinska Institutet. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Foto: Ulf Sirborn. Illustration: Istock Photos.

Gormley P, Anttila V, Winsvold BS et al. Nature Genetics May 2016

Researchers have mapped out the active genes of the pancreas

More of the year’s publications New role of nerve cells discovered Motor neurons control locomotor circuit function retrogradely via gap junctions Song J, Ampatzis K, Björnfors ER, El Manira A Nature January 2016

New genetic atlas of the pancreas THE PANCREAS’ job, among other things, is to produce insulin that regulates blood sugar. Researchers from Karolinska Institutet and AstraZeneca have now for the first time managed to produce a molecular map of the active genes in the various cells of the human pancreas. The study also described differences in gene activity between people with type-2 diabetes and people who do not have this disease. The study used the new technology of singlecell transcriptomics, developed by researchers at Karolinska Institutet. The study looked at the pancreases of ten deceased people, of which six had a healthy pancreas and four had suffered from type-2 diabetes. “We are hoping that our study will fuel the research on pancreatic diseases in the future,” says Rickard Sandberg, a Professor at Karolinska Institutet’s Department of Cell and Molecular Biology.

Single-cell transcriptome proﬁling of human pancreatic islets in health and type 2 diabetes

Predisposition for migraine can be seen in our DNA

LIST

Segerstolpe Å, Palasantza A, Eliasson P, Andersson E, Andréasson A, Sun X, Picelli S, Sabirsh A, Clausen M, Bjursell MK, Smith DM, Kasper M, Ämmälä C, Sandberg R Cell Metabolism September 2016

New technology decodes the structure and function of membrane proteins A saposin-lipoprotein nanoparticle system for membrane proteins Frauenfeld J, Löving R, Armache J-P, Sonnen AFP4, Guettou F, Moberg P, Zhu L, Jegerschöld C, Flayhan A, Briggs JAG, Garoff H, Löw C, Cheng Y, Nordlund P Nature Methods March 2016 Dementia not transferred via blood transfusion Transmission of neurodegenerative disorders through blood transfusion: A cohort study Edgren G, Hjalgrim H, Rostgaard K, Lambert P, Wikman A, Norda R, Titlestad K-E, Erikstrup C, Ullum H, Melbye M, Busch MP, Nyrén O Annals of Internal Medicine June 2016 Bariatric surgery increases risk of premature birth Bariatric surgery and preterm birth Stephansson O, Johansson K, Näslund I, Neovius M NEJM August 2016 Swine ﬂu vaccination harmless to unborn babies Risk for congenital malformation with H1N1 inﬂuenza vaccine: a cohort study with sibling analysis Ludvigsson JF, Ström P, Lundholm C, Cnattius S, Ekbom A, Örtvist Å, Feltelius N, Granath F, Stephansson O Annals of Internal Medicine september 2016 Medical Science–2017

In memory Lennart Nilsson

He showed us our inside in new ways Text: Jenny Ryltenius Lennart Nilsson visualised medical research and helped millions of people to understand the human body. Throughout his career he continued to push the boundaries for what is possible in medical photography. Among other things he photographed the process of fertilisation, the viruses that cause HIV and the parasite that carries malaria. He worked closely with researchers at Karolinska Institutet from the 1970s until he was more than 90 year old. His driving force lay 50

Medical Science–2017

in “showing what is close to us, what we all know, in new ways” and his foremost objective was to surprise and touch people. As proof of his success he received a great many prestigious prizes and awards and became a professor when the government awarded him the title in 2009. Lennart Nilsson passed away on 28 January 2017 at the age of 94.

Photography: TT/Lennart Nilsson (the egg cell), Ulf Sirborn.

The Egg, just prior to ovulation, surrounded by nutritient cells like a radiant wreth.

Help improve human health Study one of our 8 Global Programmes in health and life sciences, all in English and with an international focus. A degree at Karolinska Institutet may very well be the ďŹ rst step towards a PhD in the same or another well renowned university somewhere in the world. It can open doors to a global future. Bioentrepreneurship Biomedicine (Bachelor and Masterâ&#x20AC;&#x2122;s level) Global Health Health Economics, Policy and Management Health Informatics Molecular Techniques in Life Science Public Health Sciences â&#x20AC;&#x201C; Epidemiology Toxicology

â&#x20AC;?I heard about KI from my university back home. It was very reputable and I was intrigued by the content of the programme itself. So, I decided to apply to Karolinska Institutet and I am deďŹ nitely not regretting the decision.â&#x20AC;? Preethi Pillai, 2015 Graduate from Singapore

ki.se/masterstudies

5BLF POF PG ,BSPMJOTLB *OTUJUVUFU T .BTTJWF 0QFO 0OMJOF $PVSTFT JO -FBSO GSPN TPNF PG ,BSPMJOTLB *OTUJUVUFU T UPQ UFBDIFST o PVS .00$T BSF PQFO UP FWFSZCPEZ

.PSF POMJOF DPVSTFT XJMM TPPO CF BWBJMBCMF LFFQ VQEBUFE BU LJ TF FO FEVDBUJPO NPPD DPVSTFT

Photo: Erik Cronberg

t 1SBHNBUJD 3BOEPNJ[FE $POUSPMMFE 5SJBMT JO )FBMUI $BSF 4FMG QBDFE

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

For more information, please visit us at ki.se

The Nobel Prize Medal® is a registered trademark of the Nobel Foundation. Photos: Camilla Svensk and Erik G Svensson.

KAROLINSKA INSTITUTET – A MEDICAL UNIVERSITY