Assignment ALS

[2012-07-09] Jonathan Gilthorpe is the guy from Derbyshire who, via London and Stanford, became an ALS researcher at Umeå University. In his lab he reverses cells in their development to study what no one has seen before: how the disease begins.

In the small petri dishes in a lab at Umeå University, it is as though time is moving backward. Researcher Jonathan Gilthorpe is taking human skin cells back through their development until they behave like stem cells in an embryo. This technique, which has only been known for a few years, is now helping Gilthorpe and his colleagues at the Department of Pharmacology and Clinical Neuroscience to understand the fatal disease that is ALS. In the long term, it is hoped that their research will help to develop effective treatments.
“We know that ALS has genetic causes, and many of the mutations involved have already been mapped. But we still don’t understand the details of what happens. Why do these gene mutations cause nerve cells to die?” wonders Jonathan Gilthorpe.

Early stages of the disease

One problem for the researchers is that they don’t know what the early stages of the disease look like. Advanced ALS can be studied in deceased patients: extensive cell death and abnormal lumps of protein in the brain and spinal cord. But because the disease is detected at a late stage, and because it is virtually inaccessible to closer study while the patient is alive, no one has yet seen ALS at an early stage. No one has been able to study what makes misfolded forms of the protein SoD1, which is found in the entire body, to very selectively kill a particular type of nerve cell and leave the rest of the body unharmed.

This is where stem cells come into the picture. In simple terms, they are the way station that makes it possible for Jonathan Gilthorpe to convert skin cells from ALS patients into nerve cells. Since the cells’ DNA does not change, the result is nerve cells with a propensity for ALS. It is hoped that this will enable Gilthorpe and his colleagues to study how these cells work differently than healthy nerve cells, and what actually happens when the disease breaks out and the cells die. There are some results already, but as they have not yet been published Gilthorpe can only say that initially, the experiment has lived up to the researchers’ hopes: the cells with a propensity for ALS differ from healthy nerve cells.

A story about egg allergy and a girl

Jonathan Gilthorpe is British. He grew up in Derbyshire, England, and studied in London. As to how he came to be an
 ALS researcher in Umeå is a story that includes an egg allergy 
and a girl called Åsa from Gällivare, further north in Sweden. He met her in 2001 at a research conference in Colorado. She had recently finished her doctorate at Umeå University and was about to take the next step in her career: a post doctoral position at the prestigious Stanford University in California.

“We became a couple. I was researching in London at the time and managed to arrange a place at Stanford so I could join her. After the postdoctoral spell we moved back to London together.”

At the time Jonathan Gilthorpe’s research was focused on the early development of the brain, which he studied in chicken embryos. However, he was forced to abandon that line of research when it emerged that he had developed an egg allergy. Instead he applied his knowledge of nerve and stem cells to human medicine and began researching the diseases that attack and break down people’s nerve cells. These neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease, MS and ALS.

Swapped the UK for Sweden

In 2008 the couple swapped the UK for Sweden and two research positions at Umeå University. Today they each lead a research group at Umeå Centre for Molecular Medicine, UCMM. Åsa, now Mrs Gilthorpe, has been recognised for her research into Chronic Obstructive Pulmonary Disease, coPD, and in 2011 Swedish business magazine Veckans Affärer named her one of Sweden’s 100 super talents. As for Jonathan, the move to Umeå has enabled him to further develop his research into neurodegenerative diseases in a very suitable environment.

“My colleagues Peter Andersen, Stefan Marklund and Thomas Brännström have been researching ALS since the 1990s, and it has been very rewarding for me to come to the strong environment they’ve built up here in Umeå. And with my background in embryo development and stem cell research, I’m approaching from a slightly different direction, so we complement each other well.”

Well organised databases

He also takes the opportunity to praise the Scandinavian culture of registration. Databases, biobanks, meta data – everything is tremendously well organised and such high quality, he says.
“Getting hold of relevant tissue samples, which could be hopelessly difficult in London, is so simple here.”

Life sciences are fast-moving area at the moment. Rapid technological advancements in recent decades have accelerated research in many fields, particularly those linked to genetics. But the strong development in medical basic research is not at all reflected in equivalent success for the drug companies, Jonathan Gilthorpe observes. On the contrary, one could almost talk of a crisis for the pharmaceuticals industry, which is grappling with rising development costs and a high percentage of setbacks in their research portfolios. This is particularly true of the neurodegenerative dieses where, for example, the industry has been forced to close down several projects into Alzheimer’s disease.

“Society’s current model for developing drugs doesn’t seem to be working any longer. If the pharmaceuticals companies’ profits fall, they will cut down on research and technical development
– with devastating consequences. Look at AstraZeneca’s closure of its entire Swedish research section – a national disaster,” says Jonathan Gilthorpe.

Even if other organisations that fund research, such as national research councils, foundations and non-profit organisations, contribute funding, Jonathan Gilthorpe finds it hard to believe this could offset the cutbacks being made by drug companies. So what can be done?

Basic and clinical researchers

“There’s a growing awareness of how extremely important it is to get basic researchers and clinical researchers to work more together to develop new medicines. We need a system where knowledge from basic research reaches the clinic more quickly, and where at the same time basic research can learn more about what the important issues are in the clinical sphere.”

Jonathan Gilthorpe has recently started a job which is designed to contribute to just such a development. Coming from a basic research background, he will now be researching in a clinical environment: the department of neurology at Norrland's University Hospital. The position is part of a major investment by Umeå University and the Faculty of Medicine, alongside the County Council, to shatter the boundaries between basic research and clinical research. They are investing a total of 75 million SEK in the initiative, which comprises four parts: more basic researchers in a clinical environment, more clinical researchers in a basic research environment, support for clinical researchers to return to Sweden after postdoctoral fellowships abroad, and a research trainee programme for medical students.

There’s no mistaking Jonathan Gilthorpe’s commitment when talk turns to the initiative.
“Even during studies to become a researcher or doctor, students are schooled in only one of two different languages and two different ways of thinking. And that’s a shame. As my children
are bilingual, I’ve had reason to reflect on the value of learning more than one language early on. In a way, it’s the same thing at university: if you learn the language of research and the clinical sphere early on it becomes natural to speak them both, and easy to switch between them.

A strong international trend

“The aim of linking research more closely with clinical practice – of making research translational – has been a strong international trend for a number of years. Everyone is talking about it and wants it to happen. Greater communication between the Swedish seats of learning about how this could be achieved is therefore a good thing,” says Jonathan Gilthorpe.
“It’s so easy to brandish the latest buzz words, but what actually is a good strategy for getting translational research to work in practice? All Swedish universities have probably established a translational environment – how has it gone, and what can we learn from each other? I hope we can get a discussion going about this.”

As to whether there were any culture clashes in moving from a British university to a Swedish one, he says that at UCMM at least, where many researchers come from other countries, there is barely any noticeable difference.
“People are very open and willing to collaborate. But this idea of ‘fika’ (coffee and buns) at work – I still haven’t got used to that.”

Text: Anders Nilsson
Photo: Andreas Nilsson

New investment in young researchers

New investment from Umeå University and Västerbotten's County Council afford young researchers the possibility to build bridges between basic and clinical research. External reviewers have appointed three very promising group leaders who fulfil the criteria and are doing research in areas that are of major significance to many patients. Jonathan Gilthorpe is one of these researchers, along with Pernilla Wikström who conducts research on prostate cancer at the Department of Medical Biosciences, and Constantin Urban who does research on fungal infection at the Laboratory for Molecular Infection Medicine Sweden (MIMS).

Facts about ALS

Amyotrophic lateral sclerosis, ALS, is a disease that attacks parts of the brain, the brain stem and spinal cord, where it breaks down the nerve cells responsible for controlling muscles. This leads to muscular dystrophy in the muscles which no longer receive nerve impulses.

The disease can take several different forms, all of which gradually affect the respiratory muscles. Mortality from the disease is very high. The average survival time for serious forms of ALS is around three years. Most patients pass away peacefully in their sleep.

The disease can be found worldwide, and is estimated to affect 2-4 out of every 100,000 people per year. In Sweden around 200 new cases of ALS are diagnosed every year, and around 600-700 people in the country are estimated to have the disease. Around one in 10 patients has a previous occurrence of ALS in the family.

ALS has genetic causes. Various mutations linked to ALS have been discovered, but the underlying mechanisms have not been clarified. In Sweden, the most commonly known cause is the mutation of a gene that codes the protein SOD1. This means the protein does not fold the right way.
Source: Swedish National Board of Health and Welfare

Editor: Karin Wikman

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