Synergy #2 2017 (English)

In the wake of antibiotic resistance: The search for new cures A MAGAZINE FROM SCILIFELAB

#2 –– 2017 More Inside New knowledge about diabetes leads to more effective treatment One step closer to understanding evolution Study proteins with the Cell Atlas Extinct, but not down for the count – why did the mammoth disappear?

Extensive detective work on many rare diseases

A magazine from SciLifeLab

Synergy #2 –– 2017

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Contents

Foreword Dare to take the leap!

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ciLifeLab is now in its fifth year as a national resource center and our range of services continues to broaden and deepen. Part of our vision is to serve as a meeting place both within and between disciplines. By bringing together people with different competencies, we help meet multi-faceted challenges that require in-depth bioscience knowledge in combination with high-tech expertise.

Originating from four host universities, SciLifeLab aims to bridge universities around the country, via which researchers have a chance to meet, exchange ideas and be inspired to jointly initiate major projects. We want to be the springboard that gives researchers the courage and hope to jump further than they would otherwise do.

Our hope is that the magazine you hold in your hand will evoke thoughts about how the technologies offered at SciLifeLab can promote your research and inspire ideas for new collaborative projects to create – yes, exactly that – Synergy.

In this issue, you will meet Love Dalén, a professor at the Swedish Museum of Natural History. By mapping DNA from ancient samples, he is investigating the evolution of various species and how earlier environmental changes have affected the spread of certain organisms. We have also met Anna Wedell, whose work to develop new diagnostic methods for genetic diseases can save lives. The possibility of sequencing a person’s entire genome in just a few days and effectively analyzing the large amounts of data now helps physicians to quickly and accurately assess the condition of patients, often newborns, with suspected congenital diseases.

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Editorial staff

15 Synergy is a magazine about research, published by SciLifeLab twice a year in Swedish and in English.

The magazine may be ordered free of cost, or read online at scilifelab.se/infrastructure/synergy Editor : Sara Engström

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Editorial committee: Susanna Appel, Ellenor Devine and Annica Hulth

Design and production: zellout.se Printing: Danagård Litho Contact: synergy@scilifelab.se

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Read and let yourself be inspired!

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Photo: Mikael Wallerstedt

#2 –– 2017 Siv Andersson, Co-Director of SciLifeLab siv.andersson@scilifelab.se

02 / Foreword

06 / Reportage

Dare to take the leap!

Extensive detective work on many rare diseases

04 / In brief The honey bee's salvation, open source, SciLifeLab on Twitter and more SciLifeLab (Science for Life Laboratory) began its operations in 2010 and is a partnership between the Royal Institute of Technology, Karolinska Institutet, Stockholm University and Uppsala University. In 2013, the government tasked SciLifeLab with creating a national center for molecular biosciences. The purpose was to be able to offer access to researchers throughout Sweden to technology and expertise for advanced research at a reasonable cost.

SciLifeLab is fully integrated into the higher education institutions’ operations and is not for profit. SciLifeLab’s vision is to be a national hub for

05 / Insight – diabetes New knowledge about diabetes leads to more effective treatment

mole­c ular biosciences. Today, over a thousand research groups per year use the center’s services.

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Synergy #2 –– 2017

A magazine from SciLifeLab

A magazine from SciLifeLab

11 / Insight – antibiotic In the wake of antibiotic resistance: The search for new cures

12 / Portrait Extinct, but not down for the count – why did the mammoth disappear?

13 / Insight – proteins Study proteins with the Cell Atlas

15 / Insight – evolution One step closer to understanding evolution

16 / Hello there!

Marcela Pekna conducts research on the role of the immune system in the recovery of function after brain injury

Synergy #2 –– 2017

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In brief

Insight Text: Peter Johansson / Photo: Mikael Wallerstedt

New knowledge about diabetes leads to more effective treatment

Computing power

Photo: Mikael Wallerstedt

Did you know that the Bioinformatics Compute and Storage facility at SciLifeLab has …

11.2 795 2.3

All scientific publications associated with each article in Synergy can be found at scilifelab.se/infrastructure/ synergy

Petabyte storage space

active projects

million computing hours per month, which corresponds to 210 years on one single processor core

Molecular Masters

Tweet with us!

Two Masters programs linked to SciLifeLab are Molecular Medicine and Molecular Techniques in Life Science.

Perhaps this is something for you or somebody you know?

For anyone who wants to learn more or register, further information is available at www.scilifelab.se/education/ masters-programmes

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million computing hours has been analyzed since its inauguration in 2010

@SciLifeLab

Want to see our code?

Many bioinformaticians and programmers who work at SciLifeLab make their software code available for everyone.

Take a look at our open source portal at opensource.scilifelab.se and feel free to use – and contribute to – any of the tools.

Adaptation can be the salvation By sequencing the genome of various kinds of honey bees, researchers are one step closer to solving how the mass death of bees around the world in recent years could be slowed.

Senior Lecturer Matthew Webster and his research team at Uppsala University have compared DNA from various bee colonies and drawn conclusions about disease, behavior and the living environment.

The first results from this mapping describe how bee colonies with mixed genetic origins adapt to new surroundings or conditions. In the middle of the 20th century, a small group of African bees were introduced into South America to be hybridized with a variant of European origins cultivated in Brazilian

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hives. This new type of bee then succeeded in spreading across both American continents and is therefore suited to studying acclimatization in the honey bee, especially to new climates.

The researchers have also discovered that bee populations living in the Kenyan highlands have different DNA sequences on chromosomes 7 and 9 compared with their equivalents on the lowland savanna. This could explain why mountain bees behave differently when looking for nectar and pollen. Finding mechanisms behind such an adaptation could provide ideas for strategies to address today’s massive decrease in the bee population, which has had a negative impact on the pollination of flowers for fruits and vegetables.

This research project is part of SciLifeLab’s investment in national genomics projects in biodiversity and medicine. The sequencing within the national projects, performed at SciLifeLab’s Genomics platform, is made possible with support from the Knut and Alice Wallenberg Foundation.

A magazine from SciLifeLab

One fifth of the thousands of patients yearly undergoing surgery for obesity have type-2 diabetes. The latest research findings increase the hope that in the future, diabetes patients can be treated with medication instead of surgery.

N

ils Wierup, Senior Lecturer at Lund University,

hopes that his studies will open up a new form of more effective medication. Part of his research concerns the satiety hormone CART, which can act like the body’s own defense system to lower blood sugar levels in type-2 diabetes. Previously, CART was mainly studied in the brain’s center for appetite regulation, but the hormone also occurs in human alpha and beta cells in the pancreas. It is regulated by glucose and exists in larger amounts in patients with type-2 diabetes.

Although researchers around the world have been searching for more than 20 years, it now seems that it is Nils Wierup and his team who have identified the receptor to which CART binds. Their discovery is crucial to explaining the biological mechanisms behind the hormone’s function and developing medication that can mimic its effect.

“Today, type-2 diabetes is treated with medicines that mimic the effect of the intestinal hormone GLP-1. We hope that our findings will eventually lead to new more effective medication, possibly by combining CART based medicines with GLP-1 based drugs,” says Nils Wierup.

In parallel with this investigation, Nils Wierup's team is looking at why the majority of the type-2 diabetic patients operated for obesity recover from their illness just a few days after the procedure, i.e. long before their body weight decreases. Several changes in the intestine’s metabolism as a result of the operation have been discovered and may be part of the explanation. If the researchers also succeed in identifying this underlying mechanism, it will pave the way for more individualized operations in the short term. But it is even more interesting in the long term, since it might be possible to achieve the same results with medication as with surgery.

Nils Wierup is also looking for genes in the pancreas that differ between healthy and diabetic individuals. Thanks to collaboration with a research team at Karolinska Institutet, they can measure gene expression in individual cells, something that has led to the identification of hundreds of new genes whose role in the disease was previously unknown.

“Our next challenge is to carry out studies on a large number of patients. We might eventually be able to divide the disease into subgroups with different treatments, so-called precision medicine,” says Nils Wierup.

Technology and service In all three projects, SciLifeLab’s bioinformatics service was used to analyze RNA sequencing data. SciLifeLab checked the quality of the data and analyzed gene expression as well as the processes in which the genes are involved.

A magazine from SciLifeLab

“We hope that our findings will eventually lead to new more effective medication, possibly by combining CART based medicines with GLP-1 based drugs.”

Synergy #2 –– 2017

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Reportage Text: Per Johansson / Photo: Mikael Wallerstedt

Extensive detective work on many rare diseases

For 50 years now, children born with the disease PKU have been able to lead a normal life instead of being forced to live with severe brain damage – all thanks to research. Anna Wedell, Professor of Medical Genetics at Karolinska Institutet, works to trace the mechanisms behind inherited metabolic diseases. This is an effort where technology, research and healthcare go hand-in-hand.

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A Amagazine magazinefrom fromSciLifeLab SciLifeLab

A magazine from SciLifeLab

Synergy Synergy##2 2 –– 2017

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S Reportage

tockholms public transport’s blue line number 3 bus arrives at its final stop at the main entrance to Karolinska University Hospital. In a building a short walk away is the Centre for Inherited Metabolic Diseases (CMMS). Outside the elevator is a small waiting room. A basket with light blue plastic shoe covers to protect the floors from dirty footwear is hanging next to the door.

“Now you’re at the hospital. This is a clinic where we receive patients. But CMMS is found at several locations. We also have a large lab at Karolinska Institutet where we do the actual basic research, and we’re present at SciLifeLab,” explains Anna Wedell, once we sit down in her office in a corner of the ward.

Time and again during our meeting, she will emphasize that technology, research and healthcare cannot be viewed separately, and in her research domain, they’re never far from each other. It is the findings from patients here at the clinic that drive research forward with help from technical development. And when it comes to inherited monogenic metabolic diseases that have arisen due to changes in one single gene, the route back to the patients is sometimes quite short.

“It’s a gratifying area to work in, especially because the research results are put to clinical use so quickly and play such an important role for our patients,” explains Anna Wedell.

This is also the reason why she entered healthcare in 2014, becoming head of the CMMS clinic after having been active as Clinical Director at SciLifeLab during the previous three years.

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Reportage

“At SciLifeLab, we did everything we said we would do when we applied to start operations, plus a little more. I went back to healthcare to really bring in the new knowledge that’s now available. To make sure that research wouldn’t be just a parallel track outside,” she explains.

When patients with suspected metabolic diseases come to CMMS, they are examined by doctors and their samples sent to SciLifeLab for analysis. Thanks to the technology development, which allows a patient’s entire genome to be sequenced, these samples can today be analyzed in a vastly more efficient manner than before.

How does it work?

“The genome contains three billion building blocks and more than 20,000 genes. But we don’t look at everything.

Instead, we have built a system to extract relevant information. First, we do our strict clinical tests where we compare the sample with a database that contains all of the genes known to cause our kinds of diseases.”

Using a ranking system, a list is prepared for the medical team, who then receive a presentation of which diseases the test results indicate, without having to delve into all of the technology.

“Then we use our clinical knowledge to evaluate what matches with the patient; the symptoms, radiology results and biochemistry. Genetics alone are not enough, so we put everything together and view it as a whole,” she explains.

If a diagnosis is made, the answer is sent back to the healthcare system where the patient can get help. But if no known disease can be ascertained, the work shifts to research, as long as the patient and his or her guardians give their approval. Then it can take time. The researchers do not have the possibility to take on all patients at the same time, but rather choose cases where they believe they have the greatest opportunity to succeed based on their expertise and current research methods.

“Then, we really try to understand what has gone wrong on a molecular level.

When we conduct research on metabolic diseases, it’s very much about understanding how the brain works.”

How is the research done?

“Firstly, it’s not only about finding a gene, but also understanding what mechanisms lie behind the disease. Then we’re into advanced primary research on model organisms, such as flies and mice, and perhaps even reprogrammed cells from patients. The link to metabolism makes this exciting work, because if we can understand what’s gone wrong, we can sometimes simply compensate with a special diet or medication.”

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very individual inherited metabolic disease is uncommon in itself, but the number of different diseases is large – today, more than 1 000 are known – and this is why many patients and relatives are affected. Anna Wedell explains that they have actually only just begun work on the new large-scale genetic methods, but have already had time to make several hundred diagnoses. The most common ones are checked in all newborn children through the so-called PKU tests, a blood test that is sent to CMMS for analysis.

The PKU tests are not done with these new methods, but with biochemical methodology.

“Today, we can discover 24 different diseases using the PKU test. It’s very strictly regulated and there are several additional diseases that we are waiting to have approved by the National Board of Health and Welfare for checking with the test.”

She thinks that the inherited metabolic disease PKU, or phenylketonuria as it is actually named, is a very good example of how much benefit a relatively simple treatment can bring. The disease is due to the body being unable to convert phenylalanine, an amino acid that commonly occurs in food. This in turn leads

“The genome contains three billion building blocks and more than 20,000 genes. But we don’t look at everything. Instead, we have built a system to extract relevant information.”

A magazine from SciLifeLab

Clinical knowledge combined with research and technology is the core of Anna Wedell’s research team.

to the brain of affected individual being exposed to toxic metabolites that cause damage. But thanks to the disease being discovered just a few days after birth, those affected can today live an otherwise normal life by following a strict diet.

What happened to those who had PKU 100 years ago?

“They had severe brain damage and were cared for at institutions. They were aggressive and often screamed, probably because they suffered from an awful headache. And since it was a hereditary disease, several such children could be born into the same family.”

Even if all metabolic diseases are not as easily treated as PKU, Anna Wedell believes that it is nonetheless possible to improve the patient’s situation in the vast majority of cases, at least in a minor way.

“Being able to improve the quality of life for patients and relatives means an incredible amount. It’s also good for society’s costs. Every IQ point we can save is valuable both in human and economic terms. That’s not how we thought in healthcare long ago.”

A magazine from SciLifeLab

Zusanna Kazior at the clinical unit at CMMS purifies PCR products before sequencing.

Can your research also help against other kinds of diseases?

“We know that metabolism is involved in other more common diseases, like autism, Parkinson’s and Alzheimer’s, but we don’t understand the mechanisms. By figuring out these more uncommon diseases and learning how they work, we can gain new tools to find the metabolic components of more frequent diseases. This

paves the way for entirely new treatment possibilities, and we can go very far if we work in the right way.”

The technical leap, that she calls the successes in genome sequencing, was perfectly suited to her own research domain and was a given for her to jump into.

Why? “It fits my way of thinking, being and driving things. Holistic thinking. ➔

Synergy #2 –– 2017

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Insight

Reportage

Text: Kristina Tilvemo / Photo: Mikael Wallerstedt

In the wake of antibiotic resistance:

The search for new cures Technology and service Together with Anna Wedell’s research group, SciLifeLab’s sequencing service has developed an analysis strategy for diagnostics of rare inherited diseases. This strategy builds on whole genome sequencing of patients and, in some cases, of healthy siblings or parents. The cooperation also includes bioinformatics support and the development of tools to support clinical decision-making.

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ecause the big picture is important, she emphasizes.

It is easy to get stuck in the technology and believe that everything is about pure genetics.

“We can’t just rush ahead and believe that it’s simple. Biology is never simple.”

This is the same way she views the big picture in research and healthcare.

It has not always been easy to bring about the cooperation between the two that she feels is a prerequisite for everything to work. In her opinion, competition between areas or people active within them only leads to restraints. Then, the common goal of achieving the greatest possible benefit is not achieved.

Are you a competitive person?

“No, I’m really not, but nobody believes

The capillaries suck up the DNA sample that is going to be sequenced.

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me when I say so. It’s a discussion I sometimes end up in, but am very tired of. I believe in success through cooperation. We should set high demands on ourselves and on others. But I don’t think that makes me a competitive person. We should be the best for our patients, believe in what we’re doing, stick together and build a creative environment where we lift each other.

It sounds like a lot of rhetoric, but it’s incredibly important. I’m often asked why we have succeeded and the answer is precisely because of our working together.”

How did you become a researcher in the first place?

“Initially I thought I would become a pediatrician. But when I was done with my education, I didn’t feel finished. I still didn’t understand why people got sick.

I realized that there was so incredibly much more we need to know and that turned into a research track.”

Alongside her ordinary work, she has been a member of the Royal Swedish Academy of Sciences since 2016, where she is member number 1688.

“We represent a great social responsibility and play an important role in society, so it’s a great honor to be a member.

So far, I haven’t had much time to be active, but I’ve done a few things, including working on European cooperation.

But I devote more time to the Nobel Committee; the award committee for the Nobel Prize in Physiology or Medicine.”

“We can’t just rush ahead and believe that it’s simple. Biology is never simple.”

And you’ve been involved there longer?

“I’ve been involved since 2011 and have held the chair since 2016. It’s a lot of work, but I gather important knowledge that is also relevant to my own research.

We have long, full-day meetings with creative discussions that give me a great deal. I believe it’s important that clinicians have the strength to bear these kinds of assignments as well as being involved in healthcare management.”

Why is that?

“As a manager in healthcare, it’s important to know where the front line of the research is since that’s the direction we have to strive towards. I also believe that what I as a clinician can bring to the Nobel Committee is the broader view of what benefits mankind.”

What do you do when you’re not working?

“Science is my great interest so lying at home on the couch and reading about it doesn’t feel like work. But sure, I have a family, a house, two children, a husband and two cats. I do other things and enjoy life.”

Anna Wedell falls silent.

“But periodically it’s been pretty hard to pull this all the way to the finishing line, to bring about real cooperation with the hospital. It’s been a major effort, but a major effort by many people. A new phase is beginning now that our work is established in the clinic and I’m really looking forward to taking it further.”

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It began as an assignment to study the ability of bacteria to communicate with one another and how human cells respond to this phenomenon. The results offer hope for new alternatives to antibiotics.

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acteria are small compared with our own cells.

What enables some of them to nonetheless incite disease is that they can communicate via so-called quorum sensing. By using small signaling molecules known as homoserine lactones, bacteria can, for example, sense how many they are in a population and regulate the formation of biofilms and the production of harmful substances.

“This way, bacteria function almost like a tissue, even though they are not multi-cellular organisms. Through quorum sensing, they can regulate the production of toxins and enzymes that damage human cells and tissues, and form biofilms. Such films can be discovered, for example, when the dentist colors children’s teeth to see how well they brushed. Similar biofilms are formed in our lungs and intestines,” explains Elena Vikström, Principal Research Engineer at the Department of Clinical and Experimental Medicine at Linköping University.

But the body’s own cells can also recognize the bacteria’s signaling molecules. They can assess how quickly bacteria move and how many they are, and respond by changing their own behavior; the ability to eat up invading bacteria, as a countermeasure.

“The results of our research increase the understanding of the balance between bacteria and the immune system; whether or not an infection will develop into an illness, or if the body will deal with the attack so that we recover,” explains Elena Vikström. “In the long run, we may be able to manipulate the language of the bacteria and block their ability to produce harmful substances.”

Our goal is to find alternative cures – in pace with the increase in antibiotic resistance – that do not kill bacteria outright, but rather inhibit their ability to hurt us. For instance, the research team has shown that human immune cells with an adequate water balance can move faster and perform phagocytosis (consuming particles) better. Kind of like how it is easier to cycle with well-inflated tires.

“Right now, I’m continuing to investigate the receptor molecule IQGAP, where we are looking forward to using a new microscope,” says Elena Vikström.

Technology and service SciLifeLab has helped Elena Vikström’s team depict molecular processes and analyze the results. Using a high-resolution microscope, they have looked at the molecule IQGAP, a receptor on the surface of human cells with which bacteria interact.

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Synergy #2 –– 2017

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Portrait

Text: Anna Jansson / Photo: Peter Mortensen, Staffan Waerndt

It is 2010 and Love Dalén is at Asia’s northernmost point, the Tajmyr peninsula in Russia. His team is on the hunt for bones and other animal remnants that have been preserved in the cold for many thousands of years. They intend to bring DNA from mammoths home to their lab.

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hen Love Dalén, Professor at the Swedish Museum of Natural History, talks about his scientific investigations, the terms genetic drift and genetic meltdown crop up in every other sentence. He wants to find out what genetic effects arise in small, endangered or even extinct populations. What does the genome look like before and after a bottleneck? When it comes to the mammoth, it's simply a matter of discovering why it died out.

What’s a genetic meltdown?

“It’s when a species dies out due to genetic factors. When a population declines, its genetic material may be affected in a manner that is negative to the species’ survival. This is a major risk. What’s more, the smaller the group, the stronger the genetic drift, which in turn leads to a decrease in diversity. At the same time, the amount of harmful gene variants can increase.

So if we take the mammoth as an example, we know that the last living individuals had 20 percent less genetic variation than their ancestors. This may be the reason why they died out. But we don’t know yet.”

Are you talking about inbreeding?

“Fewer individuals leads to inbreeding, yes. And even if inbreeding in itself is not harmful to individuals, there is something called inbreeding depression, which is about harmful gene variants gaining a foothold,” he explains.

It is easy to be enthralled by Love Dalén’s tales from the field.

In his search for DNA from extinct and endangered species, he is forced to travel to hard-to-reach places, untouched areas of land with magnificent nature and little impact from mankind.

“I’ve probably seen more of the Arctic than the average person. A helicopter drops us off out on the tundra and we have to make our own way by rubber boats on the river. We almost always sleep in tents and sometimes we have Russian bear watchers with us,” says Love Dalén.

You camp among polar bears?

“Well, it’s actually the mosquitoes that are the worst. They drive people mad on an expedition like this,” says Love Dalén.

Despite the long journeys, he spends most of his time at the office or in the lab. Together with his research team, he analyzes the samples they have brought home. Samples from, for instance, endangered rhinoceroses, bison, arctic foxes, grouse and mammoths. The samples consist of bone, teeth and tusks and need not be larger than a matchbox for the team to extract the DNA that can then be sequenced to map changes in the genome.

What do you learn from the results?

“By finding out if changes occurred in the gene pool and what the change looks like, we learn how we can preserve the

Extinct, but not down for the count

Why did the mammoth disappear?

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A magazine from SciLifeLab

A magazine from SciLifeLab

Swedish arctic fox from becoming extinct, even though there are so few individuals left.”

Love Dalén explains that we can predict the results if we, for example, cross the Swedish arctic fox with its Russian counterpart. That we can mix certain genes without risking genetic problems such as destroying local adaptations in the species.

So we have to know what happens to a species that decreases in population size.

“We also find out how bad the situation actually is for an endangered species by analyzing samples from an earlier period when its population was large. Then we can see what changes occurred along the way.”

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nother important part of his research is related to genetic effects in small populations, but now focused on climate change. Here, prehistoric animals are of interest. The last time a major climate change affected the Earth was during the ice age. When we left it and moved towards higher temperatures, an increase of around 10 degrees Celsius occurred over a few decades. The animals then have two choices; adapt or move. Otherwise they die out. By bringing home and analyzing DNA from prehistoric animals, Love Dalén and his team can analyze the genome before and after the climate change. He takes the ptarmigan (a game bird in the grouse family) as an example. It disappeared from Central Europe after the ice age, but without analyzing its DNA, we do not know if the population died out or moved on. Another example is lemmings in eastern Siberia. They survived powerful climate shifts and thanks to these new research technologies, we can find out the degree to which they adapted.

“If you only knew how technology has affected this area of research. I’ve had the benefit of experiencing this revolution up close. When I began working with ancient DNA around 2004, the new generation of DNA sequencing had just arrived. And we were quick to use the new methods. Suddenly, we could find answers in samples from Neanderthals and cave bears. A lot of frustration in the research field disappeared then.”

Love Dalén explains that it was chance that took him to the mammoth hunts in the Arctic. The combination of studying biology at Stockholm University, a great interest in mountain ➔

“I’ve had the benefit of experiencing this revolution up close” Synergy #2 –– 2017

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Insight

Portrait hiking, and close contact with Professor Anders Angerbjörn led to a thesis project about arctic foxes, a subject in which he later earned his PhD. “Until then, nobody had looked at the genetics of the prehistoric arctic foxes that lived in Europe in the last ice age, which led me to ancient DNA. We began gathering samples from foxes throughout the Arctic and studied them at home using short DNA sequences.”

After he gained his PhD in Stockholm, he entered a post-doc position in Madrid that was followed by a Marie Curie equivalent position in London on mammoth genetics.

“Spain is a country I often return to, around three times a year actually.

But it has very little to do with my work and more with the fact that I am married to a Spanish woman.”

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hen we meet, Love Dalén is in the final phase of planning his next exploit; in just a few weeks, he will leave on his largest expedition to-date.

Together with botanists, ecologists and paleontologists, he will visit Wrangel Island just north of Siberia and spend a month searching for and gathering samples from the last mammoths on Earth.

“The majority of all mammoths died out around 10,000 years ago, but those on Wrangel Island were an exception.

There they lived separated from the rest of the world due to the sea level rising and totally isolating them. It was a major sensation when in 1993, researchers discovered that the Wrangel Island mam-

Photo: Staffan Waerndt

Text: Peter Johansson

Vendela Lagerholm (at left) and Love Dalén (at right) show some of the bones the research team is working with. In the sterile lab, they extract and analyze the DNA from the finds.

moths had survived for another 6,000 years,” explains Love Dalén.

The samples brought home from the expedition will mainly be used to look in detail at genetic diseases that were caused by inbreeding. Is any damage apparent? How did the mammoths live until the end? Love Dalén explains that if the genetic changes linked to inbreeding occurred at the beginning of the isolation, then inbreeding is not the reason why they died out.

“Of course, it’s also interesting to look at how they adapted to the new conditions and what genetic changes occurred based on life on a small island.

We know that they decreased in size, but they probably adapted in other ways as well.”

The search for mammoth remains will take place in the permafrost, where the group can exploit natural erosion.

This means that they do not dig deep

down into the ground, but instead find the remnants in clumps of clay that have fallen down during the warmer summer period. This takes place on the coast and at lakes and rivers. Once home, when all the samples have been tested, a new journey begins; a journey towards new answers. Perhaps, the answers from the mammoths can help us save endangered species with genetic problems before they too die out.

Technology and service Love Dalén has mainly used SciLifeLab to sequence prehistoric DNA from mammoths and ice age wolves. In some cases de novo assemblies have also been generated from modern samples and here SciLifeLab has assisted with bioinformatic analyses. One of Love Dalén’s PhD students has also attended the SciLifeLab mentorship program The Swedish Bioinformatics Advisory Program.

Insight Text: Kristina Tilvemo / Photo: The Cell Atlas

Study proteins with the Cell Atlas Since diseases often arise due to errors in one of the proteins in our cells, it is important to understand how proteins work and how they interact.

The Cell Atlas, part of the Human Protein Atlas (HPA), uses high-resolution images to show where in the cell various proteins are expressed, making it easier to study the cellular processes in which the protein is involved. The Cell Atlas is a research resource available through proteinatlas.org.

The Human Protein Atlas was the first initiative to create an atlas of human proteins at a cellular and tissue level. Today, several other large atlas projects are under way the world over, where the Cell Atlas is a key player together with initiatives from Chan-Zuckerberg, the Allen Cell Institute and the Human Cell Atlas.

In December 2016, a complete Cell Atlas was released by the American Society of Cell Biology (ASCB) and soon thereafter, an article about the work on the Cell Atlas and the conclusions drawn from it was published in the journal Science.

Technology and service SciLifeLab’s microscopy service has, among other things, contributed to mapping where in the cells the various proteins are expressed. The cells were sequenced at SciLifeLab.

One step closer to understanding evolution A hybrid zone of a few dozen kilometers in width runs through Europe and Asia separating carrion crows from hooded crows. This species barrier has most likely existed ever since the last glaciers melted around 10,000 years ago – and there is no sign that it is about to be erased.

New findings concerning the crow’s genome mean that we are one step closer to understanding evolution and what controls the formation of new species.

A key discovery has been made following several years of study under the leadership of Jochen Wolf, Visiting Professor of Evolutionary Biology at Uppsala University and since last year primarily based at Munich University in Germany.

Carrion crows and hooded crows live geographically separated as two different populations except in a hybrid zone, an area a few dozen kilometers wide that extends through Europe and Asia. In this zone, both species commonly mate and have hybrid offspring.

It is well documented that this zone has remained stable for more than 100 years. Moreover, there are no signs that the species barrier between the two crows is on the way to be erased, even though the hybrid offspring are fertile.

These offspring, which lack a distinctive black

or mixed gray color pattern, have difficulty finding partners and mating since individuals with one color probably have an inborn affinity for either black or gray mates. This has a crucial significance for whether the species hybridize or not.

Exactly why this species barrier is maintained has perplexed many researchers, so to better understand the phenomenon, Jochen Wolf’s research team generated a high-quality genome reference of the hooded crow to which they mapped more than one billion base pairs of many carrion crow and hooded crow individuals. Surprisingly, the team found that only 82 base pairs differed between the hooded and carrion crows. These results show that barriers to gene flow can arise during a short time duration and due to mutations in just a few genes. The mapping of the genome, which was done with methods that can also represent the non-coding parts of the genome, shows that so-called genomic dark matter also

contributes to populations not mixing.

“All indications point to this part of the genome being important for central processes, such as recombination and gene regulation. We might say that our and other’s studies are among the first to view the whole genomes of many individuals in natural populations. Something like this wasn’t possible just a few years ago and it paves the way for understanding how evolution takes place at the molecular level,” says Jochen Wolf.

His research team first studied the European hybrid zone, but in 2014, the investigation was extended to also cover hybrid zones through Russia and China.

“We see that the genetic changes occurring in all three zones are not exactly the same, but that the underlying physiological pattern is,” says Jochen Wolf.

Technology and service Jochen Wolf used SciLifeLab to sequence both RNA and DNA from the crows and to create a reference genome of the hooded crow. He has also used SciLifeLab’s calculation and data storage services.

Photo: Mikael Wallerstedt

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Synergy #2 –– 2017

A magazine from SciLifeLab

A magazine from SciLifeLab

Synergy #2 –– 2017

15

Hello there!

Text: Kristina Tilvemo / Photo: Mikael Wallerstedt

Marcela Pekna ... ... Professor of Neuroimmunology at the University of Gothenburg who conducts research on the role of the immune system in the recovery of function after brain injury.

Tell us, what is it that you have found?

“There are nerve cells in the brain that use electrical impulses to signal to each other what we are thinking, how we move, and what we remember. There are also three different kinds of so-called glia cells that support and regulate the functions of the nerve cells, namely microglia, astrocytes and oligodendrocytes.

We have investigated how individual microglia cells react to injury in mouse brain and shown that while microglia and astrocytes are completely different cells in the healthy brain, a new kind of cell appears following injury; a cell that resembles both astrocytes and microglia at the same time.”

How have you done this?

“With the help of SciLifeLab, we performed tissue analyses showing that the new kind of cell we found in injured mouse brain also exists in brain tissue from people who have suffered a stroke or have neurodegenerative conditions such as Alzheimer’s disease.”

What do the results mean for the treatment of patients with brain damage?

“We don’t know yet; this is just the beginning. The goal of our research is to gain new insights into the functions of the immune system in the brain. We believe that this knowledge will contribute to the development of improved treatments so that patients regain functions lost, for example, due to stroke.

Our next question is how this new cell – the blend of microglia and astrocyte – arises and what it does. We hope to be able to answer this and other questions in coming projects.”

Technology and service SciLifeLab’s microscopy service contributed with visualization of markers in tissue samples, as well as consultation.