A magazine from Karolinska Institutet
English Language Edition
2015
COOL Chill out and save the
ALSO: OBESITY / LEADERSHIP / EXPLODING CELLS
KI Alumni & Friends
Join 15 000 fellow alumni! ki.se/alumni
KI Alumni & Friends is a professional and social network for everyone who is or has been engaged in Karolinska Institutet. Together, all of our former students and employees, constitute a vast network of experience and expertise with contacts in all parts of society in over 50 countries. Through KI Alumni & Friends you can: keep in touch with old friends and class mates, search for and find new professional contacts, attend seminars and reunions, in Stockholm and abroad. The membership is free of charge.
Contents—2015 4 5
Meet the Vice-Chancellor The international KI
Advances 7 8 10 11 12
Exploding cells Research news in short A close look at pericytes Parental genes take turns The old art of helping children into the world 14 Sperm and egg donors welcome contact 15 Body journey
Focus 20 UN’s millennium goals: Both success and a fiasco 38 What muscles do to help the brain 40 Cool treatments
50
Hearing aid. Eva Karltorp took up the struggle for deaf children´s speech development.
The researchers 16 They are one step ahead 24 His heart beats for the forgotten 45 The birth of a miracle baby 48 Artistic confrontation improve leadership 50 A deaf baby gave her courage
In depth 28 Full of fat – the story of the obesity epidemic
Pericytes. Take a closer look.
20
24
10 Warmhearted. He wants cardiac care for all.
Also 46 High impact publications 49 KI News Health goals: Heading in the right direction.
14
Childrens questions. Where did I come from?
Medical Science–2015
3
Vice-Chancellor of Karolinska Institutet
D
EAR READERS, Karolinska Institutet is one of the world’s leading medical universities and has seen a very positive development in the past few years. However, it is my firm belief that our university could advance its position even further. In our new strategy, we have highlighted four areas that will help us reach the high bar that we have set for research and education over the next five years. The overarching goals in these areas – staff, infrastructure, collaboration and funding – will now be turned into detailed operational plans and activities. Karolinska Institutet has a strong focus on collaboration, on regional, national and international levels. Various stakeholders in the region – universities, county councils and municipalities – need to join forces to create a life science cluster that is powerful, even by very high international standards. Through an attractive infrastructure and an interesting critical mass of actors, the region has apparent potential to attract researchers, students, industry and venture capital from all over the world and thereby create economic growth. The Science for Life Laboratory, as one prominent example, is an important platform for regional and national collaboration alike. By virtue of its strength, Karolinska Institutet should assume a greater national responsibility in these contexts. Needless to say, Karolinska Institutet has much to gain from entering into strategic alliances with other internationally leading universities, as they enhance our profile and ability to carry out large-scale, ambitious and resource-intensive research. Such projects, in turn, facilitate external recruitment, and give us a competitive edge when competing for funding from major international financiers. Not only are we reinforcing our existing alliances in North America, Southeast Asia, Japan and Africa, we are also in discussions with top Nordic universities and leading universities and research institutes in Britain, the Netherlands and Germany. It is of particular interest to form alliances with institutions that have complementary competences in natural sciences and technical faculties, that promote cross-disciplinary collaboration, or are closely integrated with the university health care system. Research at Karolinska Institutet spans the entire medical field, from basic experimental research to patient-oriented and care research. In this year’s edition of Medical Science, you will find an array of exciting examples of research currently conducted at our university.
4
Medical Science–2015
COLLABORATIONS AROUND THE WORLD Karolinska Institutet works with international recruitment and in many exciting research collaborations. This enriches Karolinska Institutet and provides the university with a broader perspective, where the goal is to work with and attract the world’s foremost talents – whether these are students, researchers or teachers.
0 1–10 11–50 51–200 2001–1000 1000+
Photo : Gunnar Ask
Anders Hamsten:
The international Karolinska Institutet The map shows the number of academic articles published by Karolinska Institutet’s researchers in collaboration with one or more researchers from each country or territory during 2012 - 2014. USA is at the top of the list over countries that Karolinska Institutet is co-publishing with, but the university collaborates with researchers all over the world.
Info graphic : Karolinska Insitutet. Certain data included herein are derived from the Web of Science ® prepared by Thomson Reuters®, Inc. (Thomson®), Philadelphia, Pennsylvania, USA: © Copyright Thomson Reuters ® 2015. All rights reserved.
A SWEDISH ADVANTAGE Sweden and Karolinska Institutet enjoy a global competitive advantage, due to the favourable research conditions around the national outcome registries for common diseases and population statistics, connected through the use of personal identity numbers.
Medical Science is an annual English language edition of the Karolinska Institutet popular science magazine Medicinsk Vetenskap. Here you can read selected examples of current research at our university. Editor-in-chief Christina Bostedt Director of Communications Karolinska Institutet Editors Ola Danielsson Cecilia Odlind Medicinskvetenskap@ki.se Art Direction Agnes Dunder, Content Innovation Contributors Annika Lund, Fredrik Hedlund, Lisa Reimegård, Charlotte Lundqvist, Anders Nilsson, Helena Mayer, Marie Svedberg, Jacob Sjöman, Ulf Sirborn, Mattias Ahlm, Martin Stenmark, Anders Kjellberg, Henric Lindsten, Christian Andersson
PALESTINA
MYANMAR
Cover: Getty images Print E-print Translation Språkservice Web ki.se
A PLACE FOR BASIC AND TRANSLATIONAL RESEARCH Many of Karolinska Institutet’s departments are situated within or adjacent to the Karolinska university hospital or other major hospitals, creating ample opportunities for translational research. Strong basic research infrastructure is available, for example core facilities for advanced technologies, biobanks and the national Science for Life Laboratory.
Communications and Public Relations Office, Karolinska Institutet, SE-171 77 Stockholm, Sweden ISSN 1104-3822 Follow us on Facebook! Facebook.com/ karolinskainstitutetenglish
Medical Science–2015
5
MOOCs in Scandinavia Conference June 11th–12th 2015 | Karolinska Institutet, Stockholm, Sweden
Submit your contribution now!
Welcome to MOOCs in Scandinavia! Learn more about the latest trends in Masssive Open Online Courses and share your experiences with other participants.
For more information, please see ki.se
This conference is brought to you by:
#ScMC15
Photo: iStock
Join the conference and be a part of the Nordic MOOC network!
The latest in medical research
Photo: Gustav Mårtensson, Istockphoto
New approach makes cancer cells explode Together with colleagues from Uppsala University, researchers at Karolinska Institute have discovered a new way to kill cancer cells from glioblastoma, the most aggressive type of brain tumour. A substance called Vacquinol-1 induces massive vacuolization. The vacuoles can roughly be described as bubbles or balloons consisting of the cell membrane. Vacquinol-1 makes the cancer cells filled with a large number of vacuoles, to the extent that their cell membranes breaks; the cell simply explodes. “This is a new mechanism for treating cancer. Any drug based on this principle would thus attack glioblastoma in a completely new way. It is possible that this principle also works on other types of cancer, we haven’t investigated this at all,” says Patrik Ernfors, Professor of Tissue Biology at the Department of Medical Biochemistry and Biophysics. Six of eight mice with transplanted human glioblastoma cells who ingested the substance were still alive 80 days later, compared with an average survival of about 30 days in the control group who did not ingest the substance. “We now want to take this discovery from basic research all the way to clinical application. The goal is to have an initial human trial,” says Patrik Ernfors. Annika Lund Cell, April 2014
Medical Science–2015
7
Advances In short Research news from Karolinska Institutet, downloaded from
ki.se
“Fishing, like gambling, is linked to something called intermittent reinforcement” It is not the lack of money that is the cause of the increased risk of criminality and addiction seen in adults from poor backgrounds.
Addiction researcher Anders Tengström on the radio show Fiske, explaining why some people leave their homes and families to go to some mosquito-infested hole. The fact that we know that sooner or later we’ll catch something, but not when, makes fishing particularly addictive, he says. Source: sr.se
A poor childhood does not explain criminality in adults Vulnerability. A low socioeconomic status during childhood is a well-known risk
factor for criminality and drug use, but the direct causality has never actually been examined. In a new study, researchers have therefore tried to find a way to separate the economic situation when growing up from other family-related risk factors. “We now see that there is a strong statistical link, at population level, between relatively poor childhood conditions and a future risk for the children when it comes to violent crimes and drug abuse. However, this link is completely eliminated when we look at siblings who have grown up during periods where their families have had different income levels,” says Amir Sariaslan, doctoral student at the Department of Medical Epidemiology and Biostatistics. The researchers have thus seen that, in a family that goes from economic vulnerability to prosperity, the risk of the sibling who grew up during the later “rich” period being convicted of a crime or diagnosed with drug abuse may be just as high as for their sibling who grew up during the earlier “poor” period. A total of more than 500,000 people between the ages 15–21, born between 1989 and 1993 were included in the study. British Journal of Psychiatry August 2014 8
Medical Science–2015
Atlas. Our bodies consist of at least 400 different types of cells. Even though they all carry identical DNA, the cell types look different and have different functions. All these cells differ from one another depending on what parts of the genetic material they use. In the large-scale international FANTOM5 project, researchers from all over the world have created an atlas to show which genes are used in practically all of the cell types in the human body. The research groups discovered that many illnesses could be linked to mutations in a certain type of region, which controls changes in gene regulation. Nature March 2014 and other publications Cells in the body can look very different but they all carry identical DNA.
Illustration: Istockphoto. Photo: Istockphoto
This is how DNA is regulated in the different cells of the body
Exercise can improve memory in 60-year-olds
Get active before the age of 70. The memory of elderly subjects did not improve to the same extent in response to exercise.
Brain exercise. Over a three-
Photo:Istockphoto
month period, German and Swedish researchers studied a group of individuals aged 60 and older who exercised using a personalised thirty-minute session on DID YOU a treadmill three times KNOW? All dissertations a week. In the control from Karolinska Institutet group, the participants are available at performed stretching publications. ki.se and muscle relaxation exercises. In both groups, measurements were taken of episodic memory (personal experiences), the volume and blood flow in the part of the brain known as the hippocampus, and the new study, researchers have participants’ physical fitness looked at what type of cells as measured by maximal generate new muscle tissue oxygen uptake. The results in two different species of indicated that physical actisalamander when they lose vity can improve memory in a front leg. The traditional older people as it increases theory has been that the new the volume and blood flow tissue is formed by a certain in the hippocampus. It is type of stem cell, which is the first time these connecactivated when a limb is injutions have been studied in red. But in the case of these people over 60 years of age. salamanders, the theory The same results from the exercise were not observed in turned out to be true only for the participants over 70 years one of the two species, even though they are relatively of age, something which, closely related. according to the researchers, “We have shown that in suggests there may be an age limit for this type of plasticity one of these salamander species the muscle tissue is in the brain. Molecular Psychiatry October 2014 regenerated by specialised muscle cells, which are transformed and forget what Different cellular type of cells they used to mechanisms behind be, unlike the other species, regenerated limbs where the new muscles are Special ability. Salamanders formed by existing stem are known for their ability cells,” says András Simon, to regenerate lost tails and researcher at the Departother extremities, but also ment of Cell and Molecular heart and brain tissues. In a Biology.
450
These findings cannot yet be applied to humans, but they are an important part of understanding how damaged or lost tissue can be regenerated. Cell Stem Cell November 2013
ADHD medication saves lives on the road Risk reduction. Researchers
have monitored over 17,000 individuals with ADHD over a period of four years, 2006–2009, analysing the risk of transport accidents for individuals diagnosed with ADHD and how pharmaceutical treatment affects this risk. The incidence of transport accidents was lower among men with ADHD who took medication than among men with ADHD who did not. When the men were compared to themselves, i.e., during periods with and without pharmaceutical
thousand SEK. This is the average annual cost per household where one person has been diagnosed with Duchenne muscular dystrophy, according to a study from the Institute of Environmental Medicine at Karolinska Institutet. Neurology July 2014
treatment, the researchers were able to establish that pharmaceutical treatment implied a significantly lower risk of transport accidents; during the periods of pharmaceutical treatment the risk was 58 per cent lower. This study, which has now been published, does not explain the specific mechanisms behind the effect of ADHD medication on accident risk. However, the researchers believe that the results are due to the effects of pharmaceutical treatment on the basic symptoms of ADHD such as impulsiveness and distractibility, which in turn reduce the risk of getting into trouble on the road. “But we need further data before we can make any statements with statistical certainty when it comes to the effect on women. It is also important to point out that most pharmaceutical treatments entail a risk of side effects. The risks must be weighed against the benefits for every individual prescription, taking into account the individual patient’s situation,” says Henrik Larsson, researcher at the Department of Medical Epidemiology and Biostatistics. JAMA Psychiatry January 2014 Medical Science–2015
9
Advances A close look at
Pericytes Text: Ola Danielsson Illustration: Anders Kjellberg
What? Pericytes are longarmed cells that hug small blood vessels and capillaries around the body. Thanks to their ability to contract, they are thought to regulate the blood flow in capillaries.
When? Pericytes have also been shown to have a particular role when nerves are damaged, for example in a spinal cord injury that causes paralysis. When this happens, pericytes move to the site of the injury and build up scar tissue that is believed to stabilise the tissue, but which also prevents the nerves from healing.
Where? Particularly large quantities of pericytes are found in the blood vessels in the central nervous system (brain and spinal cord). Research at Karolinska Institutet has shown that pericytes play a key role in the blood-brain barrier, the extra protection in the brain’s blood vessel pathways that prevents harmful substances in the blood from coming into contact with the nerve cells of the brain.
10
Medical Science–2015
And? By studying pericytes researchers hope to learn not only how to close the bloodbrain barrier when needed, for example in Alzheimer’s disease when harmful substances leak out of the blood vessels, but also to open it up so that drugs can reach the brain. The researchers also hope to find ways to improve the ability to heal following spinal cord injuries.
Source: Christian Göritz, Senior Researcher at the Department of Cell and Molecular Biology and Christer Betsholtz, Professor at the Department of Medical Biochemistry and Biophysics.
6 Questions to Advances Text: Ola Danielsson Photo: Jacob Sjöman
Parental genes take turns in the body
RICKARD SANDBERG Senior Researcher at the Department of Cell and Molecular Biology, who is keeping an eye on our genes.
We are a genetic mixture of our parents. But new research shows that if you look closely enough, you will see that either the mother or the father is more prominent. You have discovered something new about how our genes work, tell us about it!
“It has long been known that every gene in the body exists in two variants, one from the mother and one from the father. But we did not know much about how these variants, i.e. the alleles, cooperate in the make-up of the body. We have now discovered that most often, both alleles for one gene will not be active at the same time in one cell. Instead, there are substantial fluctuations in activity from the two alleles over time, with long periods of activity from only one parental allele. Most likely these patterns are a direct consequence of the process of gene activation itself. What is the significance of this?
“It is a fundamental discovery that sheds new light on many questions. Importantly, this new mechanism could explain how cellular variation, e.g. in appearance or function, can arise in genetically identical cells under near identical environments. For example, this discovery perhaps explains why identical twins are not completely identical, despite having the same genes. One can be unlucky and have active gene variants that lead to disease, while the other will remain healthy because other gene variants are active.” Why has this not been discovered before?
“It hasn’t happened because the methods used to study the activity of genes have been based on an analysis of millions of cells at once. This provides an average in which the contribution
from both alleles of a certain gene are mixed together. We are using a new method we have developed; this makes it possible to analyse the activity of genes in individual cells.” Does this method have other applications?
“Yes, loads! Now we can begin to survey which types of cells the body is made up of. This is something that has not been known in much detail. If you look in one book, it will say there are 200 types of cells, while another book will say there are 500. These are estimates based on the cells’ appearance and certain recognised biomarkers. By analysing the activity of genes, we can now differentiate more systematically between different types of cells, and between different stages of cellular development. All cells from an individual contain the same genes and it is specifically differences in the
gene activity that results in different types of cells. Will your research lead to cures for disease?
“Hopefully it will. For example, we can now study the genetic profile of individual cancer cells circulating in the blood for the first time. In a patient there are perhaps only about ten such cancer cells, but these are very important as they can cause the cancer to spread. We are now trying to learn what characterises aggressive cancer cells and how they respond to different treatments.” What is your dream discovery?
“My dream is to gain a greater understanding of the genetic code so that I can read it as well as I can read a normal passage of text! In order to achieve this, we need to break the regulatory code that control when, where and to what extent our tens of thousands of genes should be activated.” Medical Science–2015
11
Timeline Obstetrics
Swedish maternity care: 113,000 children are born in Sweden every year. The majority are born in spring and summer. Almost all children are born in hospital in the presence of a trained midwife. 82 per cent of mothers are given nitrous oxide during labour. 50 per cent of those giving birth for the first time received an epidural. 17 percent of children were delivered via Caesarean section.
The old art of helping children into the world In the past, the risk of bleeding and infection made childbirth one of the most dangerous things a woman could do. Today, maternal mortality in Sweden is among the lowest in the world.
2000 BCE. Seated delivery. Paintings from Ancient Egypt show women sitting or squatting over birthing chairs when they give birth. These chairs were comprised of two upright boards for the woman to support herself against. A midwife is in place to deliver the baby.
2000 f Kr
Text: Charlotte Lundqvist
1500 1686. Training requirement. An ordinance stipulating that midwives had to undergo training was issued in Stockholm. Midwives now have to be literate in order to sit the examination, and the first step of the transition from an apprenticeship to a university education has been taken.
1600
The 17th century. Needle and thread. The practice of stitching ruptures following delivery begins at a school for midwives in Paris. Following the procedure, the perineum was washed with red wine. Women now start giving birth lying down. The first delivery forceps were invented in England. 12
Medical Science–2015
1700
1800
1847. Pain relief. The first woman received pain relief during labour. However, the Scottish doctor James Young Simpson was criticised for acting contrary to the will of God as Genesis 3:16 states “in sorrow thou shalt bring forth children”.
1738. A successful incision. For the first time both mother and child survived a Caesarean section. The procedure was performed by Irish midwife Mary Donally. Prior to this, Caesarean sections had only been performed on dying mothers as a final attempt to save the baby.
Photo: Istockphoto
1513. The first handbook. Eucharius Rösslin publishes the childbirth handbook “Der Rosengarten” in Germany. It covered things such as techniques for turning the child in the womb, and was distributed in several European counties.
1953. Help pulling. The first ventouse is invented by Swede Tage Malmström who was working at Sahlgrenska Hospital in Gothenburg.
1881. Antiseptic techniques. In Sweden, directions were issued that midwives were to disinfect their hands and instruments with carbolic acid, resulting in a dramatic reduction in maternal mortality.
1950
1930
1935. Focus on preventative maternal care. Early detection of high blood pressure and pre-eclampsia (toxaemia of pregnancy) is considered to have saved many women and children.
1970
1970. Improved prenatal diagnosis. Ultrasound technology is developed and it becomes possible to study the child’s growth and development during the foetal stage.
Future challenges Good global maternal health Close to 800 women still die every day in conjunction with pregnancy and childbirth. Many researchers are working to find the most effective ways to reduce the risks.
Photo: Getty Images
Reduced complications The age and weight at which we are having children are both increasing, increasing the risk of complications. Surrogacy Some people who are unable to get pregnant now travel abroad in order to find surrogate mothers, but there is currently a debate as to whether surrogacy should also be permitted in Sweden. If it becomes a reality, it will involve ethical and medical challenges in years to come. Sources: Drife J, “The start of life: a history of obstretics” History of medicine Nilsson Lennart,“Obstretik och gynekologi i Sverige under ett sekel”, Läkartidningen National Board of Health and Welfare, The Swedish Medical Birth Register The Swedish Association of Midwives, www.barnmorskeforbundet.se
2015
Cecilia Ekéus. Photo: Marcus Ranua T O D AY
Ventouse can increase the risk of cerebral haemorrhage Almost one in ten children in Sweden is delivered with the help of a ventouse. Despite this there has been very little research conducted into what this means for the mothers and children. Hence, midwife and docent Cecilia Ekéus decided to learn more about the subject. She is currently leading a research project about the use of the ventouse at Karolinska Institutet. The ventouse is most often used in cases where the child shows signs of oxygen deficiency or the delivery is taking a long time. In cases where labour is not progressing, there is also the option of performing an emergency Caesarean section. Cecilia Ekéus has compared the delivery outcomes for both approaches and has been able to establish that there is a link between the use of the ventouse and cerebral haemorrhage. “The study points to the risk of haemorrhage being higher for short mothers with large babies and for babies born preterm. We will now be studying whether it is the ventouse or the difficult labour that causes the haemorrhage, and will also follow up on children who are affected in order to see how they get on in the long-term”. Medical Science–2015
13
Advances 2 × children
Sperm and egg donors are happy to be contacted New research shows that the vast majority of those who donate eggs or sperm would be prepared to have contact with their offspring. Text: Ola Danielsson
!
to contact and the donors’ gender, age, ambivalence prior to donation or whether the donor had children of their own. This differs from previous studies in which sperm donors have A WELCOME reported greater ambivalence than VISIT egg donors, which was in turn relatPossible first after the ed to lower subsequent satisfaction child has reached the age of 18 and has chosen to with having donated. The donors make contact. had different ideas and preferences about whether they wanted to be informed that someone had requested to learn their identity. One reason for offer support to those donors who renot wanting to be informed could be quest it. You see, donating eggs or sperm to avoid waiting in vain in case the doesn’t just have consequences for the offspring chooses not to make contact. donor and the resulting child, but can One quarter of participants expressed a also be significant for the donor’s own need for counselling concerning how to family,” says Claudia Lampic, researcher handle any future contact. at the Department of Neurobiology, Care “I hope that the results contribute to Sciences and Society, who has worked greater understanding of the donors’ on the study. Fertility and sterility, October 2014 perspective and greater preparedness to
Cancer survivors’ thoughts about future children surveyed
People who have had childhood cancers and survived often feel uncertain about their chances of having children in the future. This has been shown by a new study from Karolinska Institutet in which the researchers have conducted and analysed chat discussions with 133 young cancer survivors. This uncertainty affects close relationships and many were also doubtful about having children because of the physical and mental scars left by their cancer. Cancer treatment can have a detrimental effect on the fertility of both men and women, but previous research has shown that patients often feel they do not receive sufficient information about this. Human reproduction, September 2014 14
Medical Science–2015
Photo: Istockphoto
THE LEGISLATION concerning sensitive information associated with sperm and egg donation differs between countries. In Sweden, children resulting from sperm or egg donation have the right to learn the identity of the donor when they reach maturity, usually interpreted as 18 years old. Although Swedish donors have accepted offspring’s right to information and the possibility of future contact, it is still unclear how best to make such contact. In a new study, 210 donors were asked for their thoughts 5–8 years after their donation. The results show that a majority of egg and sperm donors have a positive attitude to the idea of being contacted by their offspring, while very few reported that they would prefer not to be contacted. There was no association between the openness
Body journey Advances BRAIN
Join Medical Science on a journey around the human body and catch up on the latest research news. Smoking increases risk of hereditary skin cancer SKIN
A new study shows that people who have survived severe blows to the head have three times higher risk of dying prematurely – often in suicides or new serious injuries – than people from the general population. Researchers suspect that damage to certain parts of the brain that control judgment, decision-making and risktaking plays a part but are unsure why.
Families that are susceptible to a certain type of skin cancer also run a greater risk of developing other forms of cancer including the lungs, oral cavity, throat and stomach. Smoking appears to be more strongly associated with cancer in these families, compared to families that lack the mutation in question.
Intestinal flora may affect testicular functionality Illustration: Istockphoto. Photo: Istockphoto
T E ST E S
The blood-testis barrier, which protects the germ cells from harmful influences, is regulated by the intestinal flora. This is the conclusion of studies of mice that have been raised with a controlled intestinal flora. The levels of gonadal hormones are also affected by the intestinal flora. Researchers speculate that a change in the intestinal flora may help explain the deterioration in sperm quality and reproductive function in men that has been reported in recent years.
Fragile head
Heart attack ruled out with a blood test HEART
With a single blood test and an ECG test, it is possible to rule out the risk of a heart attack in patients who seek emergency care with chest pains. With the new method, 500 to 1,000 hospital visits per year could be avoided at Stockholm’s Karolinska University Hospital alone.
HIPS
Strong bones
According to a new study, Swedes have strong bones despite being exposed to fluoride in the drinking water. Fluoride has been suspected of increasing the risk of osteoporosis. But the study, which is based on data from approximately half a million people, refutes any such connection.
Sources: Brain: Langström N et al, JAMA Psychiatry, January 2014. Heart: Bandstein N. et al, Journal of the American College of Cardiology, March 2014. Hips: Näsman P et al, Journal of Dental Research, October 2013. Skin: Helgadottir H et al, Journal of Medical Genetics, June 2014. Testes: Söder O et al, PLoS ONE, August 2014. Medicinsk Medical Vetenskap Science–2015 №1–2014
15
A tale of three researchers
Name: Karin Modig. Title: Assistant professor at the Institute of Environmental Medicine at Karolinska Institutet. Researches: An ageing population and what it will require in terms of health and medical services in the future. 16
Medical Science–2015
One step ahead Widespread resistance to antibiotics, an increased proportion of elderly people and the health of coming generations. All these are examples of future challenges that we must work on immediately. Meet three young researchers at Karolinska Institutet who are not afraid to face the big issues.
“Are we adding healthy years to our lives?” “We live longer and longer, and one important question is of course: are we adding years of health or illness? This is a complex question, with no easy answer. The way I see it, I am completing a very large puzzle, and each new study constitutes a small piece of this puzzle. An ageing population is often described as a problem, or a burden. To me, that is a prejudiced opinion. The image emerging in my research is still relatively bright; for a large part of the population the years added will be healthy. But there are always factors that make comparisons difficult in each study. The dream would be to be able to determine the outcome more exactly. I often think about issues relating to my own life and ageing, but that is probably due to my current situation as a relatively new parent. I try to live a healthy life, and wouldn’t mind making it to 100 years. Like anyone else, I would like to remain in good health of course. There are many who say: ‘If I become ill, I’d like it to end fast’. But I think that’s a feeling that changes over the life course. Most people find out that they have a lot to live for, even after they become ill. It is not easy to guess how long people will live in the future. On the one hand, we have noticed that the age of the oldest members of our society does not tend to increase. On the other hand, there are important researchers who claim that the first person to reach the age of 200 has already been born.” As told to Anders Nilsson
Photo: Mattias Ahlm
Medical Science–2015
17
A tale of three researchers
Name: Edmund Loh. Title: Postdoc at the Department of Microbiology, Tumour and Cell Biology at Karolinska Institutet. Researches: How bacteria sense the environments and how the bacterial non-coding RNAs could be used to combat antibiotic resistance.
18
Medical Science–2015
“The Dr. Jekyll & Hyde bacterium” “The bacterium my research focuses on- Neisseria meningitidis – can act like Dr. Jekyll & Mr. Hyde. Most of the time, it lives peacefully on the mucosal membranes of the nose; however it can occasionally get into the bloodstream and rapidly cause life-threatening meningitis. Antibiotics are still effective against this bacterium, but this may not necessarily be the case in the future. When it comes to its sister bacterium- Neisseria gonorrhoeae; resistance to antibiotics is already a major problem. The increasing antibiotic resistance is a common topic of discussion among microbiologists, but I am somewhat astonished on how little this subject is being discussed elsewhere. To my surprise, not all my friends who research other topics know that interrupted antibiotic treatments could contribute to the emergence of resistant bacteria. In long term, I remain optimistic and believe that we will find new ways to combat antibiotic resistant bacteria. However, it might be a while before novel effective treatments could be developed. I think we could be facing a dangerous glitch: a period during which we lack effective treatments against infection, similar to the time prior antibiotic discovery. The current situation is urgent, but the pressure to find a solution is not what motivates me but rather pure curiosity. Every day, I start new experiments and evaluate the ones from the day before. To me, it is like having a surprise waiting for me every morning when I come to work.” As told to Anders Nilsson
Name: Béatrice Skiöld. Title: Researcher at the Department of Women’s and Children’s Health, Karolinska Institutet. Researches: The prematurely born brain.
“We want healthy little survivors” “Around five per cent of all babies are born prematurely, and more and more of those born very early are surviving. In my research, I look at the brain of premature children using different imaging technologies. The goal is to understand which factors, before, during and after the birth, determine how the children do in the long term. We are not satisfied with just saving the lives of these children; we want strong survivors without brain injuries or other problems later in life. Following an extremely premature birth, the parents are in chock. The last thing on their minds is some research study, so it’s no small thing to ask them for permission to study their child. But many of them are also grateful that this research is being done. They feel that neonatal care in Sweden is of a high quality, and they understand that we are trying to make it even better. Thanks to the progress that has been made, very few of the extremely premature babies develop severe brain injuries these days. On the other hand, it is still common to see milder development disorders, language difficulties and neuropsychiatric diagnoses like ADHD and autism. I think that in the future, we will be better at preventing these problems too, as we learn more about what the brain needs to develop normally. This may involve adequate nutrition but also things like closeness and physical contact. For me, this research is a break from all the intense feelings of despair and joy that I experience working as a paediatrician. It gives me time for thought and reflection. At the same time, my contact with the patients gives me a sense of what this research is for, so I always feel motivated. As told to Ola Danielsson
Medical Science–2015
19
Perspective UN’s Millennium Development Goals
Both a success and a fiasco The UN’s eight millennium development goals are due to be achieved next year. Three of them are directly linked to health and the outcomes vary, but the researchers are basically optimistic when they speak up about the future. Text: Lisa Reimegård Illustration: Dan Bejar/Theispot
T
HE MILLENNIUM goals were drawn up as a result of the millennium declaration, a plan for global development that focuses on the needs of vulnerable people. This was signed by 189 countries in 2000, an initiative of the UN’s then Secretary-General Kofi Annan. “In the years prior to the turn of the millennium, a number of conferences were arranged throughout the world that were concerned with various different prob-
20
Medical Science–2015
lem areas, but there was little action. The aim of the millennium declaration was to take collective action and show that all development is linked,” says Tobias Alfvén, researcher at the Department of Public Health Sciences at Karolinska Institutet and doctor at Sachs’ Children’s Hospital in Stockholm. Three of the eight millennium goals are directly linked to health and are concerned with child mortality among children under five, maternal mortality in conjunction with pregnancy or childbirth and major infectious diseases
THE MILLENNIUM GOALS ARE based on what the world was like in 1990, and state the measurable changes that should have taken place by 2015. For example, millennium goal number four states that worldwide child mortality is to be reduced by two thirds over the course of the period specified. Tobias Alfvén has many years’ experience conducting research that aims to reduce child mortality in countries like Uganda. “Many believe that child mortality hasn’t changed at all over the years, but it has decreased by almost 50 per cent worldwide since 1990. We will not achieve a two-thirds reduction by next year and the variations within and between countries are great, but we have made good progress,” he says. Despite child mortality having decreased sharply, 6.6 million children worldwide died before their fifth birthday in 2012. Tobias Alfvén describes the balance between highlighting successes and emphasising the importance of more initiatives, with measles as one example. “On the one hand, the number of children who die from measles has decreased drastically in recent years, which is a fantastic improvement. On the other hand, there is an excellent, cheap vaccine that is relatively simple to administer. So the fact that any chil-
Photo: Private
such as HIV/AIDS, malaria and tuberculosis. Other goals deal with such things as poverty, education, gender equality, access to water, the environment and aid. “The millennium goals have resulted in a significantly greater focus on health issues compared to in the past, not only on a global level within aid organisations and the UN, but also in individual countries. We now wanted to measure not simply economic development, but also health development,” says Tobias Alfvén and continues: “Economic development leads to better health, but improved health in a country also leads to better economic development. In the same way, all eight millennium goals are strongly connected to one another.”
“Economic development leads to better health, but improved health in a country also leads to better economic development.”
Photo: Private
dren die from measles in 2015 is a huge failure. But it is important to see both sides. We are making good progress, but we can do even more,” he says. Around 44 per cent of all children who die prior to their fifth birthday in 2012, died within the first 28 days following their birth. These deaths were the result of, for example, complications of premature birth or oxygen deficiency in conjunction with delivery. Other common causes of death among children under five are pneumonia, diarrhoea and malaria. Malnutrition is a contributory factor in about one third of the deaths. Tobias Alfvén is currently involved in three different projects associated with the prevention, diagnosis and treatment of pneumonia in children. In Uganda, because of a lack of healthcare, they have been training villagers to act as community health workers, whose job it is to hand out malaria medication to the children from the village who come to them with a fever. But sometimes the fever is not caused by malaria, but by pneumonia. “Consequently, in our study, the village health workers have also been given access to antibiotics that they give to the children who have a high respiratory rate and cough in addition to a fever, indicating pneumonia. The treatment results are good, but not perfect. Pneumonia is harder to diagnose than malaria,” says Tobias Alfvén. A PROJECT STARTED MORE recently, involves Tobias Alfvén and his colleagues from Uganda, collaborating with researchers from the Science for Life Laboratory in Stockholm, with the goal of developing a patient-centred rapid test that can use blood or nasal samples, to determine whether pneumonia and other infectious diseases are caused by bacteria or viruses. “We want antibiotics to be available to all those who need them, but the medication has no effect on viruses and overprescription leads to antibiotic resistance. A test like this would not only be useful in poor countries, but also
in countries like Sweden,” he says and adds: “I see huge advantages to this type of interdisciplinary project, involving doctors and engineers working together in both high and low-income countries. Everyone involved benefits and it increases our chances of continuing to improve global health,” he says. Another new study involves Tobias Alfvén and his colleagues looking at how a pneumococcal vaccine, which prevents diseases including pneumonia and meningitis, affects child morbidity and mortality in both Sweden and Uganda. Tobias Alfvén is confident that the worldwide reduction in child mortality will continue if we keep using research to
Facts The UN’s Millennium Development Goals 1) Half worldwide poverty and hunger. 2) Ensure that all children are able to go to primary school. 3) Increase gender equality and strengthen women’s status. 4) Reduce child mortality by two thirds. 5) Reduce maternal mortality by three quarters and provide universal access to reproductive health. 6) Stop the spread of HIV/AIDS, tuberculosis, malaria and other diseases, as well as providing universal access to HIV/AIDS treatment for those who need it. 7) Ensure environmentally sustainable development. 8) Promote global collaboration through increased aid, fair trade regulation and reduced debt burdens for developing countries.
discover how best to reach everyone with the existing preventative, diagnostic and therapeutic tools we currently have access to, while also continuing to develop new ones. But children’s chances of survival are also affected by maternal health. “In the poorest countries, child mortality is up to 90 per cent if the mother dies during childbirth,” says Tobias Alfvén. MILLENNIUM GOAL FIVE is devoted to maternal health and one of two interim goals is that maternal mortality is to decrease by three quarters between 1990 and 2015. So far, there has been a reduction of just over 45 per cent and close to 800 women die every day in conjunction with pregnancy or childbirth. Staffan Bergström is Professor Emeritus in International Health at Karolinska Institutet and called the result a fiasco in an opinion piece in the newspaper Dagens Nyheter last year. “If the economic resources had been invested we could have achieved the desired reduction, but aid has gone to other problem areas or failed to appear as a result of the financial crisis. Prior to the 1990s, maternal health almost never appeared in an aid context and it is thought-provoking that the millennium goal most closely related to women is still receiving so little attention,” he says. Staffan Bergström is also critical of the second interim goal, “universal access to reproductive health”. “What is ‘universal access to reproductive health’? This can mean anything from universal access to contraceptives to a universal right to be treated for involuntary childlessness. In some parts of West Africa, 20–30 per cent of the population are childless as a result of infertility caused by sexually transmitted diseases. In my opinion, this interim goal is completely plucked out of thin air,” he says and continues: “Of the eight millennium goals, the goal of improved maternal health is the one we have had the least success with.” A large proportion of all cases of materMedical Science–2015
21
Perspective UN’s Millennium Development Goals This is where maternal mortality is highest.
Facts: The goals have not been fulfilled – but development is headed in the right direction. This is where the most are infected.
9% Worldwide child mortality (percentage of children who die prior to their fifth birthday) 1990 and 2012.
Worldwide maternal mortality per 100,000 live births 1990 and 2012.
380
Worldwide new HIV infections 2000 and 2012 (in millions).
4,8% 210
1990
2012
nal mortality in conjunction with pregnancy and childbirth are due to bleeding and high blood pressure. Indirect causes such as malaria HIV/AIDS and heart diseases, complicated deliveries, miscarriages and unsafe abortions also account for deaths. “It is important to recognise that the majority of all women who die during pregnancy or childbirth are what is known as low-risk cases, it is not possible to predict in advance which of them are more likely to be affected. Consequently, the best thing we can do to improve mothers’ survival is to create functional healthcare systems in which women have the opportunity to receive emergency care,” says Staffan Bergström. He has himself been involved in several research projects in East Africa, the aim of which has been to delegate life-saving surgery such as Caesarean sections and other major interventions from doctors – who are often in short supply – to specially trained nurses and midwives. “In Mozambique, a surgical training programme for so-called non-doctors 22
Medical Science–2015
1990
2012
was begun in 1984 and 92 per cent of all Caesarean section in the country’s district hospitals are now carried out by non-doctors. Some of them have managed to perform 10,000 Caesarean sections, often without access to blood and antibiotics, with very good outcomes,” he says. A dissertation by obstetrician Caetano Pereira from 2010, supervised by Staffan Bergström, indicates that the outcomes of 1,000 Caesarean sections performed by non-doctors in Mozambique, were just as good as those of the same number of Caesarean sections carried out by doctors. In addition, close to 90 per cent of non-doctors remained at the district hospitals in Mozambique seven years after they started working there, while all doctors moved away over the course of the period in question. “Right now we are analysing the outcome of about 7,000 obstetric operations performed by non-doctors in Mozambique, nearly half of which were carried out by midwives. And this is unique. Mozambique is the first country in the
3,4 2,3
2000
2012
world to train midwives in advanced surgery,” says Staffan Bergström. In addition, Staffan Bergström leads a project in Tanzania that also partly involves delegating duties from doctors to non-doctors, but also about decentralisation; upgrading small clinics in the countryside, without access to electricity and running water, into more advanced healthcare facilities staffed by care personnel with surgical training around the clock. “We have built solar panels and operating theatres, drilled for water and installed generators. This has been significant in reducing maternal mortality in the areas in question, because women can now avoid time-consuming travel,” he says. Staffan Bergström argues that delegation and decentralisation is what is needed to reduce global maternal mortality further – and more knowledge. “We would need about 400,000 more midwives worldwide. And we need them now. The absolutely most decisive historical factor behind Sweden’s current
low maternal mortality is the establishment of midwifery services,” he says. Changing societal structures, in which child marriage and teenage pregnancies are common and the status and educational level of women are low, are also important in reducing maternal mortality, according to Staffan Bergström. MILLENNIUM DEVELOPMENT GOAL
Photo: Studio Gimlin
six, the third millennium development goal concerned with health, states that the spread of HIV, AIDS, malaria and other major diseases is to have ceased and be on the decline by 2015 and that all those who need them are to have access to HIV/AIDS treatment by 2010. “Halting and reversing the spread of these diseases have been achieved in many countries. But only about half of those who need treatment for HIV/ AIDS, currently have access to it,” says Anna Mia Ekström, Professor of Global Infection Epidemiology, with a focus on HIV at the Department of Public Health Sciences at Karolinska Institutet and at the Infection Clinic at Karolinska University Hospital. She argues that the goal to reach all those in need with treatment was unrealistic and she also makes a comparison with the measles vaccine. “If we have not succeeded in reaching everyone with a cheap vaccine provided on a single occasion, how are we to reach all those in need of expensive medications that are taken every day, that have side-effects and which are also connected with a disease that is usually associated with shame? But politicians and global policy-makers have to draw up goals they can live to and it is often good to aim high. Nevertheless, access to HIV treatment is increasing all the time and real progress is being made,” says Anna Mia Ekström. Her own research deals, among other topics, with how to get medication to the people living with HIV in a better and more efficient way than today, and how they can be made to continue their
treatment in spite of great social and financial challenges. “The medication is extremely good protection against premature death and those who receive treatment are able to live normal lives. A high level of adherence also reduces the risk of the infection spreading and of a resistance developing,” she says. Several of the research projects Anna Mia Ekström is involved in are concerned with HIV infection transmitted from mother to child in Kenya and Tanzania, the goal of which is to get more HIVpositive women onto medication while pregnant and breastfeeding. “HIV transmission from mother to child takes place in conjunction with pregnancy, delivery and breastfeeding, but if the mother takes HIV medication, the risk of infection is reduced from one in three to less than five in 100,” she says. She and her colleagues have attempted to survey the factors that govern access to treatment and adherence. “We have seen that individual circumstances, often linked to poverty and the woman’s role in relationships and the community, mean that women not only go without treatment, but also that they do not take the medication they do receive.” Thanks to this knowledge, however, healthcare personnel can give better advice and adjust their delivery to get medication to more people and get more of them to actually take it. Aside from access to treatment, the spread of HIV is primarily affected by sexual behaviour, according to Anna Mia Ekström. The most infectious are those who have themselves recently been infected, who in addition are often unaware of carrying the virus. “Transmission is greatest among those who have several sexual partners and where there is a lack of knowledge about how HIV is transmitted and how to protect yourself,” she says. Anna Mia Ekström also explains that the risk of catching HIV/AIDS is not something that people in poor countries always have the time or the opportunity to think about,
“New discoveries are important and exciting and I hope and believe that within 30 years we will be able to successfully cure HIV.”
even though many know how the virus is spread, because they often have more pressingly immediate problems. “You have to survive the day and find food for yourself and your children. The risk of being excluded or becoming even poorer if you discuss your HIV status, abstain from sex or require a condom is more immediate, especially for women, than the risk of being infected with HIV,” she says. She has studied what makes young women in South Africa subject themselves to serious risk of infection. In 2012 it was estimated that 35 million people were infected with HIV worldwide, 25 million of whom were in subSaharan Africa. Just over six million of them were in South Africa. “Just like other young women around the world, poor girls in southern Africa want to have their own income and the opportunity to sometimes buy the things they want and gain higher status among their friends. Some achieve this by having sex with older men who give them money, but at the same time subject themselves to a very high risk of both HIV and violence,” she says and proposes that educational opportunities, recreational activities, female role models and easily accessible condoms could reduce the spread of the infection among young women. ANNA MIA EKSTRÖM has high expectations that HIV/AIDS-related mortality and transmission will continue to decline after 2015. Just like Tobias Alfvén and Staffan Bergström, her demands included better healthcare systems for reaching out with treatment and knowledge that already exists. “Of course, new discoveries are important and exciting and I hope and believe that within 30 years we will be able to successfully cure HIV. Or at least a treatment that reduces levels of the virus to such a low level that those infected can live for long periods or the rest of their lives without further treatment,” she says. A large effort, concerned with what will happen once the end date of the millennium goals for global development has passed, is underway. “It is most likely that new goals will be established, probably with a wider focus that takes in more areas than the millennium goals,” predicts Tobias Alfvén. Medical Science–2015
23
Interview Lars Lund
His beats for the forgotten 24
Medical Science–2015
Lars Lund is troubled that many patients with heart failure do not receive the care they need. Through his research, he is attempting to highlight the problem in a systematic way – and find solutions. Meet the doctor who is passionate about improving cardiac care for all. Text: Cecilia Odlind Photo: Martin Stenmark Medicinsk Vetenskap №1–2014
25
Interview Lars Lund tired and old. But, having learned more, we have now realised that diastolic heart failure is a separate diagnosis. Our research goal is now to understand the disease better, find ways to treat it and make treatment available to patients,” says Lars Lund. USING EXISTING REGISTRIES
ARS LUND REMEMBERS HIS VERY first patient as a medical student. “It was heart failure, with all its symptoms: difficulty breathing, fatigue, swollen body. It all boiled down to the patient’s heart.” It is the most deadly of all the common diseases and the most common cause of hospitalization. Heart failure is common, serious and causes a great deal of suffering. “Consequently, new treatments can make a big difference for a large number of people. This gives my work meaning, both as a clinician and a researcher,” says Lars Lund, consultant physician at the Cardiology Clinic at Karolinska University Hospital and research group leader at the Department of Medicine, Karolinska Institutet, Solna. Three percent of all Swedes suffer from heart failure, wich means that the heart is not able to pump blood around the body as it should. In about half of all sufferers, the heart failure is caused by the heart muscle’s inability to contract, known as systolic heart failure. But in the other half, the problem is instead caused by the heart having a reduced ability to relax again once it has contracted. Over the past decade, we have gradually been learning more about the latter form, known as diastolic heart failure, which is the main focus of Lars Lund’s research. “This sounds strange, but until recently this group of patients, who suffer greatly from their disease, have been completely invisible. People who sought help have previously been dismissed as 26
Medical Science–2015
containing information about all of Sweden’s heart failure patients, he and his colleagues have been able to demonstrate that this form of heart failure is more common among women and the elderly, and that the reason why these patients are more frequently affected is uncertain. Registry studies are also the basis of what Lars Lund believes is his most important discovery – that commonly used blood pressure medications can improve survival in these patients. This study was published in 2012 in the well-regarded American scientific journal JAMA. “The results need to be verified, but if they are correct, this means that the lives of more than 100,000 Swedes can be extended. It’s a great feeling,” he says. In order to understand diastolic heart failure better, Lars Lund’s research group is supplementing the registry studies with basic physiological measurements of, for example, blood flow and blood pressure in heart failure patients in a special research laboratory located one floor above the coronary care unit. In this way, they hope to find
Name: Lars Lund Title: Consultant physician at the Cardiology Clinic, Karolinska University Hospital, research group leader at the Department of Medicine, Karolinska Institutet, Solna. Age: 45 Family: Partner and one son. Influenced by: Has lived in the USA for large parts of his life and undertook his entire medical training there. Motto: It is not the work you do that wears you out, but the work you don’t get done. Daydream: Sometimes I wish that I had researched cancer instead, where the goal is to find a distinct cause and an eventual cure. Why I am a good researcher: I don’t allow carelessness, vague data or illogical reasoning. I continually ask myself the question: What am I trying to do?
biomarkers that can simplify diagnosis. In addition, they are investigating in detail how the heart muscle functions by comparing molecular mechanisms in cells from mice and people with heart disease. It was during cellular studies like this that Lars Lund and his colleagues at Karolinska Institutet and Columbia University in New York made their most surprising discovery – that heart failure is visible in muscles other than just the heart. “The molecular changes that appear in the heart muscle cells in heart failure also exist in skeletal muscle cells. This indicates that heart failure is a disease that affects the entire body,” says Lars Lund. He believes it is important to understand that it is a heterogeneous disease with multiple causes. “We won’t find a gene that can explain heart failure all on its own, there isn’t one. When the heart has already suffered damage, it also becomes hard to completely cure heart failure, and it will continue to be a serious illness for many people. Nevertheless, we can already achieve real improvements for patients, such as a reduction in hospitalisation and improved quality of life, and there is hope that the future will bring new treatments,” he says. Thanks to Lars Lund’s academic questions being constantly connected to the clinical needs he sees among his patients, he has the opportunity to adapt his research to care. “Every day, the patients have questions that I attempt to tackle in my research. And I can also recruit research subjects from among the patients.” But in recent years, the opportunity to find research subjects has decreased due to serious cutbacks. The number of beds at the Cardiology Clinic at Karolinska Institutet has decreased dramatically in recent years. Similar changes have taken place at other large hospitals in the country. This has not only caused problems in recruiting research subjects, but has also, which is worse, resulted in poorer patient care according to Lars Lund. “Our research shows that the treatment of heart failure patients in Sweden is seriously neglected. Many more patients could be helped if they were given the right medication and a large proportion of those who are in need of more advanced care such as pacemakers, heart pumps or transplants, do
not currently receive them. One explanation is that many patients never get to see a specialist physician and therefore do not receive the right treatment. There are also too few beds allocated to heart failure patients in proportion to the incidence and severity of this disease,” he says. THIS PROBLEM HAS been observed in several places and a large collaborative project involving Karolinska Institutet and Stockholm County Council, called 4D, has heart failure as one of four priority diseases. The 4D project has goals that include speeding up the transformation of research results into new and improved treatments. Lars Lund is participating in the project and believes that it is a good way to avoid the feeling of dejection. He also thinks his research will have an impact on the situation: “We have recently published a study analysing how to prioritise heart failure patients when resources are limited. The hope is that this can contribute to those most in need getting the help they require,” says Lars Lund. Being committed both to the patients and to research takes time and effort. Sometimes it is hard to find the time for research; he is currently only doing it half-time. But, despite this, meeting patients is not something Lars Lund wants to do without. “I am afraid of losing the expertise. But also the link to reality - patients reflect the world in which we live.” In his role as a doctor, Lars Lund often meets relatives who are surprised by the deficiencies in the healthcare system such as the lack of single rooms, postponed treatments and stressed staff. When he speaks about this subject he gets fired up. “For me it is as clear as daylight that these deficiencies are related to how
Lars Lund on …
Do you want to have a new car or good healthcare? More people should ask themselves this question, according to researcher and heart doctor Lars Lund.
we have chosen to prioritise society’s resources. Do we want everyone to afford a flat-screen TV, a newly renovated bathroom and a nice car? It comes at the expense of a well-functioning healthcare system. But most people only realise this when they or someone close to them become ill. Personally, I think that many of those who have been in this situation would prefer to give up their new TV or car if they knew that it would give them the chance to talk to the doctor on a Saturday.” Perhaps even more so if that committed doctor is Lars Lund.
… translational research: “Really working the whole way from molecule to patient is hard for an individual researcher, but done correctly it provides a unique opportunity to link mechanisms to everyday patients.”
… good research: “Requires you to be able to formulate a strict, rigorous and specific question for yourself and others. Well-organised implementation can then later provide valid and reliable results.”
… saving money in the healthcare system: “Healthcare must be allowed to cost money. The question that should be asked is instead whether it is value for money, cost-effective and whether we are prepared to pay for it.”
… leading a research group: “It is like being a researcher and running a small business at the same time. I have responsibility for the budget, staff and production of my research group, which currently consists of 10 people.” Medical Science–2015
27
In depth In depth Obesity ty
Full of SIZE MATTERS
Many small fat cells are better than a smaller number of large ones.
YOUNG The average age of a fat cell is 9.5 years.
DANGEROUS Obesity increases the amount of inammation in the fatty tissue which increases the release of harmful fatty acids.
Due to an excess of quick calories and too little physical activity, we have created the global obesity epidemic. At the same time, the human body is very unwilling to let go of the fat that it has stored. Fighting obesity is thus essentially a battle against ourselves. Text: Fredrik Hedlund Short interviews: Annika Lund Illustration: Anders Kjellberg Photo: Henric Lindsten and Christian Andersson
REGULATORY This is where the satiety hormone leptin and the hunger hormone ghrelin are formed.
NECESSARY
fat
The fatty tissue is the body’s biggest producer of proteins.
T
HE OBESITY EPIDEMIC began in the USA sometime in the 1950s and 1960s, but it became clearly noticeable in the American society in the 1980s. In Sweden, the epidemic began to show clearly during the 1990s and is now fully evident. Currently, half of all adult Swedish males, just over one third of all women and every fifth child is overweight or obese. There are many theories and explanations about what caused this dramatic development. However, it essentially boils down to that obesity is due to eating more than you need to. And there are researchers who argue that this is exactly what we have been deceived into doing. “What mainly happened over this period was the fast food invasion. I think this is the primary explanation for the current obesity epidemic. What characterises fast food is that it has an extremely low nutritional content, but an extremely high calorie content. It’s full of fat, sugar and salt and these are what light up our taste-buds and brain,” says Erik Hemmingsson, researcher at the Department of Medicine at Karolinska Institutet and tied to the Obesity Centre at Karolinska University Hospital in Huddinge. We return to Erik Hemmingsson and his discussion, but first a few important things about fat need to be explained. Fat is good. We would not survive without fat. Fat is the body’s most important energy store. Fat is used as fuel in all of the body’s cells and is also found in the surface structure and membranes of cells. Some people have adipose tissue that does not form properly. This is a very rare condition that demonstrate what
30
Medical Science–2015
happens when fat storage does not work as it should. “These patients have very high levels of lipids in their blood and diabetes that is hard to treat. The body needs a warehouse where it can store energy for short periods. If it doesn’t have this, storage takes place in the liver and muscles and this means a huge impact on metabolism,” says Ingrid Dahlman, researcher at the Department of Medicine, Karolinska Institutet. Interestingly enough, these are the same complications seen in obesity. “This shows how important the adipose tissue is for storing reserves. We think that there is a similar mechanism in common obesity. When someone eats too much, the excess is stored in the fatty tissue. But when the ability to store energy in the fatty tissue is exceeded, this spills over into the liver and muscles and causes disorder there,” says Ingrid Dahlman. FOR A LONG TIME, the fatty tissue has only been regarded as a static storage space for fat. However, researchers have recently begun to understand that the fat cells and the fatty tissue they form is much more complicated. About 20 years ago, it was demonstrated for the first time that the fatty tissue also functions as a gland that produces hormones, enzymes and inflammatory proteins. “Fat is the body’s biggest producer of proteins. This is actually pretty surprising. It is believed that thousands of proteins are produced in the fat, but we have not yet come close to charting them all,” says Peter Arner, professor at the Department of Medicine, Karolinska Institutet, who has been studying fat for 45 years. One of the hormones from the fatty tissue that has been identified is leptin. It is perhaps most known because of the leptin mouse, which very clearly demonstrates the effects of this hormone. The leptin mouse lacks the ability to produce leptin as a result of a mutation and has an enormous appetite, which means it quickly becomes so fat that it can easily weigh more than twice what a normal mouse does. Leptin signals satiety. Another fatty tissue hormone, ghrelin, signals hunger and together these two work as the backbone of hunger/satiety regulation.
Other hormones from the fatty tissue contribute to regulating sugar turnover and blood pressure, for example. But the fatty tissue is complex in more ways than this. For example, there are two different types of fatty tissue, which have different densities. People either have lots of small fat cells or a small number of large ones. But there is no connection to whether the person is fat or thin. However, there are great medical differences between the different types of fatty tissue. “Having a small number of large fat cells is bad, as these people are at an increased risk of diabetes, insulin resistance, elevated blood fats and elevated blood pressure. So it’s bad to have few large fat cells and good to have lots of small ones,” says Peter Arner. Why people have different type of fatty tissue is still not entirely clear, but Peter Arner and his research group have recently published an article describing the first gene regulating this. “A transcription factor called EBF1 (Early B Cell Factor 1 ), appears to regulate the number and size of fat cells,” he says. In this article, the researchers also show that EBF1 is down-regulated by inflammatory signalling substances in the fatty tissue, which could explain why some people have fewer fat cells than others. But the exact link has not yet been demonstrated. Regardless of cause, the fact remains that it is good to have many small fat cells and bad to have few large ones. The reason being that large fat cells behave differently than small ones. Even if the researchers do not know exactly how it happens, the effect is that the large fat cells release more waste products such as fatty acids, which is bad for the body. But there´s more to it. “The fat is also more inflamed in those who have large fat cells than in those with small fat cells, which in turn can affect hormones controlling blood pressure and insulin sensitivity,” says Peter Arner. According to Peter Arner, having good fat is more important than the quantity of fat you have. This may explain why some fat people are still healthy and completely free of the metabolic effects of obesity. The size of the fat cells also says more about metabolic health than the Body Mass Index (BMI) does. Consequently, it would actually be good if there was some form of test for fat cell size. And this is possible, but it is not a routine test that can be carried out
Photo: Stefan Zimmerman, private
In depth Obesity
Photo: Ulf Sirborn, Istockphoto. Illustration: Anders Kjellberg
at a primary care centre today, perhaps it will be in the future, thinks Peter Arner. But until then, he has a simple test that anyone can do themselves. “We have released a measure that we call one metre waist. If your waist circumference is more than one metre, you are in the danger zone. You measure with a measuring tape at the navel, it is really simple. Those who have a large waist often have large fat cells,” he says. IN THE SAME WAY that fatty tissue was believed to be nothing but a storage space for fat, until five or six years ago it was also believed that people’s fat cells stayed the same throughout their entire lives. This was also wrong. Some years earlier, Australian researcher Kirsty Spalding had moved from Australia to work at the Department of Cell and Molecular Biology at Karolinska Institutet. Thanks to a revolutionary new method using carbon-14 to determine the age of cells, she was able, together with Swedish researcher Jonas Frisén, to demonstrate that our brain cells are renewed. The carbon-14 method is normally used to date archaeological finds or establish whether Renaissance paintings are genuine by measuring the remaining radioactivity in carbon-14 that has a half-life of just under 6,000 years. This is dealing with thousands to hundreds of years. Kirsty Spalding now used the same technique to determine the age of cells down to individual years. “We are able to do this because of the atmospheric nuclear weapon tests carried out in the middle of the 1950s and the beginning of the 1960s. Atmospheric bomb-testing created a massive increase in carbon-14 in the atmosphere between 1955 and 1963, called the bomb spike. In 1963 a test-ban treaty was signed, limiting all above-ground nuclear bomb testing, resulting in an exponential decrease in atmospheric 14C levels. We are not completely down to the levels prior to the bomb-testing period, but we are getting close,” she says. By studying cells from people born at various times along the time axis from about 1920 until present, it is possible to show whether cells have been renewed during a person’s lifetime. By accident, Peter Arner came into contact with Kirsty Spalding who, after a bit of adjustment, was also able to use her
“There appears to be a funcion that retains the higher number of fat cells despite going on a diet and losing weight” method on fat cells. They appeared to be replaced many times over a person’s life. “We gain about 10 per cent new fat cells each year. In 8.3 years we have exchanged approximately half of our fat cells,” says Kirsty Spalding. But this turnover of fat cells is strictly regulated, with the birth and death rate of fat cells balanced in weight-stable individuals. Cross-sectional studies indicate that fat cell number is stable in adults, even following significant weight loss. However, crucial longitudinal studies, where individuals and their number of fat cells are followed across the lifespan, are missing from the literature. “The number of fat cells appear to be very stable over short periods, and even people who dramatically lose weight retain the same number of fat cells. But I have a hard time believing that people
who become extremely fat only increase the volume of their fat cells. In addition, there is at least one study showing that women who gain weight can increase the number of fat cells they have in their thighs, so I think that under certain conditions we can gain more fat cells, as least in certain tissues,” she says. But just because it is possible to increase the number of fat cells, it is not necessarily as easy to go in the other direction, something which may explain why it is so hard to lose weight. “We may be programmed in a way that allows us to increase the number of fat cells when gaining weight, but there is little evidence that we can reduce the number of fat cells we have. There appears to be some function that retains the higher number of fat cells despite going on a diet and losing weight,” says Kirsty Spalding. In which case, this is bad news for all those who want to lose weight. “Yes, it is definitely a signal to take care of yourself at an early age. Because the number of fat cells appears to be maintained and if you have an increased number of fat cells when you are young, everything points to it being impossible to reduce this number later in life.”
Facts : Different types of fat
BROWN FAT When we are born, we have a thin layer of brown fat under our skin which then disappears. Brown fat can burn fat and create heat, this is important for infants’ ability to maintain their body temperature.
IN BETWEEN
WHITE FAT The vast majority of fat in adult bodies is white fat, which stores energy, but cannot burn it.
A new type of fat cell has recently been discovered which looks like white fat, but works like brown fat and has been given the name brite, from “brown into white” White fat cells are transformed into brite cells when it is cold. But researchers have now found a way to chemically stimulate white fat cells to become brite cells. Even if this is a long way from becoming a reality, this is a possible pathway for a future drug that will be able to burn fat.
Medical Science–2015
31
In depth Obesity Facts : BMI thresholds, kg/m2 Body Mass Index, BMI is calculated by dividing weight by height, squared (kg/m2).
Waist circumference. Provides a good indication of the risk of developing consequential metabolic diseases. Men 94-102 cm > 102 cm
Normal weight 18,5–24,9
But what is behind the obesity epidemic that has suddenly affected humanity? As with many other diseases, it is a combination of heredity and environment, but researchers are in agreement that genetics are not the decisive factor. “It is usually said that 60–70 per cent is genetics and the rest is environmental factors. But if you think a little further, you might realise that this is not the case actually; because you’ll never become fat if you don’t eat too much. From that perspective, you could say that it is always environmental factors. If you don’t eat too much, you don’t develop obesity, regardless of your genetics,” says Claude Marcus, professor at Karolinska Institutet and research supervisor at the Swedish National Childhood Obesity Centre at Karolinska University Hospital in Huddinge. Not even Peter Arner, who has recently published a paper on his discovery of the first gene controlling fat cell development, argues that genetics is of vital significance. “There are many who want to believe that you become fat because you have a problem with your metabolism, and this might be the case for a few people, but I have to say that the most common cause is eating too much and not getting enough exercise. Those who put on weight more easily are those who eat a little more and move a little less than others. There are quite a large number of studies indicating that this is the case,” he says. But what is it that makes people eat more than they need to? Most evidence points to a combination of social and psychological/emotional factors. In the 32
Medical Science–2015
Overweight 25–29,9
Obesity x 3 Obesity Grade I Obesity Grade II Obesity Grade III
West, there is a very distinct link between obesity and low socio-economic status. Those who become obese are often poorly educated and poor. “I believe that the social environment in which people grow up affects them a great deal. If the parents are poor, then we know that the incidence of substance abuse is higher, there is less of a social safety net, there is more exclusion, there is more criminality, quite simply more misery,” says Erik Hemmingsson. He has recently published a completely new model of how psychosocial and emotional stress contributes to obesity. “My theory is that there is a very detrimental impact on children who grow up in an insecure environment, in contrast to children who grow up in a secure and harmonious environment. This impact includes effects on stress, metabolism and compensatory habitual patterns,” he says. CLAUDE MARCUS, who has studied childhood obesity, for example in “Early STOPP” (Stockholm Obesity Prevention Project), can confirm the clear link to low socio-economic status, and that the effects on weight begin very early. “As early as at one year old, we see
”For children, primarily younger children, things are looking better now than they did five or six years ago. ”
Risk Increased Very increased
CRITERIA FOR SURGERY Criteria that are currently used: BMI >= 40 or BMI >= 35 with obesity-related morbidity. (some county councils in Sweden use BMI over 35 regardless of comorbidity).
LIPOSUCTION A COSMETIC INTERVENTION As opposed to the surgical methods, liposuction does not have any positive impact on other morbidity. Metabolic morbidity remains the same five years after liposuction, despite a large weight reduction.
that children of poorly educated parents are a little bit more obese than those of well-educated parents. We are not quite sure why.” But a comparison with the results of a similar study Claude Marcus’ research group is conducting in China clearly indicates that this effect is dependent on social factors. There it is instead the children of well-educated parents who are obese. “There, it is still considered a status symbol to give their children soft drinks and go to McDonalds,” he says. Claude Marcus’ most plausible explanation is close to Erik Hemmingsson’s theory about insecurity, but among the parents. “We believe that some form of insecurity results in the children being given too much food because their parents believe they might be getting too little,” he says. Otherwise, things are generally going in the right direction in Sweden at the moment, but not in all groups. “For children, primarily younger children, things are looking better now than they did five or six years ago. Nevertheless, it appears that segregation is on the increase. What I mean to say is that
Photo: Ulf Sirborn
Underweight < 18,5
Women 80-88 cm > 88 cm
Photo: Henric Lindsten/Lindsten&Nilsson
“I had the surgery for the sake of my health” Ellinor Westh Olsson, who is now 31, was considered chubby already in primary school and piled on the pounds over the course of her school years. Early in adult life she moved with her partner to Västerbotten and then started gaining weight faster. This is where she first felt lonely and started comfort eating, and then she began working the night shift. “Working at night create an imbalance. I actually only ate once per day, nutritious meals, but I still gained weight. I think that working the night shift did something to my metabolism.” After taking part in a behavioural medicine programme, in which she was supported in changing her lifestyle, Ellinor lost 17 kg. This happened at the same time she started working during the day, so it is unclear what caused the positive results. Then she injured her back. A heavy lift at work resulted in several slipped discs, with a loss of sensation and difficulty moving; her mobility was still not good following two back operations. Ellinor needed an operation to fuse joints in her lower back, but in order to do this she had to lose a lot of weight. It was hard to achieve this with reduced mobility, so at a BMI of 47, Ellinor decided to have gastric bypass surgery. The operation has been effective. Now she has a BMI of 30 and wears size 40/42 on her upper body. She was able to proceed with the back operation, and can now ride a bike, walk and live a normal life. “I actually didn’t have a problem with my self-image when I was overweight. I was happy in myself and with my body and I got married when I was as big as I got. For me, this was about my health. I wanted to make things easier on my back, and it’s worked,” says Ellinor. With some anger in her voice, she notes that she is now treated in a different way; more friendly and with more respect. “If I meet people on the pavement they sometimes move to make way for me. Before, it was always I who had to move, something I never thought about at the time. I am exactly the same person I was before, but yet people look at me in a completely different way. That’s not OK.” Medical Science–2015
33
Per-Åke Persson is a trained chef and works as a head chef. This is both a salvation and a curse – on the one hand, he knows exactly how to prepare nutritious food, but on the other he is surrounded by unlimited quantities of tasty treats all day long. “Food is a big part of my life. I know exactly how to create a good meal. The problem is discipline. Tasty sandwiches are a particular temptation of mine.” He slowly started gaining weight already during his childhood, when his mother prepared a lot of tasty food. When he started working, his weight gain continued. Per-Åke’s weight has gone up and down throughout his entire adult life, a few kilos down and a further few up. In the end he weighed over 120 kg. “I didn’t like myself when I was fat. I felt that people looked down on me when I was on the beach and that hurt me. But I denied that I had a problem with my weight, bought bigger clothes and stopped looking in the mirror. It was horrible. I have always thought it was wrong to be fat. It is hard to move about, you have pain everywhere, aching knees and you get other diseases.” A female colleague, who was also struggling with excess weight, succeeded in losing a lot of weight with the help of Weight Watchers. Her success spurred on Per-Åke, who came along to a meeting with her. The encouraging atmosphere where you receive praise from the group and a personal coach, in combination with strong motivation, was a recipe for success. He now tips the scales at about 78 kg. “Quite simply, I was determined that it would work. And it did. Now I’ve plucked up some courage. It is really fun to buy clothes and I’m happy with my body again.” 34
Medical Medicinsk Science–2015 Vetenskap №4–2014
Photo: Christian Andersson
“I didn’t like myself”
Photo: C Meadow, Istockphoto
Obesity In depth obesity is increasing among children in lower socio-economic groups, while in others it has plateaued or is decreasing,” says Claude Marcus. Consequently, we should be targeting more interventions at lower socio-economic groups, he argues. “There should be a huge opportunity to have an impact on the situation via paediatric primary care centres, with the help of specific support to families in more socially disadvantaged areas,” says Claude Marcus. Another way to combat excess weight and obesity is to work much more purposefully in schools and preschools. Several years ago, Claude Marcus conducted an experiment in which a number of schools with associated after-school recreation centres began having more physical activity during lesson time, improve the quality of school lunches and have zero tolerance to sweets in school at the after-school recreation centre. These would then be compared with schools and after-school recreation centres that had not changed, control schools. “We randomly selected which schools would change and which would stay as they were. But not all schools wanted to be involved; none of them wanted to be in the control group and we begged and pleaded to those who were in that group not to do too much, but they still did a bit. But what they didn’t do was to introduce zero tolerance to sweets as this was the hardest to implement,” says Claude Marcus. After four years, the researchers could still demonstrate a statistically significant difference between the schools, with pupils in the schools who changed having a lower prevalence of obesity. It appeared that the children had also begun eating better at home. “They ate fewer sweets, less fatty milk products and more fibre-rich bread than pupils in the control schools. Our hypothesis is that many parents want to say no to sweets as an everyday thing, but that it is difficult if professional educators think it is OK. We mainly saw differences among poorly educated parents. So one of the answers to the question of how to reach those who need it most are for schools and after-school recreation centres to do this indirectly by setting a good example,” he says. But for the children who are already obese, they cannot simply wait and see if it is a passing phase, rather they have to seek help as soon as possible.
The older the child is, the harder their obesity is to treat. “At the age of six or seven, there is a treatment effect over three years that has a definitive impact on health in 90–95 per cent of cases. After this, there is an almost linear decrease. If treatment begins when the children are 14–15 years old we see pretty much no effect, we succeed in less than five per cent of teenagers. The message is that you have to begin treatment early, before ten years of age,” says Claude Marcus. THE RESEARCHERS ARGUE that the society we have created is one of the primary causes of the obesity epidemic. A society where everything is available, pretty much whenever you want, and an attitude to food that has changed dramatically. “Twenty-five years ago, it was unseemly to walk along the street eating something. You would sit down to eat and would not snack between meals. Now it is standard behaviour to walk and eat and snacking is not considered immoral anymore,” says Claude Marcus.
Facts: Diseases caused by obesity Obesity is defined as a disease in itself. In addition it carries with it an increased risk of the development of other diseases. Type 2 diabetes Cardiovascular disease Sleep apnoea Liver disturbances Musculoskeletal problems Infertility Cancer Psychological problems (women in particular have an increased risk of depression, bipolar disorder, panic disorder and agoraphobia)
Erik Hemmingsson also indicates that the changes in society of the past 30–40 years are the main cause of obesity. He points specifically to the explosion of fast-food restaurants such as McDonalds, Burger King and the like. “Without a doubt, the fastfood industry bears a huge responsibility,” he says. It is even more unfortunate that these chains attract children with toys and figurines from the latest Disney films, he argues. Children do not want to go there for the food; they want to get the toys, but they learn to associate them with fast food. And the parents are happy that their children want to eat. He also argues that contemporary production methods create products that are not as good as they were in the past. “The food we ate 100 years ago, that had grown slowly in the earth, was full of nutrition. The food industry now forces production in order to get more in a shorter time, which dilutes the nutritional content,” he says. He therefore argues that we should choose organic vegetables and meat and prepare food from scratch instead of eating fast food and highly processed partially prepared products in order to make food as nutritious as possible. Claude Marcus argues that we have gone too far and must return to certain old principles that were actually pretty sensible. One of these is regular mealtimes. Today, when everyone in the family has different activities in the evening, the way mealtimes are organised has been completely changed in many families; this contributes to the development of obesity, he argues. “I believe that one of the most important factors is the regularity of food intake and not snacking between meals. I argue, almost a little neo-moralistically, that everyone should eat breakfast, lunch and dinner at the same time and only eat fruit in between times. And drink water or skimmed milk with your food,” he says. Calorie-rich drinks such as soft drinks and juices should not be consumed with everyday meals, he argues. Not only do they contain empty calories, but we also have a really hard time evaluating liquid calories. When it comes to solid food, we have a sort of calorie memory, which means that we do not feel as hungry the day after having eaten a big dinner. The Medical Science–2015
35
In depth Obesity
Physical activity is very important for general well-being and for creating muscles that burn more fat. Exercising also has a clear effect on the dangerous abdominal fat. But as a method of weight loss its results are discouraging. Objective measurements show that obese adults and children are just as mobile as those of a normal weight. And exercise as a weight-reduction treatment shows a redistribution from fat to muscle, but no effect on weight.
body controls its intake of calories in this way and maintains it at a relatively constant level over time. But this does not work at all as well with liquid calories. “There could of course be an evolutionary explanation for this. Calories in liquid form have not existed for more than a few hundred years,” says Claude Marcus. IF CONTEMPORARY SOCIETY
strongly contributes to people becoming overweight and obese, the human body makes the greatest possible contribution to maintaining the increase in weight. Those who try to lose weight are really embarking on a battle against nature. “When you lose weight, the size of the fat cells decreases. But this also lowers their metabolism, which means that the energy requirement goes down. In addition, they release a smaller amount of the satiety hormone leptin, which makes you more hungry. The entire system appears to be rigged in order to maintain the body weight you have attained. The whole of nature is working against weight loss,” says Kirsty Spalding. Something that all those who have tried to lose weight can testify to. This is also seen clearly when different treatments are evaluated scientifically. There are plenty of reviews of different diets, pharmaceutical treatments, exercise and other activities that are used for weight reduction and they all show the same thing. Treatment can lead to an average weight loss of up to eight to ten kg over the course of six months to a year that can be sustained for a few years thereafter. But sooner or later, most patients return to close to their initial weight or, not uncommonly, exceed it. What is difficult is not losing weight quickly, but maintaining the new weight and avoiding a weight rebound. 36
Medical Science–2015
Erik Hemmingsson recently published an analysis of 20 different high-quality studies encompassing over 3,000 people, which investigated different methods for avoiding this weight rebound. Following an extremely low-calorie diet that resulted in an average weight loss of just over twelve kg, the participants were randomly assigned to different weight maintenance treatments or to the control group. The comparisons falter a bit as the treatment times varied from three to 36 months in the different studies, but it shows that meal replacement was successful in reducing the weight rebound by 3.9 kg, medication by 3.5 kg and a high-protein diet by 1.5 kg, while exercise and dietary supplements did not successfully affect the weight rebound at all. “Despite some strategies being able to reduce the weight rebound, the effects were without exception modest, which clearly reflects the limitations of lowcalorie diets,” says Erik Hemmingsson. The only method that has so far been shown to result in significant and enduring weight loss is bariatric surgery. The SOS (Swedish Obese Subjects) study, run from the Sahlgrenska Academy in Gothenburg, monitors patients who have undergone obesity surgery and compares them with a control group whose obesity has been treated in other ways. The study has recently published 20-year data. “On average, those who had surgery are about 20 kg lighter after 20 years, while the controls are near their baseline weight,” says Martin Neovius, researcher at the Department of Medicine, Solna, at Karolinska Institutet. The most frequently used method of surgery in Sweden today is the gastric bypass, which involves food being directed past the stomach directly into the small intestine. It is an extreme method, but it works and the weight loss also has an impact on other obesity-related morbidity. “Aside from the weight loss, we have seen a reduced risk of myocardial infarction, stroke, cancer among women, early death and diabetes, as well as an increased chance of maintaining diabetes
BUT IF IT is not possible to perform surgery on all obese people and other treatments only have a marginal effect, something different must be done to deal with the obesity epidemic. And researchers believe that this is coming. Peter Arner argues that there are many possible approaches that could be employed by future treatments. “You could tackle the turnover of fat cells and their fat content, halt the breakdown of fat a little or perhaps affect the hormones and inflammation in the fatty tissue,” he says. Kirsty Spalding also sees several possible paths to a future enduring weight loss, even though she cautions that this must be done in a controlled way and with care. “One way could be to negatively adjust the number of fat cells at the same time as weight is lost via dietary changes in order to make it easier to maintain the new weight. Another interesting way could be to activate adipose tissue to burn fat rather than store it. This is a newly evolving field built on the recent exciting findings demonstrating brown and brown-like depots of fat in adult humans. Brown and brown-like fat burn energy, rather than storing it.
Photo: Lina Eidenberg, Istockphoto
EXERCISE DOES NOT REDUCE WEIGHT
remission among diabetics,” says Martin Neovius. However, in spite of these good results, simply using surgery to defeat the obesity epidemic is not an option. Rebuilding the entire gastro-intestinal anatomy to force changes in behaviour, which has both lifelong consequences and, as with all surgical interventions, involves some risk is a far too extreme method that should only be seen as the last option for a limited number of patients. Consequently, there are somewhat strict criteria stipulating who can be considered suitable and this is primarily based on BMI, something which is now starting to be increasingly called into question, explains Martin Neovius. “There is a whole lot of data pointing to BMI in itself not being a particularly good selection criterion. Instead, it appears to be a better idea to select patients based on diabetic status.” Discussions are ongoing regarding how to change the selection criteria. But in Sweden, people with a BMI lower than 35 who have a worse diabetes profile are already sometimes undergoing surgery.
GIVING TO KAROLINSKA INSTITUTET 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!
Donate on-line: ki.se/donate
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
Johan Wallin Director, Development Office Karolinska Institutet Telephone: +46 (0)8 524 868 25 Mobile: +46 (0)737 121387 E-mail: johan.wallin.1@ki.se
For US citizens: Make your donation via our partner organization King Baudouin Foundation United States (kbfus.org) and choose KI. For any queries, please do not hesitate to contact us at KI Development Office:
From Sweden: Bank transfer account (”bankgironummer”) 5310-6217 Bank address: SEB AB, 106 40 Stockholm
Photo: Ulf Sirborn
MAKE A GIFT
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 want to hear how you would like to become involved in helping us to achieve tomorrow’s medical breakthroughs. With your support we can reach our goal!
In focus Exercise and Depression Researchers Jorge Ruas and Mia Lindskog have studied the significance of muscles in detail.
What muscles do to help the brain The way we view muscles is changing. Previously, this tissue was regarded as simply being involved in movement in and of the body. But muscles have a much greater significance and they communicate with other parts of the body in a refined way. Text: Annika Lund Photo: Ulf Sirborn
I
T IS REGARDED AS A WELLestablished fact that physical activity protects against depression, although we know very little about why this is. Also, at a biochemical level, depression is a poorly defined disease. Indeed, in spite of this condition being so com-
38
Medical Science–2015
mon, between five and eight per cent of the population are thought to suffer from depression at some point in time, what happens in the brain at a molecular level during depression is not well understood. Two research groups at Karolinska Institutet, one focused on depression and
one on muscle physiology, decided to collaborate in order to find out exactly what is happening when physical activity has a beneficial effect on the brain. This study has recently been published and has received much attention. “Physical activity affects so much in our bodies, such as blood flow, metabolism, muscle mass and hormone production. Until now it has been impossible to say what contribution the muscles make; we wanted to try and identify the way in which the muscles can affect the brain,” says Mia Lindskog, researcher at the Department of Neuroscience at Karolinska Institutet. THE RESEARCHERS USED mice that had been genetically engineered to be born with high levels of the protein
Photo: Istockphoto
PGC-1Į1 in their muscles. It has been known for some time that this protein increases with physical activity and strengthens muscles, so being born with high PGC-1Į1 levels gave mice pysically fit muscles. Experiments were done to compare these mice with normal mice. All the mice were subjected to mild, unpredictable stress several times a day. This is a well-established method for eliciting behaviour similar to depression in experimental animals. After five weeks, all the mice showed signs of stress. The normal mice also had an inflammatory reponse in the brain, changes in the connections between nerve cells and signs of depression. But the fit mice did not have this response in the brain, despite showing clear signs of stress. All the animals became stressed, but only some of them became ill. The researchers concluded that the brains of mice with fit muscles were protected from the harmful effects of stress. Since the differences in muscles were the only thing distinguishing the mice before they were subjected to stress, the researchers decided to analyse their muscle cells. They discovered that the fit muscles had much higher levels of an enzyme called KAT. This enzyme is known to break down the substance kynurenine into the substance kynurenic acid. There are several vital differences between these two substances. Kynurenine is formed under stress and is regarded as a harmful substance that can get into the brain. High levels of kynurenine have been observed in people with mental illness. However, kynurenic acid cannot pass through the bloodbrain barrier and does not get into the brain. The result was surprising, according to Jorge Ruas, research group leader at the Department of Physiology and Pharmacology. “We thought we would discover that trained muscles produce substances with beneficial effects on the brain. But what we actually discovered was the complete opposite; trained muscles
“I have never seen such clear results in any project I have been involved in.” produce an enzyme that purges the body of harmful substances. Accordingly, the muscles function as a filter in this context and bring to mind the function of the kidneys or liver,” he says. TO ACQUIRE FURTHER evidence of this, the researchers injected the neurotoxic substance kynurenine directly into the mice, without subjecting them to stress. The normal mice became depressed while the fitter mice were unaffected. “I have never seen such clear results in any project I have been involved in. The fitter animals were clearly protected from the adverse effects of a substance that is produced in respons to stress,” says Mia Lindskog. The biochemistry of this process was further investigated using cell cultures in order to establish exactly how the muscles protect the brain. The
researchers were able to establish the following chain: the factor PGC-1Į1, generated when muscles are exercised, activates the factor PPAR, which in turn leads to increased levels of KAT, which transforms harmful kynurenine to kynurenic acid. In one further experiment, the researchers analysed muscle biopsies from human volunteers, before and after three weeks of exercise. The results were in line with the animal experiments; exercised muscle cells had higher levels of both PGC-1Į1 and KAT. According to the researchers, this discovery can pave the way for new principles concerning the pharmacological treatment of depression, with the muscles as the target. The drugs currently offered, all work directly on the brain. Jorge Ruas talks about how the researchers are now looking for molecules that can activate PGC-1Į1 in a way that sets off the “filtering” function of the muscles, thus protecting the brain. “This new class of antidepressants could have several benefits and, purely hypothetically, it is possible to imagine that these drugs acting in the muscles could have fewer central side effects. It would also be good to have several possible treatments as current antidepressants are not effective for everyone so some need other options,” he says.
STRESS HARDY The muscles of active mice produce a substance that can protect the brain.
Medical Science–2015
39
Curious about Cold
A cool treatment saves the brain Are you a shiverer? Then you cope better with the cold. But without protective mechanisms, the bodyâ&#x20AC;&#x2122;s core temperature quickly drops and there is a risk of frostbite. At the same time, a body that is cooled down copes better without oxygen, something researchers can utilise to save lives. Text: Annika Lund Photo: Mark Welsh / TT
A BIT ON THE COLD SIDE Extreme cold hit the USA at the beginning of 2014 with temperatures between 10 and 20 degrees below normal. About 15 people lost their lives as a result of the weather.
Medical Scienceâ&#x20AC;&#x201C;2015
41
T IS BELOW FREEZING in the room. A man wearing only swimming trunks, shoes and mittens is sitting on a chair. In another room there is a bath filled with water at a temperature of 15 degrees. Does it sound nice? “No, it is clearly uncomfortable. Our research subjects are thus often people who are themselves very interested in what happens to the body in extreme conditions,” says Ola Eiken, Professor of Environmental Physiology at KTH Royal Institute of Technology in Stockholm and docent in Physiology at Karolinska Institutet. He has himself participated in some of the experiments conducted at his workplace, where their investigations include looking at how the body reacts to high and low temperatures. This largely involves basic research in which the goal is to find markers indicating which individuals run an increased risk of local cold injuries, in the worst case frostbite. The fact is that this is rather unknown today. Cold can damage us in two ways; either through local frostbite in a body part, or through hypothermia, where the core temperature of the body drops. And people with a strong defence against cooling down appear to have an increased risk of local cold injuries. When exposed to cold, their vessels contract, so that blood flow to primarily the fingers and toes decreases. Then, from time to time, the body releases the blood flow again so that a surge of warm blood reaches the extremities, possibly a physical defence against local frostbite. The disadvantage is that the 42
Medical Science–2015
blood then cools down, which reduces the body’s core temperature. How often and for how long the body releases the blood flow in this way is individual. A limited reinstatement of flow to the extremities leads to greater risk of frostbite, but reduces the risk of cooling down, and vice versa. The body’s main defence against cooling down is shivering, and how effectively we shiver is also individual. Some of the research subjects who bathe in the 15-degree water shiver violently. This causes the muscles to release energy, providing warmth and keeping the body temperature up. But others do not shiver at all and are unprotected against the cold. Their body temperature falls quickly. After 20–25 minutes, it can be as low as 35 degrees. Violent – or effective – shiverers can remain in the 15-degree water for longer, some of them for more than an hour and a half, while fundamentally maintaining their body temperature. “This is something of a mystery today. The research subjects who are perceived as homogeneous differ greatly on this point and we don’t know why,” says Ola Eiken. But which group feels that they are freezing the most – the shiverers or those whose body temperature decreases? “It has not been possible to confirm any patterns there either,” says Ola Eiken. Studies show that well-trained people who shiver can increase their metabolism by a factor of six and generate a lot of heat. But this is tiring work. Energy stores are depleted and the body becomes exhausted. The defence against the cold is temporary and in order to survive, you need to find external heat sources. Every year, 30–45 Swedes die in accidents where they have been cooled down. In many of these accidents, the victims have consumed alcohol or drugs, which reduces the body’s ability to shiver and
“The goal is to save lives and reduce brain injuries among children with acute oxygen deficiency.”
constrict the blood vessels. People with mental disorders or dementia and those involved in recreational activities who are taken by surprise by cold weather are among those more likely to die from hypothermia. And it is probable that the statistics don´t show all the deaths – for example, some of those who are found drowned with a life jacket have actually died of hypothermia. When it comes to local frostbite injuries, some occupations are more exposed, such as reindeer herders, sailors, fishermen and farmers. People involved in recreational activities also belong to those vulnerable, with mountaineers and snow mobile drivers found among those affected. Frostbite also occurs among the homeless and some people with mental illness. The experiment Ola Eiken leads is always called to a halt when the body temperature of a research subjects falls to 35 degrees. Such a small drop is actually completely harmless. But major changes take place at lower body temperatures (see the graphic on age 44. Despite this, seriously hypothermic people can survive and escape with no injuries whatsoever. The Swede Anna Bågenholm survived an accident in which she remained under ice for 80 minutes. Her body temperature decreased to 13.7 degrees and she had a cardiac arrest that lasted for over two minutes. Anna Bågenholm survived without serious injury, but was forced to change her job from surgery to radiology due to impairment of the fine motor control in her fingers. That the body is able to withstand such an event is due to the decreasing metabolism. The lower the body temperature, the lower the metabolism. This means among other things that the organs use less oxygen. It is this mechanism that is now being deliberately used in several ways in healthcare. For over ten years, it has been customary to use cold treatment to prevent brain injury following cardiac arrests that take place outside of hospital. This is rarely required for cardiac arrests in hospitals as patients who are resuscitated quickly suffer less oxygen deprivation and injuries. Cold treatment normally begins with the patient being injected with cold fluids. This rapidly cools the patient’s body temperature down to about 33 degrees. The low temperature is then maintained for 24 hours using cooling blankets that use circulating cold fluids
Photo: Ulf Sirborn
Curious about Cold
Photo: Fotogruppen Södersjukhuset, Istockphoto
or with other, more advanced methods. The patient is given muscle relaxant drugs in order to prevent any resulting shivering. The patient is also kept under general anaesthetic, which further reduces their metabolism. HOWEVER, IN MOST cases cooling is only begun several hours after the cardiac arrest, following transport to hospital in an ambulance , investigations and admission to the intensive care unit. This is something that Per Nordberg, cardiologist and PhD student at the Department of Clinical Research and Education at Stockholm South General Hospital, Karolinska Institutet, wants to change. He is researching a new method for cold treatment that the paramedics can begin while they are administering cardiopulmonary resuscitation. The patient is equipped with a nasal catheter similar to those used to provide oxygen, a hose with two prongs that are inserted into the nostrils. This delivers chilled gas to the patient, lowering the temperature locally in the brain. The rest of the body is cooled down later in the hospital. “By beginning cold treatment early, we think that there is potential to save the nerve cells that die as a result of oxygen deficiency during a cardiac arrest. We also believe that we can limit the second wave of cell death that follows a cardiac arrest,” says Per Nordberg. The brain is stressed as a result of the oxygen deficiency during cardiac arrest and a cascade of biochemical processes begins. For example, the nerve cells begin uncontrolled release of the signalling substance glutamate, something which ultimately results in an excess of calcium – leading to the death of the nerve cell. Slowing down the brain’s metabolism by early cooling may be one way to counteract these negative processes. However, this idea is not new. An American study was published at the end of 2013 in which cardiac arrest patients had been randomly chosen to receive cooling in the hospital as normal or in the ambulance. But the study showed there was no benefit to fast cooling. Many patients had another cardiac arrest before they arrived at the hospital. This may be because the quick cooling in the ambulance was
performed by injecting large quantities of cold fluids, up to two litres, immediately after the heart was restarted. According to Per Nordberg “it is probably too great a load for the newly started heart to pump such a large volume of fluid around the body. I was not completely surprised by the study’s results.” Thus, the study is not entirely dismissive of quick cooling, rather of how this is done, he believes. He is now leading a large study in which the patients are randomly selected for cooling in accordance with current procedures or while they are in the ambulance – except that cooling is done via the nose. A total of 500 patients will be included in the study and it is hoped that it will be completed in 2015. The hypothesis is that early cooling will lead to fewer brain injuries among the patients, so that they end up with fewer problems in terms of impaired memory or physical disabilities. Per Nordberg believes that cooling to protect the brain can help more patient
groups than it is currently being used for, such as stroke patients. As opposed to cardiac arrest patients, however, these people are often conscious, and the use of cooling via the nose requires the patient to be unconscious or anaesthetised. “We have tested the spray on healthy test subjects when they were awake, but they became very stressed due to the discomfort caused by having your nostrils cooled. Their blood pressure and heart rate rose, which is counterproductive in this context,” says Per Nordberg. HE ALSO BELIEVES that cooling treatment can be refined further in the long-term, with better data concerning which body temperature is actually optimal and how long the cooling should last. “I wouldn’t be surprised if future studies indicate that the body temperature should be reduced even further and that it should be kept at a low for longer, perhaps 72 hours.” Cooling treatment for 72 hours is customary in another area of healthcare, namely neonatal care. Sweden was one of the first countries in the world to introduce cooling treatment for children with acute oxygen deficiency, born at 36 weeks or earlier. Every year, between 100 and 200 such children are born in Sweden. About one quarter can be kept alive or saved from severe brain injury by cooling. Despite this, not all children receive the treatment they need – at least in 2011, according to a review conducted by the Swedish Brain Foundation and researchers from Karolinska Institutet. One reason is that the treatment must be initiated within six hours of birth. Because the majority of hospitals cannot offer cooling, the frail, newborn
Facts: Three ways to survive the cold Newborn infants cannot shiver. Instead they are born with large quantities of brown body fat, an energy store that can be turned into heat when required. Animals that hibernate also keep warm partly with the help of brown fat. Frogs and reptiles are cold-blooded, which means that they cannot warm themselves with their own body heat. They survive winter by finding a place that the cold does not really reach. Some frogs and reptiles can counteract ice forming in their bodies – they can partly freeze, yet survive. When the temperature drops, frogs increase the amount of the sugar glucose they produce in their body fluids. Glucose reduces the freezing point and this protects their cells from freezing and being destroyed. Medical Science–2015
43
Curious about Cold
WE ARE SPEAKING over a somewhat crackly Skype link from Vietnam, where Linus Olson is involved in a research study testing the mattress on newborn children with acute oxygen deficiency. Cooling treatment is currently only available at a couple of hospitals in Vietnam, which has a population of 90 million. In this study, the mattress will be used to allow cooling treatment already during transport to and at additional hospitals. “The goal is to save lives and reduce brain injuries among children with acute oxygen deficiency. If the study confirms that the mattress is effective in 44
Medical Science–2015
Nine degrees below freezing
40 39 38 37 36 35 34 33
BELOW 37 DEGREES The body begins to shiver and the teeth chatter. Peripheral blood vessels contract.
32 31 30 29 28
BELOW 28 DEGREES It is often difficult to tell whether someone is alive or dead. The body appears to be in rigor mortis, breathing is shallow and so slow that it is hard to notice. There can be up to one minute between weak heartbeats.
BELOW 35 DEGREES Metabolism drops and the body begins to go into energy-saving mode. Energy-intensive but protective shivering normally stops. The nervous system is affected and movements, speech and cognitive ability become worse. It becomes hard to grasp and swim, which naturally is deadly for those who are in the water or far from shelter and warmth.
27 26 25 24 23 22 21
28 DEGREES Most people fall unconscious. The heart beats slowly and there is a clear risk of cardiac rhythm disturbances or cardiac arrest. The muscles become stiff.
C
these contexts, there are plans to introduce it more permanently in neonatal care in Vietnam. In the long-term, other countries with less developed neonatal care will be of interest,” says Linus Olson. The cooling mattress is also being tested in a study in Sweden. In the first stage, newborns with oxygen deficiency will be randomly selected to be transferred by air, either in a normal transport incubator or on the cooling
mattress. The next stage will involve the same thing, but with normal ambulance transfers. The outcome being studied is how many children in each group dies or have serious brain injuries by the age of six; the study’s results are thus a long way off. “If it turns out that transfers with the cooling mattress are better than using the transport incubator, there is good reason to consider a change to current procedures.”
Photo: Ulf Sirborn
babies must be immediately transferred; requiring a quick decision by a skilled paediatrician. During the transfer, the child is often placed in a normal transport incubator or in a type of cooling suit, which requires a special ambulance. “There are examples where the body temperature has decreased too much during the transfer, as low as to 28 degrees. This is not good and can affect the outcome of the cooling treatment. There is a need for simpler and safer transfers of children who need cooling treatment. It would also be good if it could be initiated earlier,” says Linus Olson, PhD, civil engineer and researcher at the Department of Women’s and Children’s Health. He has produced a cooling mattress that works without either electricity or water, which means it can be used in all ambulances and hospitals. It consists of a plastic cover filled with a so called phase-change material, which can transform from a solid to a liquid phase, using the child’s body heat as a source of energy in the process. After about half an hour on the cooling mattress, the child reaches a temperature of about 33.5 degrees. “A big plus is that the mattress then maintains this temperature in a very stable way. It is also very much cheaper than the equipment that is currently used for cooling treatment. In addition to the opportunity to improve transfers in Sweden, we see the potential for improved neonatal care in developing countries,” says Linus Olson.
The moment As told to: Cecilia Odlind Photo: Mattias Ahlm
“It was a true miracle to everybody present” Her research recently yielded eagerly awaited results: A miracle baby. Kenny Rodriguez-Wallberg was present at the birth. “When my future patient Lotten was diagnosed with cancer in 1999, she was told that the cancer treatment would damage her ovaries and that she would not be able to get pregnant naturally later on. At the same time, she was asked a crucial question by her oncologist: Did she want to have her ovarian tissue frozen, which could then possibly be used in the future? She was one of the first women in the world to be asked this question. And she said yes. Many years later, she contacted us at the Reproductive Medicine clinic of Karolinska University Hospital. I was assigned to re-transplant the frozen tissue into her abdomen, so that the eggs could develop. However, her abdominal tissues had been damaged by the radiation she had received in her cancer treatment, so many believed the procedure would not work. After two failed attempts, about half of the tissue she had saved remained. There were many voices saying: ‘So what are the odds it will work this time?’ I couldn’t tell them, since there were no statistics available. But I knew one thing: If we didn’t try, the chance of success was zero. I suspected that it was important to transplant a fairly large amount of tissue. So we invested all tissue we had left in one last attempt. And it worked! We were able to stimulate egg cells to grow, which were then fertilized in vitro, and Lotten became pregnant. The pregnancy went well. Lotten was cautiously excited, but she didn’t dare to believe that the pregnancy would go full term. So when the baby was finally born, it was complete bliss. Seeing Lotten with her newborn daughter - that was a true miracle for all those involved in the process. This work has given me so much, and it encourages me in my dayto-day work with improving fertility-preserving measures for women with cancer.”
Name: Kenny Rodriguez-Wallberg Title: Associate Professor and Researcher at the Department of Oncology and Pathology, Karolinska Institutet and Senior Consultant at Karolinska University Hospital. Researches: Efficacy and safety of fertility preservation in cancer patients.
Medical Science–2015
45
Top publications A selection of the most recent publications from Karolinska Institutet in the world´s leading scientific journals.
DNA origami as a tool in cancer research IT HAS BEEN KNOWN FOR A WHILE
that the EphA2 receptor plays a part in several forms of cancer, such as breast cancer. The protein that communicates with the receptor is known as an ephrin molecule. Researchers have had a hypothesis that the distance between different ephrin molecules affects the level of activity in the communicating receptor of the adjacent cells. To test this hypothesis, they used DNA building blocks to form a stable rod. This functioned as a very accurate measuring rod to measure and change the distance between molecules. The researchers then attached ephrins to the DNA rod at various intervals, and then put the DNA rods in a solution containing breast cancer cells. In the next step, the researchers looked at how active EphA2 was in these cancer cells. It turned out that if the ephrin 46
Medical Science–2015
molecules were placed close together on the DNA rod, the receptor in question became more active in the cancer cells, and the cells also became less invasive in respect of the surrounding cells, which could mean that they became less prone to metastasis. This ocurred even though the amount of protein was the same throughout the experiments, i.e., the number of attached molecules remained the same. The researchers describe the cell communication as a form of braille, where the cells somehow sense the protein patterns of nearby cells, and where the important thing is not only the number of proteins, but to a great
extent also the distance between them as well. “This is a model that can help us learn more about the importance of proteins in cell signalling, something that will hopefully pave the way for a brand new approach to pharmaceuticals in the long term. Today, the function of the pharmaceuticals is often to completely block proteins or receptors, but it is possible that we should rather be looking at the proteins in their biological context, where the clustering and placement of various proteins are relevant factors in respect of the effect of a drug,” says Ana Teixeira, researcher at the Department of Cell and Molecular Biology who led the study along with Björn Högberg, researcher at the Department of Neuroscience. Spatial control of membrane receptor function using ligand nanocalipers Shaw A, Lundin V, Petrova E, Fördös F, Benson E, Al-Amin A, Herland A, Blokzijl A, Högberg B, Teixeira AI Nature Methods July 2014
Photo:Stefan Zimmerman. Illustration: Björn Högberg.
In a new study, DNA has been used as a construction material to create a nanometre measuring rod. Such rods have then been used to examine how cells react to other nearby cells.
Illustration: Istockphoto. Photo: Ingrid Kåhler, Stefan Zimmerman (Jacobsen).
Rare mutations may increase the risk of schizophrenia A NEW STUDY shows that more mutations affect the risk of developing schizophrenia than was previously thought to be the case. The researchers have used large-scale sequencing technology that makes it possible to read the DNA code for all our genes, i.e., “exome sequencing”. The study analysed around 2,500 Swedish individuals diagnosed with schizophrenia and 2,500 healthy control subjects, which makes it the largest exome sequencing within psychiatry so far. The results indicate that many rare mutations, located in a large number of different genes, contribute to an increased risk for schizophrenia, rather than a small number of risk genes. “Both individuals with schizophrenia and healthy individuals carry rare mutations, but the difference is where in the genome these mutations are located. In people with schizophrenia, you can see a cluster of rare mutations in several groups of genes that are important for the communication between brain cells,” says Anna Kähler, researcher at the Department of Medical Epidemiology and Biostatistics, and one of the Swedish co-authors of the study.
A polygenic burden of rare disruptive mutations in schizophrenia Purcell SM, Moran JL, Fromer M, Sarah E Bergen, Anna Kähler, Patrick KE Magnusson, Christina M Hultman et al Nature January 2014
Our DNA reveals the risk of schizophrenia.
Cancer stem cells, essential for tumour growth.
LIST
More of the year’s top publications
Cancer stem cells identified BY MAPPING THE cellular origin of major cancer mutations, an international research team has succeeded in identifying cancer stem cells in patients with the blood-related condition myelodysplastic syndrome. The study thereby provides definitive proof for the existence of rare cancer stem cells in humans. The research was led by Karolinska Institutet and Oxford University, UK, and it settles a question that has long been debated among cancer researchers the world over. “We have proven that the root of this particular cancer is a small group of cells which are essential for sustaining tumour growth, in the same way that regular stem cells give rise to normal tissue. The concept is of clinical importance as it means that treatments targeting the cancer stem cells will strike at the very foundation of the disease, but it also means that you have to get rid of the cancer stem cells for the cancer not to return,” says Sten Eirik W. Jacobsen, who is professor at the MRC Weatherall Institute of Molecular Medicine in Oxford and at Karolinska Institutet.
Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo Co-authors at Karolinska Institutet: Kjällquist U, Erlandsson R, Ngara M, Deng Q, Karimi M, Scharenberg C, Mortera-Blanco T, Tobiasson M, Sandberg R, Hellström-Lindberg E, Linnarsson S, Jacobsen SEW Cancer Cell May 2014
New mechanism for gene packaging in stem cells Citrullination regulates pluripotency and histone H1 binding to chromatin Christophorou MA, CasteloBranco G, Halley-Stott RP, Slade Oliveira C, Loos R, Radzisheuskaya A, Mowen KA, Bertone P, Silva JCR, Zervicka-Foetz M, Nielsen ML, Gurdon JB, Kouzarides T Nature januari 2014 New findings on the potential of neurons to regenerate after a stroke The age and genomic integrity of neurons after cortical stroke in humans Huttner HB, Bergmann O, Salehpour M, Rácz A, Tatarishvili J, Lindgren E, Csonka T, Csiba L, Hortobágyi T, Méhes G, Englund E, Werne Solnestam B, Zdunek S, Scharenberg C, Ström L, Ståhl P, Sigurgeirsson B, Dahl A, Schwab S, Possnert G, Bernard S, Kokaia Z, Lindvall O, Lundeberg J, Frisén J Nature Neuroscience april 2014 Prostate surgery is beneficial, but not for all patients Radical prostatectomy or watchful waiting in early prostate cancer Bill-Axelsson A, Holmberg L, Garmo H, Rider JR, Taari K, Busch C, Nordling S, Häggman M, Andersson, S-O, Spångberg A, Andrén O, Palmgren J, Steineck G, Adami H-O, Johansson J-E NEJM mars 2014 The gearbox of the nervous system mapped out Separate microcircuit modules of distinct V2a interneurons and motoneurons control the speed of locomotion Ampatzis K, Song J, Ausborn J, El Manira A Neuron augusti 2014 Both genes and the environment contribute to autism The familial risk of autism Sandin S, Lichtenstein P, KujaHalkola R, Larsson H, Hultman CM, Reichenberg A JAMA maj 2014 Medical Science–2015
47
4 Questions to
JULIA ROMANOWSKA has recently gained a PhD at the Department of Neuroscience, Karolinska Institutet.
Artistic confrontation improves leadership A new study reveals that the confrontational artistic concept Shibboleth can be used to provide better managers and healthier employees. Text: Marie Svedberg Photo: Ulf Sirborn
Can you describe the artistic concept Shibboleth?
“It is a literary and musical performance, followed by individual written reflection and group reflection. The ensemble consists of two actors, a sound technician and a moderator. Interwoven with music, the actors take turns to read various passages about poignant human catastrophes and malice, as well as human greatness and dignity. The performance is directed, but unpredictable, which is precisely the point. The audience has to focus and concentrate; it is difficult to shield yourself, you exist in the now. The brain organises the impressions, which leads to a release of control and a change in thought patterns.” What gave you the idea to research Shibboleth and leadership?
“I used to work as a musician and 48
Medical Science–2015
music teacher and am a trained percussionist. I have also worked with the military’s leadership training programmes and in parallel hosted a literary and musical salon where the Shibboleth form took shape. From this the idea was born to investigate whether an artistic model could be used as an alternative to the conventional leadership programmes. My thinking was that the Shibboleth format and content would ‘shake up’ the audience, resulting in greater humanism, and would break down stereotypical behaviour among managers.” Does it work?
“Yes, the results show that employees identify changes among their managers after they have undergone Shibboleth – they took more responsibility, were more courageous and were prepared to ‘stand up’ in situations that are difficult
to handle. Self-awareness increased, as did their humility. I also saw mental and biological health-promotional effects among both managers and employees, for example improved self-esteem and ability to cope with stress. In the control group, which was given traditional leadership training, the results were the opposite.” What explains these effects?
“Traditional leadership training is based on managers using themselves as a basis for guiding other individuals to fulfil objectives. The point of the Shibboleth concept is to do the opposite; using other individuals as the point of departure and seeing the world through their eyes. It is possible to do this through art. Many participants were affected in a way they had never been before. By feeling compassion for others, they began to process their own feelings and re-evaluate their selfimage. A new concept I have introduced is aestemethics. This is an attitude the participants adopted – a combination of aesthetic (fantasy-based), emotional and ethical elements – which led to a new self-image. This involved people taking greater responsibility for others and their own leadership.”
Karolinska Institutet News PROFESSOR HANS ROSLING participitated in the first course held.
Aid workers trained in emergency care During the autumn of 2014, a brand new training programme was held at Karolinska Institutet for people who will be working with Ebola patients in West Africa. The course was created as a direct result of the acute lack of aid workers in the affected areas. Course participants were trained in important procedures, such as sample handling, how to put on and remove protective equipment, hygiene procedures and safe burials. The camp, where the participants train, was built
Photo: Gunnar Ask, Gustav Mårtensson
”Blood on the tracks: a simple twist of fate” is the name of an album and song by Bob Dylan, but it is also the title of a scientific article by researchers at Karolinska Institutet.
in accordance with the organisational principles for a Ebola treatment unit by Doctors Without Borders. “It is important to practice in as realistic an environment as possible, to prepare for the stress they will be exposed to,” says Taha Hirbod, senior researcher in infectious diseases, who was called in at short notice as project manager of the training centre. Most of the participants have a background in health care, but other professional categories have also been represented, such as electricians, HR-
Dylan quotes crop up in publications “Good music, like Bob Dylan’s, is innovative. The same applies to good research,” says researcher Konstantinos Meletis, who is one of five researchers taking part in an internal competition at Karolinska Institutet. The researcher who quotes Bob Dylan the highest number of times in scientific publications before retiring, wins the competition. The Dylan competition has received considerable coverage in the global media. Lisa Reimegård
specialists, economists and journalists. The last course ended in December 2014 as there are indications that a sufficient number of health-workers have now been deployed to the affected areas. The programme was organised by the Centre for Research on Health Care in Disasters at Karolinska Institutet in collaboration with the National Board of Health and Welfare, Doctors Without Borders, the Public Health Agency of Sweden and the Swedish Civil Contingencies Agency. Jenny Ryltenius
“This past decade has seen more progress than any other decade in the history y of global health.” In his lecture in Karolinska Institutet’s Aula Medica in March 2014, Bill Gates spoke about how extreme poverty can be eradicated from the world during our lifetime. Medical Science–2015
49
The moment As told to: Helena Mayer Photo: Mattias Ahlm
“Meeting Johan, 8 months old and deaf, gave me courage”
Hearing help. A processor that sits outside the body, behind the ear, is connected to the cochlear implant.
50
Medical Science–2015
Name: Eva Karltorp Title: Senior Research Fellow in Audiology at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet. Currently: Published a thesis in December 2013 on why children are born deaf and the optimal age at which to give them a cochlear implant.
Meeting a deaf baby caused Eva Karltorp to dare to question the established treatment of congenital deafness. Now the majority of deaf children can talk as well as those with hearing. “Normally, one child per year was diagnosed as deaf at our hearing clinic. But in one week in 1997, four children were given the same diagnosis. I thought this was remarkable. The fourth child, Johan, eight months old, was actually the one who made me begin my research, because when I met him I began to doubt whether the deafness was actually due to the normal explanation that it was an inherited injury. Instead, I thought that it could be a congenital viral infection and one year later I found a research group that was looking for the causes of deafness, and joined it. Gradually, it became clear that cytomegalovirus was the cause of congenital deafness in three of these four children. At the time, it was common to surgically implant a hearing aid called a cochlear implant at the age of three or four. The idea was for the child to use sign language prior to the surgery; this was thought to be best. But the results were very poor; when the child had the surgery, they had had so many years of silence that their ability to speak and understand spoken language never caught up with that of their peers. At the same time, I had begun to become aware that the results were better in other countries where the surgery was performed earlier and children’s speech and language development was supported, for example, with the help of speech therapists. I thought: Why not give our children the same chance? I talked with Johan’s parents and they were prepared to go ahead. He was given the cochlear implant when he was only two years old and his parents arranged for a speech therapist themselves. Johan then became the first child with congenital deafness in Sweden who started mainstream school in year one. Now children’s hearing is tested directly after birth with neonatal hearing screening and they have the surgery from five months of age. And the majority of children who have the surgery early have an ability to speak consistent with their age group by 1.5 years of age. Having been involved in turning this ship around has been fantastic. ”
Bioinformatics. Affinity Proteomics. Bioimaging. Clinical Diagnostics. Drug Discovery & Development. Functional Genomics. Structural Biology. National Genomics Infrastructure. Chemical Biology.
Your quest. Our technologies.* Advancing Life Sciences
Scan for more information, or visit www.scilifelab.se
* Services available for researchers in Sweden. Subsidized by governmental funding.
Help improve human health ’I see myself communicating both with physicians and patients, trying to change healthcare services to the best they can be.’ Dina Titkova, Bioentrepreneurship
Study one of our Global Master’s Programmes in health and life sciences, all in English and with an international focus. A degree at Karolinska Institutet may very well be the first step towards a PhD in the same or another well renowned partner university somewhere in the world. It can open doors to a global future. t t t t t t t
Find out more about our programmes and read our student blogs at ki.se/masterstudies
Bioentrepreneurship Biomedicine (Bachelor and Master’s level) Global Health Health Informatics (joint with Stockholm University) Public Health Sciences Toxicology Molecular techniques in Life Science (joint programme with KTH and Stockholm University)
KAROLINSKA INSTITUTET – A MEDICAL UNIVERSITY Karolinska Institutet is one of the world´s leading medical universities. Its vision is to significantly contribute to the improvement of human health. Karolinska Institutet accounts for over 40 per cent of the medical academic research conducted in Sweden and offers the country´s broadest range of education in medicine and health sciences. The Nobel Assembly at Karolinska Institutet selects the Nobel laureates in Physiology or Medicine.
For more information, please visit us at ki.se
The Nobel Prize Medal® is a registered trade mark of the Nobel Foundation. Photo: Camilla Svensk and Erik G Svensson.
POSTTIDNING B