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Contents

2013

4

Meet the President

Advances 5 6 7 8 10 21

Cold cases Buzzing research Spider silk Exercise in detail DNA origami Reversing cells

In focus 22

Malariafree vision

24 Climate medicine 42 New air passages bring hope 46 Identical twins:

Why researchers love them

12

Death as a collegue. The professor of Forensic Medicine believe he can help living people.

8

Meet the researchers 11 12

He mapped his DNA

Exercise. Effects examined in detail.

With death as a colleague

20 She studies her own disease 34 The lifestyle professor’s top tips

34

50 Meeting the first HIV patient started his career

Lifestyle professor. Not afraid to debate.

In depth 26 Prematurely born: From survival to a vision of lifelong health

Also

22

16 Timeline 38 High impact publications 40 KI News

Cover: Istock Photo

Malaria. His dream is to eradicate it.

Insert: Learn all about Karolinska Institutet. Medical Science–2013

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President of Karolinska Institutet

D

ear readers, It is with joy and pride that I, as the newly appointed President of Karolinska Institutet, write these words. Karolinska Institutet is a fantastic place for research and education. For more than 200 years, Karolinska Institutet has contributed to the improvement of people’s health. The expectations on us are great: from the research community, from the students, both of today and of the future, from the health care sector, from enterprise, from political leaders regionally and nationally and last, but not least, from the general public. at Karolinska Institutet we conduct research and education throughout the whole of the medical field, from cell to society. students, teachers and researchers from the entire world come here in order to, together, contribute to improving human health and development in a spirit of creativity, optimism, and with the satisfaction of a job well done. Together we will change the world. It is a strong and expanding Karolinska Institutet, in a state of rapid change, that I have been charged with leading. One project that we are now realising is sciLifeLab, a collaboration with KTH royal Institute of Technology, stockholm University and Uppsala University, which has taken on the role of a national resource for basic and translational cutting-edge research within molecular biosciences. We will shortly begin building Biomedicum, which will become one of europe’s largest research laboratories. In addition, we are working intensively, in close collaboration with stockholm County Council, to design an entirely new university hospital and the healthcare system of the future. an ImPOrTanT CHaLLenge for Karolinska Institutet lies ahead; that is to further strengthen the university’s role as a leading international research institute. In order to accomplish this, we plan to, aside from recruiting the best researchers from around the world, design a clear career structure for our younger researchers and mobilise significantly greater internal resources to support the most promising young researchers at the early stages of their careers. another important goal is to further strengthen Karolinska Institutet’s undergraduate courses so that we can attract the most energetic, enthusiastic and creative students from all corners of the globe. Karolinska Institutet’s future is made up of the creativity, brilliance, enthusiasm, competitive spirit, loyalty and, not least, hard work of all our co-workers. In this magazine, you have the opportunity to meet some of our prominent researchers, and read about a number of current examples of the latest breakthroughs, resulting from the goal-oriented research which is conducted every day at our university.

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Medical Science–2013

Editor-in-chief Christina Bostedt Director of Communications Karolinska Institutet Editor Cecilia Odlind medicinskvetenskap@ki.se Art Direction Johan Blomgren & Per Boström Content Innovation Design Johan Sundqvist Print Kaigan 2013 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/ karolinskainstitutetenglish

Photograph: Gunnar Ask

Anders Hamsten:

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.


The latest in medical research

Lost without a trace – but researchers cracked the case

Photograph: Istock Photo

In 1965 a boy disappeared. Over 40 years later, researchers at Karolinska Institutet have helped to show what happened. In 1965, a four year-old boy disappeared in northern Canada. They feared that the boy had drowned in the nearby river, but the body was never found. Three years later, a hunter found parts of a child’s cranium downstream at the same river. However, the police investigation concluded that it could not be the same person, as it was concluded that the cranium was from a child about twice as old. When the cranium was investigated again, a few

years ago, Karolinska Institutet’s researcher Kirsty Spalding was recruited to the Kirsty Spalding. case. Using Photograph: Stefan Zimmerman Spalding’s carbon dating method, the Canadian investigation discovered that the age of the cranium had been incorrectly assessed, and that it did indeed match

the missing four year old. It could then be established that it really was the same person, through a mitochondrial DNA analysis. The case is one of more than a dozen where the method has been used alongside other techniques to identify deceased persons. “The cases include both recent crimes and older, ”cold cases” in Sweden, New Zealand and Canada. I am now getting calls from police in the USA, where there are

many cold cases,” says Kirsty Spalding. The method utilises the fact that the amount of carbon-14 increased significantly between 1955 and 1963 due to the nuclear tests conducted in the atmosphere by the super powers. Since then the amount has slowly declined. By measuring the amount of carbon-14 in tooth enamel, it is therefore possible to conclude with a high degree of precision when the tooth was formed, and thus establish the year of birth. “I developed the method with Professor Jonas Frisén over ten years ago, to study the creation of new brain cells. Today I use it to study the renewal of fat cells. The forensic applications are an exciting side project,” Spalding says. Anders Nilsson Medical Science–2013

5


Framsteg Advances

Xxxxxx

What more can researchers learn from flying insects:

Buzzing research.

Research that’s creating a buzz Just like humans, bees need to be flexible in their work. A new study shows that epigenetic changes are the key.

Photograph: Istock Photo

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n the bee society, different bees have different roles. Some tend to larvae in the bee hive, whilst others concentrate on searching for nectar and pollen outside. The occupation of the individual bee varies depending on the needs of the bee society. Researchers have now shown for the first time that the behaviour of the bees is linked to “epigenetic changes” to their DNA. The attachment of methyl groups to DNA affects the gene expression and explains how bees can change task so quickly when this is required. Can this knowledge be applied to human genetics? Medical Science–2013

“Epigenetic changes that regulate gene activity also occur in the human body. For example, they govern how the body’s cells acquire their various tasks during the body’s development. But whether they can also explain behavioural changes among humans is something which future research will have to determine,” says Andrew Feinberg, at the Johns Hopkins Medical University. He is one of the researchers involved with the study and also a visiting professor and Honorary Doctor at Karolinska Institutet. Cecilia Odlind

Tip! Read more about how epigenetic changes affect us on pages 54-57.

Midge mega chromosomes studied under the microscope RNA molecules function as messengers in cells when genetic information from DNA is to be translated into proteins. Researchers at Karolinska Institutet are trying to find out the details of how this transfer of information occurs. They use cells from the salivary glands of the Chironomus tentans midge since their chromosomes are very large and easy to study. Using electron microscopes, the researchers can visually track the transport of the messenger particle from the DNA, through special pores in the nuclear envelope and out into the surrounding cytoplasm. Improved flight capability for flies with Alzheimer’s Alzheimer’s disease causes the toxic accumulation of beta-amyloid proteins in the brain. To try to prevent the occurrence of, or find a cure for Alzheimer’s disease, researchers at Karolinska Institutet are trying to find new ways of influencing this process on a molecular level. With the aid of a genetically modified version of the fruit fly Drosophila melanogaster, which creates beta-amyloid, the effect of substances and proteins that bind and affect accumulation of the protein is tested. Researchers then observe the changes to the flies’ flight patterns and have so far found substances that can reduce both the accumulation and the toxicity of beta-amyloid.   Cecilia Odlind


Framsteg Hello there Xxxxxx Anna Rising

Club of South Africa who told us we were welcome to come to South Africa and collect spiders. We did, and after a few weeks we came home with 104 spiders.

who has managed to make spider silk in the laboratory

Then what happened?

“We extracted DNA from the spiders and it turned out the gene that encodes the silk protein is gigantic. But we only used a small part of the gene, barely a tenth of it, and injected it into E.coli bacteria which could then produce silk. They make the proteins in a soluble form, but when we collect the purified protein in test tubes, very strong threads are spontaneously formed: They can withstand temperatures of 260 degrees Celsius and ethanol baths. To some extent they resemble the fibrillae formed by Alzheimer’s disease – which is why we are at the Alzheimer’s centre at Karolinska Institutet. How can spider silk be used in medical research?

Her research is hanging by a thread Anna Rising is working on a unique project – creating spider silk using bacteria. The material could in the future be used for wound healing and repairing nerves.

How did you become interested in spider silk?

“I’m a vet, originally, and ended up by chance in an EU-financed doctoral project where the goal was to produce spider silk. According to measurements, the strongest silk is found among Euprosthenops australis spiders, and I started by sending out emails around the world to locate these spiders. I heard back from the Spider

In a few years time, how could your spider silk be usable in a clinical context?

“I think it might be possible to use the thread itself, maybe as a suture material or to heal wounds. There are also studies that show that spider silk allow damaged peripheral nerves to heal. This is where I think our manufactured silk may be of use. But we need to be able to demonstrate that the material is safe to implant into the body. Lotta Fredholm Medical Science–2013

Photograph: Mattias Ahlm

”I’m not afraid of spiders. When we collected spiders in the bush, there were other, more dangerous animals to be worried about,” says Anna Rising, researcher at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet.

“We have recently published a study where the spider silk is used as a matrix to culture neural stem cells. These cannot attach themselves directly to the plastic plate – a biological surface is required. Currently, animal proteins are often used as matrix, but due to the risk of contamination, cells cannot be used clinically and the material is subject to variability. However, our material is created from bacteria and we know exactly what it contains. Another advantage is that it is stable enough for cells growing on or in the material to, for example, be transferred from the dish and into a patient. We now hope to create three-dimensional matrices to be able to cultivate cells, and eventually it may be possible to create entire tissues. In a separate project, diabetes researchers use the silk as a base for making insulin-producing beta cells divide and multiply outside of the body. The idea here is that the cells will then be reintroduced into the body in a way that combats diabetes.

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Advances

Irisin increases calorie consumption

Pontus Boström is a researcher at the Department of Cell and Molecular Biology, Karolinska Institutet.

Three questions to Pontus Boström who discovered the irisin hormone, which has the same effects as exercise: 8

Medical Science–2013

What were the reactions to the discovery of irisin?

“The response has been beyond all expectations. There is something about the word exercise that gets journalists going. Of course it is great that the research attracts attention, but it has been reported in greater proportions than we would have liked. Exercise has an enormous number of effects on the body and irisin only explains a small part of them. As a researcher, I find the fact that we have found a completely new neurotransmitter in the body the most exciting. Discoveries like this have mainly been done

in earlier decades.” What is the next step?

“There must be a receptor for irisin in the body and I work almost around the clock trying to find it. We are also going to study the way irisin is regulated in the body and initiate large-scale trials on humans to see if it is possible to develop a drug based on irisin.” What results are you expecting from the research?

“A treatment against diabetes and possibly against obesity. Exercise will still be the most important treatment against these diseases, but there are many patients who have difficulties being sufficiently active for various reasons, and for these patients, a drug that enhances some of the effects may be very favourable.” Ola Danielsson

Photograph: Istock Photo, Sam Ogden

In the pursuit of the molecules of exercise

Pontus Boström, along with colleagues at Harvard University, discovered the irisin hormone that is produced in the muscles during physical activities. Irisin transforms white fat into brown fat, which burns faster. The hormone also keeps the blood sugar at a steady level. When the researchers gave irisin to mice, they had a substantial increase in energy consumption and a small weight loss, without being more active than other mice. The name derives from the Greek goddess Iris, who quickly conveyed messages between different parts of the country.


Exercise changes the DNA

The genetic heredity a person is born with isn’t that impossible to change as one might think. Researchers showed that when healthy but inactive men and women are made to exercise it actually alters their DNA – in a matter of minutes.

T

Photograph: Johan Bergmark

he underlying genetic code stays the same. However, the DNA molecules within the muscle cells gets chemically and structurally altered in very particular ways, by gaining or losing marks of methyl groups on certain familiar DNA sequences. Those so called epigenetic modifications to the DNA, at precise locations, appear to be an important part of the physiological benefits of exercise. “Our muscles are really plastic,” says Juleen Zierath, Professor of Clinical Integrative Physiology at the Department of Molecular Medicine and Surgery. ”We often say ’You are what you eat.’ Well, muscle adapts to what you do. If you don’t use it, you lose it and this is one of the mechanisms that allow that to happen.” Their study shows that the DNA within skeletal muscle taken from people after a burst of exercise bears fewer methyl groups than it did before exercise. Those changes occur in stretches of DNA that serve as landing sites for different kinds of enzymes, called transcription factors, which in turn are involved in turning ’on’ genes already known to be important in muscles’ adaptation to exercise.

JULEEN ZIERATH LIKENS transcription factors to keys that unlock our genes. With those methyl groups firmly in place, transcription factor ’keys’ are prevented from entering those DNA ’locks’. But when the methyl groups are removed, it allows the keys to turn the locks and boosts the capacity of muscle for work. “Exercise is already known to induce changes in muscle, including increased metabolism of sugar and fat”, Zierath says, “Our discovery is that the methylation change comes first.”

When the researchers made muscles contract in lab dishes, they saw a similar loss of methyl groups. Exposure of those muscles to caffeine had the same effect as well, as caffeine induces a release of calcium in a way that mimics the muscle contraction that comes with exercise. However, the researchers don’t recommend anyone to drink a cup of coffee in place of exercise, as it isn’t clear that caffeine has all the other beneficial effects of exercise.

“Exercise is medicine, and it seems the means to alter our epigenomes for better health may be only a skiing tour away”, says Juleen Zierath.

Cell Metabolism March 2012 Medical Science–2013

9


Framsteg Advances DNA molecules are building blocks for DNA origamists.

Some medical uses of DNA origami: Drug delivery Here the nano structure acts like a bag containing active drug molecules. On the outside are molecules that recognise cancer cells, so that the “bag” only opens and delivers its payload when it encounters the proper target.

He folds DNA like others fold paper

DNA origami is a new technique for building nanostructures from DNA that can be used for a wide range of medical research purposes.

Photograph: Ulf Sirborn

“We can use DNA origami to design small structures like those that exist in the body and then study them,” says Sweden’s only DNA origamist, Björn Högberg, researcher at the Department of 10

Medical Science–2013

Neuroscience working at the Karolinska Institutet’s Swedish Medical Nanoscience Center. Dr Högberg designs tiny, nano-scale DNA structures for a wide range of medical research purposes. First he builds digital models of structures on his computer, and

Björn Högberg.

then manufactures them using long, single-strand DNA molecules, bonding them with shorter DNA stands to force them to fold into the required three-dimensional shapes. Proteins or other molecules can then be attached to the new structures. Cecilia Odlind

Cell signalling In one ongoing project being conducted with Ana Teixeira at Karolinska Institutet, researchers are trying to learn more about a the Eph receptor, which is found in relatively high numbers on the surface of certain breast cancer cells. It is believed that the location and density of the receptors on the cell surfaces help to determine which signals the cells transmits to their neighbours. DNA origami can be used to test this hypothesis by creating structures with differing receptor densities. The goal is to learn more about the part these receptors play in breast cancer. Bacteria maps Researchers are trying to make bacteria like E. coli produce special iron-bearing nano-structures, which in turn can be tracked with an MRI scanner. The method could replace more unwieldy methods of monitoring the movement of bacteria in the body.


A researcher’s story

Name: Sten Linnarsson Title: Researcher at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, head of DDPDGENES, an EU project characterizing genes in cells involved in Parkinson’s disease.

He knows all about his DNA

The mapping of DNA sequences is happening all the more quickly as technology develops. Whether genetic preconditions should be mapped, and what that might lead to will be an obvious question in the future. We have talked with a researcher who mapped his own DNA.

Photograph: Mattias Ahlm

P

ersonally I wasn’t worried, but I asked for my wife’s permission before I decided to map all of my DNA. You can find out about hereditary diseases that may affect your future, and that may have been inherited by our children. She said yes. But the list of interesting facts turned out to be very short, large due to my considerable scepticism. As a scientist, I know that there are still large gaps in our knowledge, not least concerning how the combination of different genes affects the risk. You may carry risk genes, but at the same time you may also carry other genes that reduce the risk; the end result is

currently very uncertain. For example, knowledge is increasing all the time. I the results of my analysis showed that think the concern that people will be I have a disposition towards male patupset or depressed by their results is tern baldness, but at 40 years old I still very much exaggerated. But everyone have a fine head of hair. The is different and, as I’m analysis also indicated that familiar with situations like I have a disposition towards these, I’m sure I can assess being tall, which is correct and handle the risk inforas I am 2 metres tall. But the mation. The development of genes could only explain a gene mapping methods is 1½ cm excess above average happening at an incredible height. This shows how pace, and since the 1970s Sten Linnarsson complex these things are, the costs have been halved with many factors intereach year. In ten years I acting to produce an end result – the expect it will basically be free to map same thing is true for, for example, your DNA.” As told to: Cecilia Odlind cardiovascular diseases. However, our

”In ten years I expect it will basically be free to map your DNA.”

Medical Science–2013

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Framsteg A tale of three Xxxxxx researchers Name: Henrik Druid Title: Professor of Forensic Medicine at the Department of OncologyPathology, Karolinska Institutet. Researches: How the diagnostics concerning the cause of death when a person has died unexpectedly or in a manner that the police consider unnatural can be improved.

With death as a colleague In our society we do our best to keep death at bay. Many adult humans have never seen a dead corpse, and do not wish to think about death unless it is absolutely necessary. But some think differently: We have talked to three researchers who have chos-en to work full-time with death. Photograph: Mattias Ahlm

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Medical Science–2013


Framsteg

Xxxxxx

“I can help with the grieving process” “The fact that I became a forensic pathologist, and later a researcher in forensic medicine, was due to a combination of chance and the fact that I wasn’t happy with my work conditions in the health services. As a doctor I did not feel that I could give the time required to my patients, something which I can do as a forensic pathologist. I have carried out around 6,000 autopsies, and in many of these cases I have been in contact with the next of kin. My research include studies aiming at developing better methods to determine the cause of death, something which can be particularly hard when drugs are involved. This

is information for which the next of kin tend to be thankful, and in this way I feel that I can help them in their grief. We try to always make the body look as clean and intact as possible, and I usually recommend the next of kin to see it. I think it helps people understand and accept what has happened. Our view of the dead body is culturally conditioned. I personally saw a dead person for the first time when I was 17 years old. It was my grandmother and it looked peaceful, but also weird and I felt uneasy. In India, where I worked for a while, people have a different attitude. When someone dies, close relatives will take care of the body and take it to the morgue and back when released. Death is there seen as a more natural part of life, and I think we can learn something from these cultures. There is nothing dangerous in seeing or touching a dead person.” Told to: Ola Danielsson

Medical Science–2013

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A tale of three researchers

“I have become less afraid of death” “I started my research on terminally ill cancer patients in the 1980s and I saw that they were not getting the optimal level of support. I felt that I could make a real difference for them, but it was an uphill battle as the issues I brought up seemed alien. Today I think that we have become good at easing physical symptoms, but we are not always as good at tackling existential anxiety related to life and death issues. I try to develop this in my research. The time just before a person passes away is almost always quiet and peaceful. But before that point, many who are near death naturally pass through stages of despondency. Death is a situation that we cannot escape, instead it forces us to choose a perspective. The extremes are allowing

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Medical Science–2013

death to spread out and dominate all aspects of your life, or allowing the reality of death to become the source of an increased feeling of being alive. Today, existential questions have become a natural part of the health services, and through discussions you can help a sick person to rediscover their sources of meaning – and the fact that you can live as long as you are alive. By studying and meeting hundreds of dying people and their next of kin, my own fear of death has decreased significantly, while I still understand and respect people who feel anxiety in the face of the unknown. I have become more aware of the fact that death is a part of life, as a framework that defines that which is inside it – that is to say, life. It has helped me face the big questions in life, about what is important in my life and what is not, and I try to live my life more consciously now, when I am alive and healthy.” Told to: Helena Mayer

Name: Peter Strang Title: Professor of Palliative Medicine, especially Oncology, at the Department of OncologyPathology, Karolinska Institutet, consultant physician at Stockholms Sjukhem. Researches: How to best ease and improve the trying final times of dying persons and their next of kin.


Name: Ulrika Kreicbergs Title: Researcher at the Department of Women’s and Children’s Health, Karolinska Institutet, registered nurse. Researches: How the risk of mental ill health can be reduced among family members when a child dies of cancer.

“Many advised against conducting the study” “As a newly graduated nurse I started working at the children’s oncology ward at the Karolinska University Hospital and witnessed how three young boys died in a short period of time, and how their parents handled this in different ways. It affected me deeply, and I eventually started to research how to best approach parents who lose a child, and what is important to them in our care for the child and the family. Many of my colleagues advised against conducting the study, as they believed it would open old wounds and stir up feelings amongst the parents who had lost a child. But the parents wanted to talk about their experiences, and the study showed that almost all parents felt that the study was valuable, and that not a single parent later regretted speaking to their child about death. The staff should therefore, before it is too late, encourage parents who are unsure about if they should talk to their children to do so especially if the child is aware of his or her imminent death. During the study my children wondered why I did this work when all the stories made me cry. But with the support of family and colleagues I got through it, although I will always carry those stories with me. I do not even want to think about losing my own children, but seeing how parents manage and move on makes me less afraid. Witnessing how children – these young, brave people – have faced death, I too have become less afraid of death. I believe it is easier to learn from children than from adults. Children live until they die and often have a naive view of death, such as it leading them to Nangijala. We have much to thank Astrid Lindgren for.” Told to: Helena Mayer

Medical Science–2013

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Timeline Type 1 diabetes

From voluntary starvation to insulin aid

1000 BC / The Indian teacher Sushruta Samhita describes a disease that he calls ”honey urine”, as the urine tastes sweet and attracts ants.

At the beginning of time, type 1 diabetes meant a guaranteed, painful death within two years. Today it looks much brighter.

100 BC / The Greek physician Aretaeus describes the symptoms, including thirst and large volumes of urine, and explains that the fluid uses the person as a pipe to run through. He names the disease diabetes, roughly translated as ”running through”

1 00 BC

Text: Ola Danielsson

1850

1921 / The blood sugar-lowering hormone insulin is discovered by Frederick Banting and Charles Best who manage to extract it from the pancreases of dogs.

1889 / Scientists discover that the pancreas is disabled when suffering from diabetes. Dogs that have their pancreas removed develop all the signs and symptoms of diabetes and die shortly thereafter.

1875

1900

1925

1922 / The first insulin injection is administered to a diabetes patient, the severely ill 14 year-old Leonard Thompson. In only two hours, his blood sugar levels sank drastically. A year later, around 10,000 patients are treated daily with insulin injections.

Start of the twentieth century / The age of extreme diets. According to one school, starvation is the best way to lower your blood sugar (death could be postponed by up to a year); according to another, your diet should contain no carbohydrates and at least 85 per cent fat. The methods turn out to be about equally useless. Source: Svenska diabetesförbundet (Swedish Diabetic Association), Historien om diabetes och insulinets upptäckt (The history of diabetes and the discovery of insulin), by Tord Ajanki.

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Medical Science–2013


Photograph: Ulf Sirborn

Future challenges What causes diabetes?

If the fundamental causes are discovered, it could be possible to develop preventative treatment strategies and cures.

More beta cells are needed

There is a major shortage of beta cells for research and transplantation. Researchers are trying to solve the problem by growing beta cells from stem cells.

2012

Better transplantation methods

Per-Olof Berggren.

The transplantation of beta cells into a patient currently requires cells from two dead bodies, which is not sustainable. A possible solution is to learn how to transplant beta cells from animals.

T O D AY

The researchers’ goal: preventing autoimmune attacks Unique method monitors the beta cells

1936 / The difference between type 1 diabetes, caused by a lack of insulin, and type 2 diabetes, caused by a resistance to insulin, is described.

Photogrpahs: Istock Photo, Science Photo Library, Ulf Ström

1940

1966 / The first pancreas transplant to a diabetes patient is conducted. Today, more than 10,000 such operations have been conducted. Most patients can stop relying on insulin injections after the transplant, but rejection issues may arise.

1943 / For a long time, insulin was in short supply as it had to be extracted from mammals such as pigs and oxen. During the second world war, the Japanese were able to extract insulin from the giant pancreases of whales.

1975

1974 / The first transplant of islets of Langerhans (groups of insulinproducing beta cells) is conducted. The islets are much simpler to transplant than an entire pancreas, but the lack of glands from which to extract islets is still significant.

1985

The 1980s / Gene-modified yeast fungi and bacteria start to be used to produce insulin. This makes the supply of insulin almost unlimited, and provides cleaner insulin, identical to that produced in humans.

Type 1 diabetes is caused by the insulin-producing pancreatic beta cells being attacked and killed by a person’s autoimmune system, but no one knows exactly why this happens. One dilemma facing researchers is that beta cells in the body are hard to study, whilst lab-grown beta cells cannot answer the question of why the autoimmune system turns against the body’s own cells. Researchers at Karolinska Institutet have recently solved this problem by transplanting isolated islets of Langerhans to the anterior chamber in the eyeballs of mice, where they quickly attach themselves, are provided with vascular and neural connections and can thus be studied in a living organism. An unexpected result of the method, which according to the researchers neither affects the eyesight nor causes pain, is that beta cells in the eyes cure mice that the researchers have made diabetic. ”We are now investigating if beta cells can be transplanted into the eyes rather than the liver of diabetes patients, which is what we currently do. This could mean that immunosuppressive agents can be administered directly, locally to the eye in the form of eye drops, which could mean lower concentrations and consequently less severe side effects,” says Per-Olof Berggren, Professor at the Department of Molecular Medicine and Surgery, the Rolf Luft Centre, Karolinska Institutet. Medical Science–2013

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Advances

Study shows efficacy of new rheumatoid arthritis drug

Anders Behring Breivik’s violence would have been difficult to predict with the current assessment methods according to researchers at Karolinska Institutet.

Difficult to predict violent crimes

It is easier to predict those who probably will not become violent than those who will, new research shows.

Photograph: Scanpix, Istock Photo

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t is always difficult to predict the future, but such predictions are needed within psychiatry, forensic psychiatry and the correctional services, for example, to be able to evaluate whether or not a person should be granted probation. But the assessment instruments that are used, where various risk parameters such as gender, substance abuse or previous history of violence are weighed, tend to be unreliable. Martin Grann, Adjunct Professor of Psychiatric Epidemiology at the Centre for Violence Prevention, the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet has, alongside American and British colleagues, compiled 73 studies from 13 countries, encompassing a total of 25,000 assessments of the future propensity of men for violence, using nine Martin Grann. different assessment instruments. All turMedical Science–2013

ned out to be lacking in some respect. “We noted that they were able to predict, with a 91 per cent certainty, whether or not a person risks committing a violent crime. But when it comes to predicting if the person in front of you is dangerous, the instrument only has a reliability of 41 per cent, says Martin Grann. Classic persistent offenders have a good chance of being spotted, unlike the �needles in the haystack�. “For example, you wouldn’t have spotted Breivik,� he says. But the main message is not to stop conducting assessments of persistent offenders. “They are needed, but it’s important to keep their shortcomings in mind. The exaggerated optimism surrounding them is partially fueled by commercial interests, as entrepreneurs in the field make a living on selling training programmes in how to use various instruments,� says Martin Grann.   Lotta Fredholm British Medical Journal July 2012

A new study demonstrates the efficacy of Tofacitinib, a new drug for rheumatoid arthritis. According to the study, which is published in The New England Journal of Medicine, the drug is just as effective as biological medicines, but unlike them can be taken in tablet form. The present study was a phase III trial of Tofacitinib, and included 717 people with rheumatoid arthritis. The participants were divided into three groups, who received either a high or low dose of the drug, the already approved substance Adalimumab, or a placebo. Adalimumab is a biological drug, one of a group of substances that were introduced onto the market at the end of the 1990s. AFTER SIX MONTHS , the patients who had been given Tofacitinib showed most improvement according to the ACR20 criteria, a composite assessment of the patients symptom profile. Over 50 per cent of those who had received Tofacitinib had gained some symptom relief, compared with 47 and 27 per cent in the Adalimumab and placebo groups respectively. “The new substance, Tofacitinib, has thus proved to have Ronald van an efficacy on par Vollenhoven. with the biological Photograph: Ulf Sirborn drugs,� says Ronald van Vollenhoven, Professor of Clinical Therapy Research, Inflammatory Diseases at Karolinska Institutet. “This finding is very welcome as we need more efficacious drugs for treating rheumatoid arthritis.�

New England Journal of Medicine August 2012


Scientists tackle highly lethal infections Common bacteria that end up in the wrong place kill and disfigure hundreds of people of all ages in the Nordic region every year. A new research project on serious deep tissue infections will now seek to find out how this can be avoided.

Photograph: Istock Photo, Ulf Sirborn

B

acteria that normally cause uncomplicated infections like tonsillitis can, in rare cases, lead to necrotising soft tissue infections, a feared and rapidly progressive form of deep tissue infection. The disease, which is estimated to strike around one hundred people every year in the Nordic region, can lead to amputation and, in over 30 per cent of patients, death. To explore the causes of these severe processes, Karolinska Institutet is Anna Norrbylaunching a new EU-funded project, Teglund. Photograph: INFECT. Camilla Svensk “We will be studying the entire course of events, from how the patient is first identified to how Amputation can in rare cases be the result of normally uncomplicated bacteria and host-specific infections. Researchers try to understand the mechanisms behind this. properties influence the progression of the disease in time and space,” says Professor Anna Norrby-Teglund, who is co-leading the project with Dr Mattias Svensson, Docent, both at Karolinska Institutet’s Department of Medicine Huddinge. A key pArt of the project is to establish a patient registry in order to produce guidelines for classification and treatment. The researchers also hope to create quicker diagnostics and new, improved therapies. Participating in the project are 14 partners from Swedish, European and American universities and hospitals. cecilia odlind

Read more about the project: www.fp7infect.eu

Gene switch important in cancer discovered Scientists at Karolinska Institutet and the University of Helsinki in Finland have shown that the ’switches’ that regulate the expression of genes play a major role in cancer. In a study, conducted in mice, scientists analyzed one particular single nucleotide variant in a region associated with increased risk for developing colorectal and prostate cancers, but whose mechanism of action has been unclear. The scientists removed the gene region containing the risk variant from the mouse genome. They then found that when these mice were tested for the ability to form tumours after activation of an oncogenic signal that causes colorectal cancer in humans, they showed dramatic resistance to tumour formation. The removed gene region thus appears to act as an important gene switch promoting cancer, and without it tumours develop much more rarely. “Our study highlights that growth of normal cells and cancer cells is driven by different gene switches, suggesting that further work to find ways to control the activity of such disease-specific switches could lead to novel, highly specific approaches for therapeutic intervention”, says Jussi Taipale, Professor at the Department of Biosciences and Nutrition, who led the study. Science November 2012 Medical Science–2013

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Framsteg A researcher’sXxxxxx story

I

t wasn’t until I studied rheumatology that I realised that I was actually suffering from the disease myself. It was a relief to have an explanation for the symptoms that I had experienced since my teens, but which my doctors had ignored. Through my studies I learned that patients with rheumatism should only use static exercise, i.e., exercise that does not combine weight with movement. But this was alien to me, who led an active life and felt good as a result. As a patient, I did not understand what physiotherapy could offer me and instead I tried my own methods. Since I was convinced that physical activity was positive for most rheumatic patients, I decided to

“I was convinced that it was good to exercise”

She knows what she’s talking about Most medical researchers are driven to find cures and treatments for various diseases. We met a researcher whose career started when she herself became ill. As told to: Cecilia Odlind Photograph: Mattias Ahlm

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write my thesis on this subject. It was considered controversial at the time. Thanks to having such a clear goal – investigating whether or not physical activity could have the reverse effect to that which was currently believed to be the case – it was easy for me to get involved with the research as a doctoral student. Today we know, thanks to my own research and that of others, that physical activity is positive for persons with rheumatism – both physically and mentally. A great deal of our research now concerns how to ensure that patients exercise regularly. To personally have the disease has meant that patients and test subject trust me more, as I know what I am talking about. When it comes to my own physical activity, I guess it’s like it is for most people, it has its ups and downs. I’m currently looking for a new form of exercise to get my motivation back.” Name: Christina Helging Opava. Title: Professor of Physiotherapy at the Department of Neurobiology, Care Sciences and Society. Researches: Physical activity and health in connection with rheumatic diseases.


Advances Induced stem cells, adult skin cells that have been genetically reprogrammed to mimic embryonic stem cells. The work was accomplished by researchers in the laboratory of James Thomson at the University of Wisconsin-Madison, USA.

Reversing cells move brain research forward Just as a train can reverse, change track and carry on in a new direction, cell development can be re-routed by scientists. The technology behind induced pluripotent stem cells (iPS) is now gaining a foothold in the research establishment. Anna Falk, researcher at the Department of Neuroscience, Karolinska Institutet, uses the technology to study mental impairments and brain diseases. It is almost impossible to acquire brain cells from patients. She therefore creates them herself in a laboratory by converting patients’ skin cells into stem cells, and then into nerve cells. These nerve cells have the same DNA and muta-

tions as the patients’ normal nerve cells. “From a single tiny skin sample we can Anna Falk. produce an Photograph: unlimited Ronny Falk number of cells that are relevant for the disease that we want to study. With the right

methods, iPS cells can be transformed into any bodily cell you would like,” says Anna Falk. Other uses include research concerning medicinal effects on various cell types and basic research into stem cells, which are also hard to acquire but which can now be created through the reprogramming of normal cells. In the future, researchers might be able to transplant reprogrammed cells to combat various diseases, for example, diabetes or Parkinson’s disease. Anna Falk is also the head of a new facility that will help researchers at Karolinska Institutet to reprogram cells in their research.

“The reprogramming of cells opens fantastic new possibilities – but it is resource-intensive. It takes four months to transform a skin cell into a stem cell, and a further three months for it to mature into the cell that you want to study,” she says. Ola Danielsson The Nobel Prize in Physiology or Medicine 2012 was awarded jointly to Sir John B. Gurdon and Shinya Yamanaka for the discovery that mature cells, for example skin cells, can be reprogrammed to become stem cells that, in turn, can be cultured into other cells, for example nerve cells. Medical Science–2013

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Malaria

Cause: Single-cell parasites, spread by the blood-sucking mosquitoes of the genus Anopheles. Symptoms: Shivering and sudden fever, nausea, vomiting, headache, diarrhoea, myalgia and a general feeling of discomfort. Since the malaria destroys red blood cells, the parasites cause anaemia in the infected person. If treatment is delayed, patients may die of cerebral malaria and other complications. Affects: 220 million people are affected, and around 780,000 die each year, mainly children under five years of age. The disease is most wide-spread in sub-Saharan Africa.

A k i r A k A n E ko ’ s d r E A M :

The Eradication of Malaria Akira kaneko will not rest until the island is free of malaria. After having eliminated malaria on an isolated island in the outer reaches of the global malaria epidemic, it is time for the next challenge – the severely malariastricken islands in Lake Victoria, kenya. Text: ola danielsson Photograph: Jezzica Sunmo

Man’s enemy no 1.

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northwest, but Aneityum is still very isolated. The influx of potentially infected persons is limited to a few small aircraft and boats per month. The lack of road traffic means that the villages on the island are also relatively isolated from each other. The island was a perfect microcosm for combating malaria. AkirA kAneko commenced his work and established an organisation for his project. All 718 islanders were involved. “It was very important to involve the local population. They had to understand that the project could only succeed if everyone collaborates. Even persons who do not exhibit any symptoms must take their medicine, in order to stop the parasite from spreading to others,” says Akira Kaneko. And as if curing malaria was not challenging enough – the island’s mosquitoes also needed to get rid of the malaria parasite. To do this, combined measures were taken just before the rainy season, when mosquitoes breed and the malaria parasite risks being transferred from infected persons to new mosquitoes. The islanders were weekly massmedicated for nine weeks, in order to remove the malaria parasite from their blood. During the same period, impregnated mosquito nets were installed in their simple houses. In order to decimate the annual army of newborn mosquitoes, researchers also planted fish that like to eat mosquito larvae in ponds around the island. There was then a long surveillance period, to ensure that the disease

Photograph: Istock Photo

A

s mosquitoes ignore human boundaries, fighting malaria might seem like a hopeless project. Many ambitious attempts to eradicate the disease in various places around the world have ended with the parasite invading once again from adjacent areas. These bitter experiences shaped his view of combating malaria, when Akira Kaneko moved to the Vanuatu group of islands in the Pacific Ocean in the 1980s. He had been hired by WHO, the World Health Organisation, to work on the malaria control programme in the area. “It was a demoralising time. The WHO had given up trying to eradicate malaria and focused instead on reducing the spread of the disease. Few believed that the disease could be eliminated,” says Akira Kaneko, newly appointed Professor of Global Health at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. But he knew of a boundary that mosquitoes do respect – water. A mosquito who sets off to sea will not get more than a few kilometers before it falls into the water and dies. The possibilities of using this boundary were especially good on the small island of Aneityum. Not only is it on the outer reaches of the island group, it also marks the outer boundary of the global spread of malaria. Southeast of Aneityum, there are no mosquitoes that can carry malaria. There are other malaria-stricken islands to the


Akira Kaneko looks to his next challenge.

did not return. Anyone getting off the small plane was met, and still is to this day, by a microscopist who examines the blood of all passengers. By the year 2000, Akira Kaneko and his colleagues could report in The Lancet that they had succeeded. No trace of the malaria parasite Plasmodium falciparum could be found in the islanders’ blood samples following the mass-medication. They could also show that from the year 1996, the other malaria parasite present in the area, Plasmodium vivax, had also disappeared completely. “I believed it would work all along, but obviously I was overjoyed when I saw the results,” says Akira Kaneko. Aneityum has even had a small tourist boom after proclaiming the island to be free of malaria. Every other week, a boat load of travellers arrive to unwind on the small pacific island. Akira Kaneko looks pleased as he shows us diagrams of how the number of visitors has increased as the occurrence of malaria has decreased. “It is very gratifying. Some of the tourist money goes to the malaria project and is used to prevent the disease from returning,” he says.

For his next project, Akira Kaneko plans to take on an island in Lake Victoria in Kenya. The area suffers greatly from malaria, and constitutes a much bigger challenge. Vanuatu is the isolated outpost of the malaria epidemic. Lake Victoria is the opposite – it was there that malaria originated with the first humans and spread throughout the world. The area is currently teeming with different cultures and is characterised by major genetic diversity, both amongst humans, mosquitoes and malaria parasites. This makes combating malaria a more complex project, since new medicines need to be combined, for example. Akira Kaneko has developed an action plan after several visits to the island, but the financing is still unresolved. Many researchers have been inspired by the success on Vanuatu, and the eradication of malaria is once again a stated goal for the WHO. The obvious final question in Akira Kaneko’s story is whether his methods could be used to eradicate malaria on the mainland, and maybe one day on a global basis. “It’s possible, but it won’t be easy. It requires hard work, resources and money,” he says.

“It was very important to involve the local population. They had to understand that the project could only succeed if everyone collaborates.”

Medical Science–2013

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“We must be one step ahead” Heat-waves, the contamination of recreational waters and the dispersal of infectious diseases. Climate change is already affecting our health, and further effects are in the pipeline. Text: Annika Lund

Photograph: Johnér bildbyrå

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n the summer of 2003, a heatwave swept across Europe. The heat claimed many lives; up to 70,000 people, mainly the elderly and those suffering from heart disease, were estimated to have died as a direct result. “It was a wake-up call for our politicians. It was suddenly clear that we need to have a plan for how our health is being affected by the changing climate” says Dr. Elisabet Lindgren at the Institute of Environmental Medicine at Karolinska Institutet. Recurrent heat-waves are to be expected in Europe. We can also expect extreme rainfall which can flush contaminants into drinking and bathing water. Emerging infectious diseases will also pose new challenges for public health. Along with other researchers,

Medical Science–2013

Elisabet Lindgren has analysed more than 30 infections that are expected to spread throughout Europe as a result of climate changes. The analysis was conducted at the request of the European Centre for Disease Prevention and Control (ECDC) and was recently published in the academic journal Science. A risk assessment was conducted, weighElisabet Lindgren. ing up the infecPhotograph: tions’ association Ulf Sirborn with climate change against their impact on society. More prevalent infections or more serious symptoms were considered as having a significant impact on society. Using these criteria, seven climate-related

infections were highlighted: leishmaniasis, chikungunya fever, Rift Valley fever, dengue fever, TBE, vibrio and Lyme disease. “These climate change-sensitive infectious diseases are considered to be especially significant threats to society, due to the lack of appropriate surveillance” says Professor Jan Semenza, the senior investigator on the research team and an Jan Semenza. employee at ECDC in Photograph: Ulf Sirborn Solna. All these diseases, apart from vibrio, are spread via vectors, i.e. insects or other animals that can carry disease. One example is the invasive tiger mosquito; this insect is currently established in Italy, France and Switzerland and has even been found in greenhouses as far north as the Netherlands. In 2007, Italy had an outbreak of chikungunya fever. It started with one man being infected abroad; when he returned to Italy, he was bitten by local tiger mosquitos which then infected over 200 other people, resulting in one death. Europeans have also contracted dengue fever at home, as a result of it being spread locally in France and Croatia by domestic tiger mosquitos. In these cases, the authorities concerned were well aware that there was an abundance of tiger mosquitos in the area which made it possible to stop the spread of the infection by combating the mosquitos and isolating those who had been infected. Dr. Lindgren and her colleagues are now recommending vector surveillance to monitor the mosquitoes. In order to better control the spread of the seven highlighted risk diseases, researchers suggest that a duty to report them be implemented across Europe. This, combined with vector control measures, should provide a very good picture of where outbreaks can be expected. This will allow local information and health care measures to be implemented quickly, in the event of an outbreak of the disease. “We need to be one step ahead” says Dr. Lindgren.

The researchers’ recommendations are currently being discussed by the European Commission.


Photo: university of toronto

GivinG to KarolinsKa institutet

MaKe a gIft

Former national ice hockey captain and nHl professional Mats sundin celebrating his induction to the Hockey Hall of Fame, toronto, together with the Director of Karolinska institutet Development office, Dr Mikael Horal. Mats sundin has previously made an initial contribution of 330 000 usD to establish an elite scientific exchange program between Karolinska institutet and the university of toronto.

People’s health and quality of life is what drives Karolinska Institutet. Through our history we have contributed to vital medical breakthroughs, that have helped to alleviate human suffering. We are determined to pursue this endeavor with undiminished energy. With your support we can realize our visions! Thanks to generous gifts from Swedish and international friends, Karolinska Institutet is continuously breaking new ground. If you share our vision to create a future with better health and quality of life for everyone, please do not hesitate to contact us. We are eager to listen to how you would like to become involved in helping us to achieve tomorrow’s medical breakthroughs.

BANK TRANSFER From abroad: Bank account: 5439-10 286 89 IBaN: Se 12 5000 0000 0543 9102 8689 SWIft CODe: eSSeSeSS Bank address: SeB aB, Se-106 40 Stockholm From Sweden: Bank transfer account (”bankgironummer”) 5310-6217

Donate on-line: ki.se/donate

For US citizens: for further information on tax exemption for your gift to Karolinska Institutet, please contact: Mikael Horal Director, Development Office Karolinska Institutet telephone: +46 (0)8 524 865 13 Mobile: +46 (0)70 824 20 14 e-mail: mikael.horal@ki.se


T h e m e : p r e m aT u r e ly b o r n

From survival to a vision of

Lifelong health Text: Fredrik Hedlund Photograph: Martin Stenmark

The last 40 years have seen major advances in neonatal care - what could only be dreamed of in the 1970s is now routine, which has resulted in a dramatic increase in the survival rate for premature babies. There are now as many as 100,000 under-18s in Sweden who were born prematurely, and the big question is: What happens next?

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Photograph: Lennart Nilsson, Scanpix

g


L

T H E M E : P R E M AT U R E LY B O R N

LESS THAN A YEAR AFTER Annette and Dan Landgren had lost a daughter to a late miscarriage at 26 weeks, they were expecting a child again. And once again, something was amiss. The baby was due in mid-August but by the beginning of April something was wrong. Annette had already begun to dilate and was admitted to Helsingborg General Hospital for observation. However, nothing happened and everything seemed to be under control for a few weeks. But suddenly her waters broke one morning and she was rushed by ambulance down to Lund where doctors tried to stop the labour. Which they did – but only temporarily. In the early hours of the following morning she gave birth to a little boy, three and a half months early. Born in week 24, he was just 28 cm long and weighed a meagre 670 grammes. The doctors in Lund had already explained that there were no guarantees that the baby would survive, and that he would have to show clear signs of life for them to go ahead with treatment. He did just that, and 11 years on Eliott Landgren is today a lively lad at secondary school. He is one of the “new survivors” as Swedish doctors call them. “Before 1970 over 90per cent of all babies under a kilo died, whereas today almost 90per cent survive,” says Hugo Lagercrantz, Professor of Paediatrics at Karolinska Institutet and former head of neonatal care at the Astrid Lindgren Children’s Hospital in Stockholm. Every year 6per cent of all babies born in Sweden - around 6,000 in total - are delivered Hugo Lagercrantz. prematurely, and nePhotograph: arly all now survive. As Stefan Zimmerman such, there are a large number of premature babies who are living and growing up in Sweden. “It’s no longer rare,” says Lagercrantz. “We now have around 100,000 under18s in Sweden who were born prematurely.” It is often difficult to pinpoint exactly why a baby is born prematurely in individual cases, though researchers have identified a number of risk factors

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at group level. The most important of these factors is genetic - 20-30per cent of all premature births can be attributed to genetics. Others include socioeconomic background, smoking during pregnancy, infection, overweight, twins, and maternal age, be it very old or very young. “Ideally mothers would be 24 when they give birth, but it’s not that common these days in Sweden,” says Lagercrantz. “Apart from among immigrants, who frequently have babies at this age, and also have fewer problems in this respect.” Although many of the risk factors for premature birth have changed over the last few decades - smoking, for example - the proportion of babies born prematurely in Sweden has, strangely enough, held steady at around 6per cent since the Swedish Medical Birth Register was set up in 1973. It may well be that improvements in some areas have been offset by a deterioration in others, but this is something that researchers do not currently have answers to. Annette Landgren has yet to be given an explanation as to why Eliott came as early as he did. “They did loads of tests on both Eliott and me, but they didn´t pick up on anything unusual,” she says. “And the fact that we lost our first child had nothing to do with Eliott’s early arrival, according to the doctors.” PREMATURE BABIES ARE NOT fully developed and are not ready to come into the world. “It’s a huge leap from being a foetus on the life-support system that is the placenta to coming out and making it on their own,” says Mats Blennow, Adjunct Professor of Perinatal Brain Research at Karolinska Institutet and Paediatrician at Karolinska University Hospital, Huddinge. “It’s remarkable that it works out as often as it does.” Blennow researches how the newborn brain can be protected from

“Ideally mothers would be 24 when they give birth but it’s not that common these days in Sweden.”

conditions such as hypoxia, which is often down to how the lungs and the brain work together. In extremely premature babies - those born between 22 and 27 weeks - the lungs are still immature. The majority, even among the tiniest of babies, can actually breathe themselves immediately after birth, but their lungs are unstable and the alveoli collapse after Mats Blennow. every breath. Unassisted, their breathing is often unable to oxygenate the brain and the body, and these babies develop respiratory distress syndrome (RDS), which can be fatal. It has long been standard practice to pump oxygen into incubators. However, it is difficult to control oxygen levels in babies and many sustain damage to the retina known as retinopathy of prematurity (ROP), which results in impaired vision or total blindness. Respirators were introduced in the 1970s to help babies breathe, a move that produced mixed results. They were then supplemented with an oxygen tube with continuous positive airway pressure (CPAP) to keep the lungs inflated. This produced better results, though some children were still affected by ROP on account of excess oxygen. The alveoli collapse in immature lungs because they have yet to start production of a surfactant that normally coats each alveolus and supports it during exhalation. Following several significant breakthroughs by various researchers around the world, Swedish doctors Bengt Robertson and Tore Curstedt, both from Karolinska Institutet, managed to produce a surfactant from pig lungs in the mid-1980s. This was approved as the medicine Curosurf (Curstedt-Robertson surfactant) in 1993. This halved the number of deaths in extremely premature babies and was a huge step forwards for neonatal care. When it was then discovered that it was also possible to shock-start babies´ own production of surfactant by giving mothers a high dose of cortisone immediately before birth, the effect was even better. But practitioners were still stuck in the traditional approach when it came to using the treatment. “The surfactant was given only where CPAP and respiratory care weren´t suf-


Annette and Dan Landgren show their son Eliott what it was like when he was at the neonatal care unit in Lund. ”I was the size of a pack of butter”, he says.

ficient,” says Blennow. “Then someone realised that if the problem was that the babies didn´t have surfactant, why not give it to them immediately?” He recalls very clearly the first time he used the method after reading about it in a scientific journal. It was New Year’s night, 1998. “It went amazingly well - the baby picked up immediately, and then I went out into the magnificent night and the entire hospital was enveloped in frost. It was just beautiful,” he says. As with the lungs , the brains of extremely premature babies are very immature. Instead of the traditionally crumpled walnut-like cerebral cortex, the brain in these children is still completely smooth, the signals travel slowly and the networks are not yet particular-

ly well developed. “The difference between the brain of an extremely premature baby and that of a full-term baby is greater than the difference between the brain of a full-term baby and that of an elderly person with dementia,” says Blennow. “So there are enormous changes taking place while they´re in our care.” This is why many neonatal wards try to do as much as possible to replicate the womb - the optimal environment for the brain’s development, as Blennow likes to call it. This involves being warm and snug, dark and fairly quiet. Doctors and other staff try to take samples and do tests when the babies are awake and can cope with them. The premature brain does not yet have a system for protecting itself against major swings in blood pressure,

which means that very high blood pressure can lead to cerebral haemorrhages, and very low blood pressure to brain damage caused by lack of oxygen. One in three extremely premature babies suffers at least one cerebral haemorrhage while in hospital, but fortunately the bleeding tends to be in a part of the brain where it does not result in any lasting problems. Two out of three babies who suffer a haemorrhage at an early stage generally come through without any problems whatsoever. Ulrika Ådén is a Docent at Karolinska Institutet and Paediatrician at Karolinska University Hospital, Solna. She researches factors that have a negative impact on the premature brain’s development during the early stages, the consequences as the children get older, and what can be done to reduce the Medical Science–2013

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T H E m E : p r E m AT U r E Ly b o r n

other children. But even though these conditions are more common in this group, most of the children develop well.” Children who are born prematurely and have their brain developed outside the womb do not necessarily have some form of brain damage. When slightly older children Ulrika Ådén. Photograph: who were born premaEva Gripstad turely do IQ tests they fall on a normal distribution curve, just as with other children, albeit shifted a little downwards. “This means that the group as a whole has a slightly lower IQ than other children, but also that some of the children in the group have a normal IQ and some have a high IQ,” says Ådén. In tHe case of elIott landgren,

Likes to be close. Eliott Landgren often wants to sit near his parents and feel physical contact. Here with his mother Annette.

risk of this negative impact. Ådén and her research group therefore monitor children as they go through school to see how they develop and how well they get on. “We have, for example, discovered that those children who need an operation for an open ductus - the blood vessel that links the pulmonary artery to the aorta as a foetus, but should then be shut off - are several times more likely to be affected by brain damage,” she says. ”Now we´re going back to see whether we can improve the ductus operation to minimise the risk.” Her researcH group is also part of a major national study where all babies born extremely prematurely in Sweden between 1 April 2004 and 31 March 2007 are monitored as they grow up. “We´re currently looking at them aged six and a half,” says Ådén. ”The 30

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results aren’t ready yet, but most of them seem to live a good life without any obvious physical problems.” “But when we do neuropsychological tests we can see that many of them have problems with their working memory, for example. Attention-deficit problems similar to ADHD or autism are also more common in this group than in

“eliotts school friends have been fantastic. It’s amazing how they rally round and help him.”

things have gone both well and not so well. His time on a respirator resulted in damage to his retinas, which means that his vision is now very impaired. He has an assistant who acts as an extra pair of eyes at school, as well as cameras that magnify the whiteboard and text in books onto screens where he sits. However, he goes to a normal school and follows a normal curriculum. “Eliott’s school friends have been fantastic. It’s amazing how they rally round and help him,” says his father Dan Landgren. The way they make life easier by describing things to him is completely natural.” Eliott did not have any cerebral haemorrhages while in hospital and avoided infections during his first three weeks. But he did have a ductus operation when he was three weeks old, albeit without complications. School is going well and he has no problems keeping up in most subjects. “He’s struggling a bit with English at the moment, and handwriting too,” says Landgren. “But they do groupwork in class and everyone wants to work with Eliott as he’s by far and away the fastest at typing on the computer.” The care of premature babies has made enormous progress over the last 40 years. Had Eliott been born just 20-30 years earlier it is unlikely that he would


Parental contact reduces time in hospital

Annika Örtenstrand. Photograph: Miami Parik

and worry felt by the parents. It’s therefore important for parents to be on the ward so they can get the help and support needed to gradually increase their involvement.”

Family-centred care, where parents live on the ward 24/7 with their premature baby, has been an option in Stockholm for a number of years. Paediatric nurse and researcher Annika Örtenstrand has studied what effects this has. Why is family-centred care important for premature babies? “All babies in hospital need their parents, and parents need to be near their babies. Otherwise there is a risk of the bond between parent and child being delayed or maybe never materialising. This may be down to the child, but may also be due to the stress

have survived. It was simply not possible to save such small premature babies. “When I was training at St Göran’s Hospital in the late 1970s the doctors said that we just weren´t interested in babies weighing less than a kilo,” says Mats Blennow. SWeDeN HAS lONg BeeN among the frontrunners in neonatal care and currently has one of the highest survival rates in the world for extremely premature babies. “This is partly because we enjoy a good standard of living and partly because we have good neonatal care that is well organised,” says Mikael Norman, Professor of Paediatrics with a special focus on Neonatology at Karolinska Institutet, and Operational Head of neonatal care on the wards of Karolinska University Hospital.

Your study shows that, on average, family-centred care enables premature babies to go home five days earlier. So is it really just a way of saving money? “As far as I’m concerned, it’s great that there are savings, but it isn´t the main aim, just an added bonus. Babies shouldn´t spend any more time in hospital than they have to - there’s so much in a hospital environment that can have negative effects. The quicker they get out, the better.” What support do parents get? “NIDCAP is a way of learning to read signs of wellbeing and stress in the infant, and is a very important part of family-centred care. Babies who are born prematurely or are ill after delivery put out weak or immature signals,

Recent figures show that 85 per cent of live births in week 26 in Sweden survive. They weigh, on average, one kilo. The earlier a baby is born, the lower the chances of survival, but no fewer than 82 per cent survive in week 25, 67 per cent in week 24 and just over 50 per cent in week 23. There is then a gap as barely 10 per cent of live births in week 22 survived between 2004 and 2007. And this appears to be where the line is drawn - there is no reliable evidence that babies born in Mikael Norman. week 21 have survived, Photograph: be it in Sweden or Stefan Zimmerman anywhere else in the world. The improvement in survival rates for increasingly premature babies, combi-

so parents need a lot of help with learning how to interpret their childs needs and respond to them.” How does NIDCAP help premature babies? “There is much to suggest that time on a respirator is reduced, as is time in hospital, and the child’s cognitive development is positively affected. The brain in very premature babies is delicate, and this method can ease the burden. So it’s an important method in neonatal care.” Is care for premature babies now as good as it can get? “We’ve come a long way in Stockholm in terms of the childs environment, but we need to work more on guidelines and attitudes so that all parents get the support they need to participate safely in their child’s care.

ned with Swedish abortion legislation, does however highlight the question of when a foetus becomes an individual, a person. Under Swedish law, a woman may, with permission from the Swedish National Board of Health and Welfare, abort a foetus up until week 22. However, babies born in week 22 do actually survive on the neonatal wards. This is an ethical dilemma that the doctors approach in slightly different ways. “The ultrasound dating scans for babies are often accurate to within one or a few days, but can also be up to a week out, which is why I think that it’s strange that we have these regulations,” says Mikael Norman. ”On one floor of the hospital we´re aborting foetuses and on another we´re looking after them in intensive care, and both are legal here in Sweden.” “I personally think that it is probleMedical Science–2013

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matic that the limits are so close to each other, especially when survival rates for babies born at 22 weeks have increased over the last two to three years.” “Yes, it is an ethical dilemma, but abortions after week 18 are done only in tragic, complicated circumstances that always require special dispensation,” says Mats Blennow. “Juxtaposing them with the fact that some babies survive at week 22 is oversimplifying the problem.” Ulrika Ådén objects to the notion that there can be a set time for when a foetus becomes a person. “I view all my patients as individuals,” she says. ”It’s more about giving it everything we´ve got if we can see that things might work out. In which case, we view the baby as an individual, of course we do.” Hugo Lagercrantz feels much the same way and thinks that the issue is more an artificial journalistic construct than an actual medical dilemma, at least for him. “Not until birth does a baby awaken from its foetal slumber and develop

Eliott Landgren suffered from “retinopathy of prematurity”, ROP, during the neonatal stage which severely affected his vision. But with technical assistance and a personal assistant he can still attend a regular school and he is happy about that.

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human consciousness. A foetus is not conscious or a person in that way. Which is why setting the abortion limit at 22 weeks is quite appropriate, as it isn´t possible to survive outside the womb before then.” All four do, however, agree that the limit has now been reached and that it is neither possible nor desirable to save babies who are born more prematurely than this. Instead, the future Is about

taking the long view when it comes to these children and their health. To date everything has been so focused on the initial period after the birth that it has almost been forgotten that these babies then grow up. Together with Ophthalmologist Lena Jacobson, Lagercrantz wrote an article last autumn for Swedish national newspaper Dagens Nyheter emphasising that premature babies often fall between two stools as they can develop problems that are too great for normal schools to cope with, but not sufficiently bad to warrant special schooling.

“People talk about miracle babies and are so happy, but when they hit school age there can be a whole host of problems - problems that are often different to normal disabilities, says Lagercrantz. They can have problems with their vision and dyscalculia, where they find it hard to work with numbers. They can have special disabilities that make it hard to find their way to the classroom, or to recognise teachers and classmates. Children with cerebral palsy, or who are blind or deaf, are catered for, but that’s just not the case for these children.” However, studies show that most premature babies who survive to school age have a fairly positive outlook. Although they have some disabilities they are often quite content with their life. And if they grow up in a secure environment with good support from home, they cope almost as well with school as their full-term friends. “So it’s not a case of saving loads of children only to condemn them to a life of misery. No, that’s not the case at all,” says Lagercrantz. Researchers are now also looking at


how these children get on after they leave school. “As a group they´re slightly worse off than their full-term peers: they earn a lower average wage, a lower percentage are university-educated, and psychological disorders are slightly more common, but most live entirely independent lives,” says Mikael Norman. “They´re also at greater risk of cardiovascular disease, high blood pressure and diabetes as adults, though we don´t yet know what’s on the cards when they reach middle age or old age. They´re a new type of survivor and we haven´t got many generations to draw on in our research, so we just don´t have that knowledge at the moment.” FuRTHERMORE, THE PREMATuRE

babies now entering middle age were born in the 1960s and 1970s. Given that neonatal care has made such enormous advances since then, it is far from certain that the knowledge gained from this cohort about the increased risk of health problems and will actually apply to premature babies born today.

“It’s partly about giving babies a better supply of nutrition - even though we think we’re doing our best, it isn’t good enough.” The researchers´ primary focus now is to develop neonatal care to minimise the health risks of starting life prematurely. Norman pinpoints three clear areas for improvement. “It’s partly about giving babies a better supply of nutrition - even though we think we´re doing our best, it isn´t good enough. It’s also about staying clear of infection. It’s not OK for some babies to get septicaemia and die. Which is why Karolinska University Hospital has set up a five-year plan that aims to ensure that nobody gets care-related infections.

“Finally, we have to improve care and reduce stress during the new-born period. We think that much of the stress that these children frequently feel is because they were very stressed while in care, and this leads to a kind of oversensitivity that they can´t get rid of. “Once we´ve made improvements in these three areas, I think we´ll see a reduction in the long-term health problems of children born prematurely.” In the meantime, Eliott Landgren is taking one day at a time. He is playing games on the computer and might go out with his father on the tandem a bit later. But what the future holds for him when he grows up is not something that he dwells on. “He won´t be able to drive, we know that,” says mum Annette. ”When we´re in Lund for an eye appointment he usually says that he´d like to be a scientist or an eye doctor.” “But right now he quite fancies being a baker,” says dad Dan. ”He doesn´t really have any special aspirations like I did as a kid - he lives very much in the here and now.”

Premature babies who have changed the world Being born early may not be the best start in life, but it hasn’t stopped history being littered with premature babies who have gone on to change the world. Here is just a selection:

Johannes Kepler, the German astronomer and mathematician, was born two months early on 27 December 1571. His IQ has been estimated at 160 (the average is 100) and his laws of planetary motion would help Newton to develop his theory of gravity.

Isaac Newton, the English scientist behind the theory of gravity, was born prematurely on Christmas Day 1642 weighing just three pounds (1.3 kg).

Victor Hugo, the French writer best known for the novel Les Misérables, was born on 26 February 1802 and was, according to his mother, “no longer than a knife”. She is said to have ordered him a cradle and a coffin at the same time.

Mark Twain, the American author of The Adventures of Tom Sawyer, was born two months prematurely as Samuel Langhorne Clemens on 30 November 1835.

Albert Einstein, the German scientist who developed the theory of relativity, was born three weeks early on 14 March 1879 and went on to be awarded the Nobel Prize in Physics in 1921.

Stevie Wonder, the American musician and composer, was born prematurely on 13 May 1950. Like many premature babies, he was affected by retinopathy of prematurity (ROP), which caused him to be blind. Source: Life’s Little Treasures Foundation and Wikipedia. Medical Science–2013

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Interview

She knows all about the right way of life The question is which is worse: the sedentary lifestyle of the Swedes or the ongoing dietary infatuation with saturated fats. Mai-Lis Hellénius believes that both are dangerous to our health and she is not afraid to argue this.

Text: Lotta Fredholm Photograph: Mattias Ahlm Medicinsk Medical Vetenskap Science–2013 №2–2012

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Maj-Lis Hellénius takes the stairs up to her office on the 6th floor.

IT IS A DAY LIKE ANY OTHER and Mai-Lis Hellénius has just run up the six flights of stairs to her office at the Department of Medicine, Solna research division. She does this all the time, but not usually in a shimmering grey dress and leopard-print high heels . And she does not usually sit in her chair and fan herself with a research grant. It turns out she has just received SEK 250,000 which is to be invested in a research project called ”Is physical inactivity an underrated cardiometabolic risk factor?” “For 35 years, the common theme of my work has been lifestyle issues. Fortunately, it’s the same type of advice concerning nutrition and physical activity that prevents all kinds of ill health, be it cancer, dementia, type 2 diabetes or cardiovascular disease,” says Mai-Lis Hellénius. She is a doctor, and since 2006 a Professor of General Medicine with a focus on cardiovascular prevention, at Karolinska Institutet. She is also active at, to date, the only county council financed lifestyle clinic in Stockholm, which was founded five years ago. “Despite there being a huge amount of new research in the lifestyle field over the past 10 years, the information is not widely disseminated, either among the health services or the general public. There is a real demand for it now, and we need to step up and make sure that the information is communicated,” says Mai-Lis Hellénius. She takes the responsibility seriously, and racked up 130 lectures on the subject last year. Another way to reach a wide audience is via the web-based course known as Sundkurs (Healthcourse), which was created with the help of the Swedish Heart-Lung Foun-

Mai-Lis Hellénius on…

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dation and provided by the Karolinska Institutet Continuing Professional Development services. It targets employees in the health services who, in six steps, are taught about physical activity, diet, alcohol, tobacco and stress. The website also features a free course with similar content, aimed at the general public. This also bears witness to an interest in lifestyle issues. “It’s been a while since I looked, but back then we had 35,000 participants,” she says. TO PREVENT DISEASES means investing resources now, while the results will not be seen until later. She believes that this is one reason why it is so hard to acquire grants for preventive work. “Admittedly, it can be costly to find

...disgusting food “I will pretty much eat anything if I have to, but I try to avoid offal. And when it comes to goose liver, which many view as a delicacy, all I can see is a fatty liver right in front of me.”

...writing books “To me it’s a hobby, and it’s great fun to work with design and editorial professionals. I also view it as an important part of disseminating information to the public.”

the individuals who risk becoming ill, and to prevent this through the use of information and follow ups. But studies show that there is profit for the society, as resources are saved when people are rescued from becoming ill in the first place. There’s an excellent return on the investment! An important issue is the fact that only a quarter of all Swedes get enough physical activity. When she started as a doctor at a health care centre in Sollentuna back in 1987, they were among the first to prescribe physical exercise to patients. Today this is commonplace, and the idea has also been exported abroad. Her group works on several research projects that aim to assess how exercise affects health. A doctoral student is studying how physical

...beauty standards “It’s terrible that we’re obsessed with being skinny! Diets are often sold on the promise of losing weight quickly, despite the fact that we know that it is more healthy to be curvy and mobile than thin and sedentary.”

...her dream project “To add a chef to the staff of the three lifestyle clinics that are planned in Stockholm. Imagine having an on-site kitchen where patients can, for example, compare the carbohydrate content of fruit and soft drinks.”


Name: Mai-Lis Hellénius Title: ”Lifestyle professor”, her official title is Professor of General Medicine with a focus on cardiovascular prevention at Karolinska Institutet. Age: 58 years. Family: Husband, adult son and a cat. Relaxes by: Jogging, cooking and wrapping Christmas presents – all year round. Hobbies: Aerobics instructor in the Sports for All Movement (“Korpen”). Motto: Life isn’t always easy, but it’ll work out in the end. Role model: Steven Blair, lifestyle professor from South Carolina, USA.

activity can affect the future health risks among men and women in respect of “metabolic syndrome”; another has constructed a ”step box” to easily measure muscle strength in an increasingly weak population. Another project is to work with collected data from the “60 year cohort” which involves over 4,000 men and women. A doctoral student is currently reviewing how the health was affected in those whose leisure time was especially sedentary. “She shows that those who were sedentary in their spare time had a generally higher risk of cardiovascular disease, even if they exercised twice a week,” says Mai- Lis Hellénius. It’s a matter of making day-to-day physical activity a habit, and this is where she practices what she preaches: take the stairs instead of the elevator and make sure to alternate standing up and sitting down when doing desk work. The telephone rings and it turns out to be the medical journal Läkartidningen, who are wondering about a text that she is submitting to them. Mai-Lis Hellénius assures them that it is on its way. She is generous with her time when it comes to talking o the media, and one reason for this is that her field of expertise is a public domain that affects everyone. And, according to Mai-Lis Hellénius, it can be educational to meet journalists, in order to to learn the types of communication that do or do not work. “I’m not looking to get exposure for myself, it’s about acting as a messenger for the knowledge that we need to disseminate outside of the scientific community,” she says. “Personally I’m a bit naive and can’t help defending science. This means taking some stick from time to time,” says Mai-Lis Hellénius, continuing: “I like debating, it can be fun to hone

your arguments. But it is not fun to be subjected to personal attacks and to get unpleasant emails and telephone calls, or even threats. THIS BRINGS US ON TO the diet debate, where she has chosen to confront those who promote that which is known as the LCHF diet. This advocates that a large share of the daily energy should come from saturated, animal fats. In a number of well-conducted scientific studies, researchers have shown that it is more healthy to consume fat in the form of unsaturated fatty acids. Recently, a group of experts in the USA have reviewed all recent dietary research. The dietary recommendations that were published in the last year, based on this study, say that no more than 10 per cent of the daily energy intake should be saturated fats. Sympathy for this view is something that is not easy to acquire from the general public. “Today there are more than 200,000 published studies – epidemiological studies, intervention studies that have examined the effect of different diets, and those that highlight new molecular biological mechanisms – and the majority show that saturated fats are not healthy in large doses. As scientists we should look at this overall picture and create a synthesis; those who advocate LCHF just cherry-pick a few results and publish them as a universal truth,” says Mai-Lis Hellénius. So could you then conduct an optimal study, for example, give people a certain diet under controlled circumstances, and follow their health over a long period of time – a study to end the debate? Mai-Lis Hellénius believes this would be difficult, since the information that we have today indicates that high-fat diets are bad for your health. “Based on what we know today, I cannot see an ethical committee approving a study where people would be subjected to a high-fat diet with a large amount of saturated animal fats,” she

“Personally I’m a bit naive and can’t help defending science. This means taking some stick from time to time.”

says. When she has been on TV talking about the fact that it might be wise to substitute butter with oil for health reasons, the following entry appeared on a well-known pro-fat doctor’s blog. “It’s terrible that she makes people scared of healthy, Swedish butter, and instead wants us to eat factory-produced, imported “junk-fats”. Without any scientific basis whatsoever”. The entry was quickly followed by a number of comments with a similar tone. Why does the dietary debate tend to be so heated? “I think that it’s because food is so central, and so closely associated with emotions, traditions and personal memories. We like to associate tastes with events and it becomes a tough balancing acts: I do not want to kill off people’s joy of food, rather to allow more people to eat healthily and enjoy it at the same time,” she says. She has thought about backing away form the argument but feels this would be cowardly. “It is my duty as a doctor and researcher to stand up for evidencebased science!”

Five lifestyle tips The lifestyle professor’s five evidencebased tips that increase the likelihood of having a healthier and longer life: (1) Try to get enough exercise to make you warm five days a week. (2) Do some sort of strength training twice a week. (3) If you have a sedentary job, try to get up a few times per hour. (4)Do not eat too small portions;, instead, exercise enough to allow you to eat filling portions and get all the nutrients you need. (5) Be aware of fats and carbohydrates. Make sure you get your essential fatty acids via, for example, oils, avocado, fatty fish and nuts and do not get rid of pears, coarse bread or root vegetables to reduce the amount of carbohydrates.  More information is available at: Dietary Guidelines for Americans 2010 from USDA Center for Nutrition Policy and Promotion: www.dietaryguidelines.gov. Quantity and Quality of Exercise for Developing and Maintaining Cardiorespiratory, Musculoskeletal, and Neuromotor Fitness in Apparently Healthy Adults: Guidance for Prescribing Exercise American College of Sports Medicine July 2011

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

Unhealthy food and lack of physical exercise increases the risk of type 2 diabetes. Researchers have now discovered an entirely new approach to the treatment of the disease.

An international team of scientists, led from Nature Karolinska Institutet, have discovered a new approach to the treatment of type 2 diabetes. The therapy involves the blockade of signalling by a protein, VEGF-B. In experiments on mice and rats, the scientists have managed to both prevent the Ulf Eriksson. development of type 2 Photograph: Stefan Zimmerman diabetes and reverse the progression of established disease. The study is published in the prestigious scientific journal Nature, where it is described as a breakthrough in diabetes research. The findings are the result of a joint effort by Karolinska Institutet, the Ludwig Institute for Cancer Research and the Australian biopharmaceutical company CSL Limited, amongst others. Published in:

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“We discovered VEGF-B back in 1995, and since then the project has been a lengthy sojourn in the wilderness, but now we’re making one important discovery after the other. In this present study we’ve shown that VEGF-B inhibition can be used to prevent and treat type 2 diabetes, and that this can be done with a drug candidate”, says Professor Ulf Eriksson of the Department of Medical Biochemistry and Biophysics. Type 2 diabetes is normally preceded by insulin resistance caused by obesity. When this happens, the cells no longer respond sufficiently to insulin, which leads to elevated levels of blood sugar. Insulin resistance is related to the storage of fat in the ’wrong’ places, such as the muscles, blood vessels and heart, although exactly how this relationship works is not fully known. What scientists do know is that the VEGF-B protein affects the transport and storage of fat in the body tissue.

A total of four related studies are reported in the Nature paper. In one case, mice bred to spontaneously develop diabetes were given a drug candidate called 2H10, which is an antibody that blocks the effect of VEGF-B. The mice subsequently developed neither insulin resistance, nor diabetes. The team also crossed the diabetes strain of mice with one that lacked the ability to produce VEGF-B, and found that the offspring were protected from developing the disease. In another two studies, the scientists took normal mice and rats that had not been specially bread to develop type 2 diabetes, and left them to develop the disease as a result of a fat-rich diet and the resulting obesity. In these cases, progression of the established disease was halted and reversed to varying degrees after treatment with 2H10. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes Carolina E. Hagberg, Annika Mehlem, Annelie Falkevall, Lars Muhl, Barbara C Fam, Henrik Ortsäter, Pierre Scotney, Daniel Nyqvist, Erik Samen, Li Lu, Sharon Stone-Elander, Joseph Proietto, Sofianos Andrikopoulos, Åke Sjöholm, Andrew Nash, Ulf Eriksson Nature September 2012

Photograph: Istock Photo

Breakthrough for new diabetes treatment


In short : New method enables ”smarter” analysis of individual cells A novel genomic seNature Bio- quencing method called technology Smart-Seq can help scientists to do complete mapping of the gene expression of individual cells. The method has many possible applications, including helping scientists to better understand the complexities of tumour development. This is viRickard tally important as many Sandberg. clinically important cells exist only in small numbers and require single cell analysis. “While our results are preliminary, we have shown that it is possible to do studies of individual, clinically relevant cells,” says biomedical scientist Rickard Sandberg, researcher at the Ludwig Institute for Cancer Research and principal investigator at the Department of Cell and Molecular Biology of Karolinska Institutet. ”Cancer researchers around the world will now be able to analyze these cells more systematically to enable them to produce better methods of diagnosis and therapy in the future.” The study was conducted in collaboration with the University of California, San Diego and Illumina Inc. Published in:

Impaired quality of life: a warning signal after oesophageal cancer Globally, oesophageal cancer is the eighth most common form of cancer. The only curative treatment includes extensive surgery. Some 30 per cent of patients survive at least five years. A study including 117 patients who had undergone surgery for oesophageal cancer in Sweden between 2001 and 2005, Pernilla and survived at least five Lagergren. years, found that most Photograph: Johan Bergmark patients had an unchanged or improved quality of life, that was comparable with that of the normal population. However, one in six patients experienced a considerable deterioration in quality of life, which was persistently much lower than that of the normal population at five years post-surgery. “The patients who show early signs of impaired quality of life should be identified and helped through a more intensive follow-up to avoid a persistently low quality of life”, says principal investigator Pernilla Lagergren, Professor of Surgical Care Sciences at the Department of Molecular Medicine and Surgery at Karolinska Institutet. “Depending on the problems identified by the patients, targeted intervention is often possible. For example, a patient with particular nutritional problems can be referred to a dietician with specialist knowledge of this patient group.” Published in:

Journal of Clinical Oncology

Health-related quality of life among 5-year survivors of oesophageal cancer surgery a prospective population-based study Derogar M, Lagergren P Journal of Clinical Oncology January 2012

Full-Length mRNA-Seq from single cell levels of RNA and individual circulating tumor cells Ramsköld D, Luo S, Wang YC, Li R, Deng Q, Faridani OR, Daniels GA, Khrebtukova I, Loring JF, Laurent LC, Schroth GP, Sandberg R Nature Biotechnology July 2012

The complete mapping of the gene expression of an individual cell is now possible to perform.

Study adds new insight into risk of thromboembolism in patients with RA Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization Holmqvist ME, Neovius M, Eriksson J, Mantel Ä, Wållberg-Jonsson S, Jacobsson LTH, Askling J JAMA Oktober 2012 Improved survival for patients with chronic blood diseases Patterns of survival among patients with myeloproliferative neoplasms diagnosed in Sweden from 1973 to 2008: a population-based study Hultcrantz M, Yngvi Kristinsson S, Andersson T M-L, Landgren O, Eloranta S, Rangert Derolf Å, Dickman PW, Björkholm M Journal of Clinical Oncology July 2012 Homeless are hard hit by infectious diseases Prevalence of tuberculosis, hepatitis C virus, and HIV in homeless people: a systematic review and meta-analysis Beijer U, Wolf A, Fazel S Lancet Infectious Diseases August 2012 Sex differences in fertility information to young cancer patients Sex differences in fertility-related information received by young adult cancer survivors Armuand GM, Rodriguez-Wallberg KA, Wettergren L, Ahlgren J, Enblad G, Höglund M, Lampic C Journal of Clinical Oncology May 2012 New discoveries on depression Dysfunctional astrocytic regulation of glutamate transmission in a rat model of depression Gómez-Galán M, De Bundel D, Van Eeckhaut A, Smolders I, Lindskog M Molecular Psychiatry February 2012 Risk of suicide and fatal heart attack immediately following a cancer diagnosis Suicide and cardiovascular death after a cancer diagnosis Fang F, Fall K, Mittleman M, Sparén P, Ye W, Adami H-O, Valdimarsdottir U New England Journal of Medicine April 2012 Mapping of protein inhibitors facilitates development of tailor-made anticancer agents Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors Wahlberg E, Karlberg T, Kouznetsova E, Markova N, Macchiarulo A, Thorsell AG, Pol E, Frostell A, Ekblad T, Öncü D, Kull B, Michael Robertson G, Pellicciari R, Schüler H, Weigelt J Nature Biotechnology February 2012

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KI news

Melinda Gates honored for her engagement Honorary doctor of medicine Melinda Gates and Martin Ingvar, former Dean of Research at Karolinska Institutet.

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n August 2012 Melinda Gates received an honorary doctorate at Karolinska Institutet in recognition of her support for scientific work on global health issues at the Bill & Melinda Gates Foundation. The award recognizes the couple’s active and long-term contribution to improving human health where the need is greatest, achieved through their work with partners worldwide.

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“Together, we are changing millions of lives and I find it inspiring and energizing to witness firsthand the Karolinska Institutet’s ability, knowledge, and resources to help people around the world live a better life”, said Melinda Gates, co-chair of the Bill & Melinda Gates Foundation. Guided by the belief that every life has equal value, Bill and Melinda Gates created the foundation to help all

people lead healthy, productive lives. In developing countries, the foundation focuses on improving people’s health and giving them the chance to lift themselves out of hunger and extreme poverty. In the United States, it seeks to ensure that all people – especially those with the fewest resources – have access to the opportunities they need to succeed in school and life.

A new lecture hall complex – scheduled for completion in the summer of 2013 – will enable Karolinska Institutet to arrange major public events, such as the Nobel lectures, which attract audiences from around the world. Wingårdh Architects have designed the building, the form and geometry of which contrasts with the traditional low-rise brick buildings on the Solna Campus. The building will house a 1,000-seat auditorium, office space for approximately 90 staff, 100 conference seats and restaurants. The auditorium, with the exception of the office and service facilities, has been fully financed by a private donation from the Erling-Persson Foundation.


Historic investment in SciLifeLab Four Swedish universities is behind the Science for Life Laboratory, a huge new investments in life science research.

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n 2013, SciLifeLab is becoming a national research institute for major research in molecular biosciences and bioinformatics. SciLifeLab will grow to employ about 1000 scientists and have a turnover of about 1 billion SEK within a few years. In addition to funding from the government, the Knut and Alice Wallenberg Foundation will invest 220 million SEK on technology laboratories in SciLifeLab and Astra Zeneca intends to invest 5-10 million

USD annually for five years. SciLifeLab is a joint venture between four universities; Karolinska Institutet, KTH Royal Institute of Technology, Stockholm University and Uppsala University. The medical research focuses on investigating the molecular basis of complex human diseases, and seeks to find biomarkers that can help diagnose diseases and monitor their progress. SciLifeLab has facilities both in Stockholm and in Uppsala.

Photograph: Ulf Sirborn, Erik Cronberg, Pierre Zoetterman, Camilla Svensk

SciLifeLab Stockholm is situated in Karolinska Institutet Science park in Solna.

Karolinska Institutet and AstraZeneca strengthen their collaboration The development of new drugs and the swifter introduction of new clinical methods and treatments – this is the aim of the new translational research centre set up by Karolinska Institutet and AstraZeneca 2012. Translational research is based on questions raised within healthcare. The research is done in laboratories and the results are then fed back as new methods of treatment and diagnosis. The new centre is to discover biomarkers - biological traces in the blood or tissue that can signal whether a person is ill, or risks becoming so later in life. Identifying and understanding new biomarkers will help scientists prevent disease and produce more effective treatments and new drugs. Chronic diseases such as dementia, cancer, rheumatism, cardiovascular disease, metabolic disorders and mental ill-health, which currently account for 80 per cent of the country’s health costs, will be the centre’s main focus. The centre will initially be running for five years. During 2012 Karolinska Institutet and AstraZeneca also started a three year collaborative research agreement that will apply state-of-the-art molecular imaging technologies to generate novel diagnostic imaging tools.   Medical Science–2013

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Synthetic trachea save the lives of dying patients Is it possible to manufacture organs that work just as well as donations? Yes - and it has already been done. So far, the surgeon Paolo Macchiarini has given five patients new trachea made from nanotechnology and the patient’s own stem cells.

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he first two operations performed using these techniques were reported worldwide in 2011. In both cases, the patients were young men under 40, with late-stage tracheal cancer. In order to survive, both patients needed their cancerous trachea removed immediately - a task which was not possible, as no replacement donor organs were available. “They had, in effect, been given a death sentence. As a last resort, they elected to try this method. Seeing them get a new chance to live their lives was fantastic, a great experience”, says Paolo Macchiarini, Visiting Professor of Regenerative Surgery at Karolinska Institutet, and responsible for the surgery. However, less than four months later in March 2012, one of the patients died; a man from the USA who was operated

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on at the Karolinska University Hospital in Huddinge. The death occurred suddenly at a hospital in the USA. “Of course it was shocking to discover that the man died. I’m not at liberty to discuss the more in-depth details behind his death, due to patient confidentiality, but it was not linked to our interventions. Nevertheless, we have evaluated everything and looked to what we can improve. Naturally this must be done, as we are dealing with previously untested technology. Each operation provides us with further important knowledge. We must always be humble and try to do better”, says Paolo Macchiarini. As A result of this evaluation, Paolo Macchiarini and his team have chosen a new material for the manufacture of the synthetic trachea. Nanotechnology is

still being used, but hopefully the structure of the new material will encourage the stem cells to bond even better than previously. With this new, fine-tuned technology, a further three patients have received new trachea. All of these patients were operated on during the summer of 2012; two in Russia and one at the Karolinska University Hospital in Huddinge. These patients are doing well, as is the very first patient to receive the transplant, a man from Ethiopia. The three new patients, however, received the surgery under different circumstances than previously, as they did not have cancer. Instead they are patients whose trachea had been damaged by other incidents, such as accidents. Synthetic materials and tissues have previously been used in many other areas; for example, it is relatively common to use synthetic blood vessels. The

Photograph: Staffan Larsson

Text: Annika lund Photograph: Istock Photo


technique of covering an organ donated from a deceased person with a patient’s own stem cells has also been used previously. Both trachea and urinary bladders have been transplanted. In 2008, for example, Paolo Macchiarini gave a new trachea to a Spanish woman with tuberculosis - a donor organ covered in her own stem cells. The new aspect of these well observed operations is that two previously known techniques have been combined; it is a synthetic organ that is covered in the patient’s stem cells. The result is a partially synthetic body part that develops biological functions. For example, the new trachea have fully functioning phlegm production and are completely flexible when

the patient turns their head. It is possible to ”tickle” the trachea and produce a coughing reflex, to name just a few examples that were impossible to achieve with trachea made from solid plastic. Furthermore, biopsies from the new constructed trachea have shown that they partially comprise of cells that are unique to the airways and were not present when the trachea was transplanted. Therefore they must have developed from the stem cells that covered the artificial trachea, or they developed as a consequence of the presence of stem cells. Nevertheless, new, healthy cells have developed where the patients previously had a cancerous trachea and these healthy cells have grown after the operation.

Paolo Macchiarini believes that it is possible to develop this discovery, in the best case into a ground-breaking innovation. He believes that it may eventually be possible to place tissues covered in stem cells in areas of a heart severely damaged by a heart attack. Here, the tissues will then begin to build healthy cells to replace those damaged. It could work as a cure for patients who are currently waiting for a donor organ. “I am pretty sure that we will have achieved this within ten years. It should be possible to use the technique on different types of tissue, such as liver and lungs”, says Paolo Macchiarini. Do you mean that this could replace organ donations?

“That would be the best option. An organ transplant is an aggressive procedure for the body and it would be wonderful if a patient could avoid this.” Medical Science–2013

43


Patients received new air Five pioneering operations have been performed so far, the forst taking place in 2011. The first patients were in an advcanced stage of cancer, but the surgery was also performed for other reasons.

1

A FEW DAYS BEFORE THE OPERATION, 200 ml of bone marrow was extracted from the hip bones of the patients. Some cells were removed, leaving only stem cells and progenitor cells – cells that have reached a further step in their development. Meanwhile, the patient was treated with a drug that forces stem cells into the blood stream, in order for them to later attach to the new trachea, once it is in place.

Stem cells

Progenitor cells

2

A CT SCAN OF THE PATIENT’S trachea and bronchus was conducted. This provides an exact, three-dimensional image. Trachea

Graphics: Idégrafik

Bronchus

44

3

FROM THE IMAGE, a ”skeleton” was created – a scaffold or template for the new trachea. This is made out of an advanced plastic material, the surface of which gives the stem cells a chance to attach and start growing.

Medicinsk Vetenskap №4–2012

Sources: The Lancet, November 2011; Philipp Jungebluth; Ola Hermanson.


passages

+ 4

THE TEMPLATE, the patient’s stem cells and a nutrient solution with growth factors are mixed in a bioreactor the size of a shoe box. The template rotates, ”roughly like a chicken being grilled”, while the cells attach themselves.

5

AFTER TWO TO THREE DAYS, the new trachea has a layer of endogenous stem cells and can be transplanted. No immunosuppressive drugs were administered. However, agents that promote the growth of the stem cells were administered.

The nano-structure before and after cells have attached themselves.

6

FOLLOW-UPS HAVE so far shown that patients are in good health and have no problems as far as rejection of the transplants is concerned. One patient has died, though not of causes that can be linked to the procedure, according to the current information. The patients can cough and both mucous formation and immune systems are working. Medicinsk Vetenskap №4–2012

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Curious about twin research

One twin is healthy, the other is ill – despite having the same genes. Identical DNA makes identical twins the perfect research subjects for studying how our genetic heritage and our environment affect us. Text: Annika Lund Photograph: Istock Photo The researchers’ favourites. Identical twins have the same DNA but are still afflicted by different diseases – this is something researchers can utilise.

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Medical Science–2013


I

dentical twins share the same DNA and have, in principal, the same set of genes. But they already start to differ while in the womb. When they are born, they are no longer identical – they do not, for example, have the same fingerprints. This is due to minute changes in the womb’s environment and to other random events. The fact that twins are of special scientific interest was highlighted as early as the 1870s by the British scientist Francis Galton. One of his theories was that intelligence was hereditary, an idea that was controversial at the time. He proposed to compare twins who had grown up in different environments as a method to study this. He was especially interested in twins who were very similar – he compared them to the double yolks that can occur in a hen’s egg. Eventually, the genetic difference between identical twins, who share 100 per cent of their DNA, and fraternal twins, who only share 50 per cent, was discovered. This allowed twin research to enter a new phase – if identical twins are more similar than fraternal twins, you could conclude that genetic heritage is of significance. The method is currently a standard model in epidemiological research, where results from twin studies are considered very reliable. Medicinsk Medical Vetenskap Science–2013 №4–2012

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CURIOUS ABOUT TWIN RESEARCH

TODAY IT IS CONSIDERED to be proven that genetics explains around 70 per cent of the differences that exist between individuals, as far as intelligence is concerned. “In other words, genetics is fairly important, but you should remember that environmental factors are also important. After all, we can influence our memory and our risk for developing dementia through exercise, both physical and mental,” says Nancy Pedersen. When it comes to other character traits, such as being jolly or extrovert, hereditary factors are estimated to account for roughly 40 per cent of individual differences – in this regard, the environment to which one has been exposed whilst growing up plays a much bigger part. To allocate quotas concerning genes and environment in different contexts has always been a fundamental issue for twin research. This applies not only to various diseases, but also to character traits. For example, twin studies have shown that the hereditary component of ADHD can be estimated at between 45 and 90 per cent. Autism, alcoholism, asthma, bipolar disorder, schizophrenia and physique are also considered to be largely dependent on hereditary factors. 48

Medical Science–2013

“For some abilities, for example problem solving, the genetic factors seem to lose importance as one gets older.” Other information based on the register includes the fact that smoking not only damages the lungs but also causes cardiovascular diseases – a revelation that was ground-breaking in the 1970s. Currently, there are more than 30 research projects being conducted on Swedish twins. They concern everything from behavioural problems in children to cardiovascular disease and schizophrenia in adults. Several studies concern diseases among the elderly. Some of them are based on a special set of data that is especially exciting for the scientists, for various reasons. This is the data concerning approximately 900 pairs of identical twins who have grown up in different homes. Of these, many have participated in surveys or interviews, some upwards of ten times. These twins are now elderly, and many of them are ill. In many cases, only one of the twins has become ill, which gives

researchers a unique opportunity to study how their different childhood environments may have influenced them. Previous twin studies have concluded that the susceptibility to Alzheimer’s disease is around 80 per cent due to hereditary factors; it is therefore extremely interesting to try to understand which environmental factors constitute the remaining 20 per cent. Major risk factors that have been identified so far include obesity in midlife. Other interesting discoveries have also been made, such as the fact that the influence of our genes and our environment changes throughout our lives. This means that the same individual can be more influenced by hereditary factors during their childNancy Pedersen. hood, and later in life Photograph: be influenced more by Camilla Svensk their environment. “For some abilities, for example problem solving, the genetic factors seem to lose importance as one gets older. This may indicate that epigenetic effects are more noticeable later in life,” says Nancy Pedersen. The epigenetic effects to which she refers concern the grey area between genes and environment. What happens in the body when a hereditary

How we become who we are Outgoing Genetic heritage vs environment Some traits depend largely on your genetic predispositions, whilst others are more dependent on your environment.

Genetic heritage : 40%

Verbal

Source: The Swedish Twin Registry

At the start of the 1960s, the foundation was laid for the Swedish Twin Registry, which today is the most comprehensive twin register in the world. It includes almost 180,000 persons, born from 1886 onwards. The registry is administered by Karolinska Institutet and was originally founded to research whether or not smoking was dangerous – something that was not considered scientifically proven 50 years ago. Since the registry was founded, tens of thousands of twins have completed comprehensive surveys concerning their lifestyles, undergone medical exams and been interviewed. There is a large number of collected biobank samples, including almost 15,000 blood samples and more than 30,000 saliva samples. “This is a veritable gold mine from a scientific perspective, and we get a great number of requests from both Swedish and foreign researchers who want to utilise our data,” says Nancy Pedersen, Professor of Genetic Epidemiology at the Department of Medical Epidemiology and Biostatistics, and one of the researchers who uses the registry.

Genetic heritage: 70%

Environment: 30%

Height Environment: 25% Genetic heritage: 75%

Environment: 60%


Two epigeneTic mechanisms that

are considered fairly well investigated are DNA methylation, where methyl groups attach directly to the DNA strand, and histone modifications, where the proteins around which the DNA strand is wound are modified. In both of these cases, the expressions of nearby genes are affected – they become activated or deactivated, depending on the nature of the modification. It is also known that RNA molecules have an epigenetic significance, due to their important role in regulating genes and transferring information from the mother cell to the daughter cells during mitosis. But so far it has been far from established what controls the epigenetic processes in various tissues and cell types. Within cancer research, epigenetic issues have been in the spotlight for several years, but within, for example, diabetes research, rheumatology and neurology, it is still a far younger field of research. Tomas Ekström uses twins to study epigenetic issues associated with systemic autoimmune diseases. This narrow field of research is beset by practical difficulties – it requires a great deal of patience to collect a large number of identical twins, where only one twin in each pair has developed a

“in cases where the genetic dispositions are identical, the individuals are affected by something else.”

relatively rare disease. For example, last year saw the publication of an article in the renowned medical journal Nature based on only three pairs of identical twins, where one twin had MS and their sibling did not. The study garnered a lot of attention, despite researchers not being able to identify any epigenetic differences that could explain why only one person in each pair had the disease. Thanks to collaboration between several research groups at Karolinska Institutet, it has been possible to amass 25 pairs of identical twins, where one twin in each pair has developed rheumatoid arthritis. Half of these have an especially aggressive version of rheumatic arthritis and are what is known as ACPA positive. One research group headed by Tomas Ekström has studied white blood cells from these identical twins and made several interesting discoveries. “There are clear epigenetic differences in genes that are of functional interest for the disease,” he says. However, an obvious problem in these studies is that there is no way of telling if the observed differences are a consequence of the disease – or if they are the cause of the disease. Nor is it possible to see when differences have arisen and what environmental factors caused them. ”It could have happened in the womb,” says Tomas Ekström. In the long term, the Tomas Ekström. goal is to understand Photograph: how the epigenetic Stefan Zimmerman processes play out in the genes that are important in terms of various diseases, such as rheumatic arthritis. Hopefully it will be possible to tell which genes are activated or deactivated and how this is done. And as the epigenome, i.e., the modified genes, is changeable, it should be possible to reverse the process. “This is a possible treatment strategy that lies far in the future. If we can, for example, reverse DNA methylation or histone modification so that relevant cells no longer express that which causes the disease, this could be a possible route to treating the diseases. But this only applies when the disease is caused by an epigenetic change – if it is caused by a mutation, the DNA sequence is modified and it cannot be reversed,” says Tomas Ekström.

Photograph: Annika Karlbom/Hallands Nyheter

propensity for a disease is activated in one individual but remains dormant in another? When, how and why can some genes be activated and switched on, while others remain passive and shut off? To study identical twins is of special interest in these cases, as they have the same genes. “In cases where the genetic dispositions are identical, the individuals are affected by something else. Epigenetics can explain how these factors affect us as it encompasses everything that a person has been exposed to, such as various infections, traumas, diet, smoking, sedentary lifestyle or environmental toxins,” says Tomas Ekström, Professor of Molecular Cell Biology at the Department of Clinical Neuroscience, Karolinska Institutet.

“it feels good to be part of it”

emma and sofia help the researchers A few years ago, identical twins Emma and Sofia Sandgren were contacted by researchers at Karolinska Institutet. They were asked to participate in a study concerning behavioural genetics. The study would, among other things, concern risk-taking. They accepted – an easy choice to make, they say. “It feels good to help with research. And it wasn’t particularly hard – we got to sit in a large room and answer questions, and then give a saliva sample. The only thing that was strange was that the room was full of twins – that was a bit odd,” says Sofia. The questions were about how much money they would be willing to bet in various hypothetical scenarios. They were also asked about the colour and brand of car they preferred. Directly after leaving the room they compared their answers, which turned out to be practically identical. “Of course it was exciting to find that out. We are alike in many ways, but not all,” says Emma Sandgren. They have stuck together throughout their school years but are now planning to go their own ways: Emma will eventually specialise in cardiology, whilst Sofia plans to be a neurologist. “I think it will be nice not to spend all our time together. It gives us the chance to develop our own personalities,” says Sofia. annika Lund Medical Science–2013

49


The Moment

“We struggled together for six months” As a young doctor, Anders Sönnerborg was confronted by early Swedish AIDS cases. Meeting the dying patients became the start of his career in HIV research. Told to: Anders Nilsson Photograph: Mattias Ahlm “I started out as a doctor at Roslagstulls infektionssjukhus (Roslagstull Infection Hospital) in May 1983. In addition to the normal cases, such as pneumonia and jaundice, the hospital had started receiving some patients with a new disease – AIDS. The first patient in my care was a young man who until recently had been completely healthy. He was an athlete, and in very good shape – during the summer he had run both the Stockholm marathon and the Midnight Run. He came to us only three or four weeks later, suffering from high fever and severe diarrhoea. It quickly turned out that he was carrying the new, still unnamed disease. The diarrhoea was caused by another virus, CMV, which is a normal complication. We struggled together against the disease for his remaining six months on earth. This patient

relationship affected me deeply, for several reasons. Partly on an emotional level: it was so incredibly gripping to get so close to a young, dying patient, almost of my own age. We met every working day, and I spent a great deal of time in his room, talking. Partly on a biomedical level: I became aware of the potency of the virus – how quickly a body that had been so strong and healthy could be broken down. We had temporary successes in his treatment, moments when there seemed to be hope. My strongest memory is when it seemed like we had managed to remove the inflammation in his intestine. The man was practically free of

Name: Anders Sönnerborg Title: Professor of Clinical Virology at Karolinska Institutet, chief physician at the Karolinska University Hospital’s Department of Infectious Diseases in Huddinge. Currently: Chair of the steering committee at Karolinska Institutet’s newly formed centre for HIV research. The centre includes more than twenty research groups, all focusing on HIV. 50

Mediccal Science–2013

symptoms and was growing stronger and stronger. We started discussing letting him go home. But the same day that I was going to discharge him from the hospital, the fever and the diarrhoea returned. We had failed. That day we spent several hours talking in his room, him and I. It was the first time I delivered the AIDS diagnosis. I remember how hard it was to pronounce the word. But he had already understood, several of his friends had died of the disease. He was calm and collected; we talked about how the funeral should be arranged, and what would happen with his flat. Such practical, rational issues. He died in early 1984. By then, we had so many AIDS patients that we had to open a new ward, which was still not enough. The fear of AIDS in society was reaching boiling point. It was all around us, but not at Roslagstull itself. To an infectious disease physician, it was already fairly clear how the disease was transmitted, but everywhere else the fear of being infected was widespread, which caused us many problems. No intensive care units wanted to receive our patients. My meetings with this patient, and my other early experiences at Roslagstull, were determining factors for my continued choice of career. The painful deaths, the unresolved medical issues, the repulsive way in which society treated the infected – it all caused me to quickly decide to focus on HIV and also to committ to becoming a researcher. ”


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