Neurons derived from mouse embryonic stem cells

This picture appeared in the 14th edition of El·lipse, the PRBB monthly newspaper.

This picture, taken by my good friend Sabrina Desbordes, of the hematopoietic stem cell biology and differentiation group at the CRG, shows colonies of neurons derived from mouse embryonic stem cells (mESCs) using specific common protocols. Neurons (seen in green) are obtained after two weeks of differentiation on stromal cells, which confer a neural fate to mESCs. Using adequate cytokine cocktails, different neuronal cell types can be differentiated. The nuclei of the cells are stained in blue.

“Being a scientit is a way of life”

This is an interview that appeared in the 18th edition of El·lipse, the PRBB monthly newspaper.



The daughter of a painter and a neurosurgeon, Mara Dierssen has always known what she wanted to be. This 46-year old researcher is the head of a leading research group in neurobiology at the CRG, teaches at three universities, organises many outreach activities, sings in a rock and roll band and has four sons.


When did you become interested in science?
You can tell a scientist from early on, we are the ones who always want to know everything... I was always fascinated by the nervous system, specially the big questions such as how do we keep memories, or why we feel emotions. After studying Medicine I did my PhD at the University of Cantàbria in neuroscience.

After a postdoc at the UAB I went back to Cantàbria to start my own lab. I started from scratch, but soon people arrived to work with me in mental retardation. It was a very productive period.

And then you came back to Catalonia...
Yes, to the Institut de Recerca Oncológica with Xavier Estivill, who had a very potent group in the genetics of Down syndrome (DS). These years were very good and I learned a lot.

From there you came to the CRG. What are your main research lines?
We basically study mental retardation, specially DS, and also neuropsychiatric diseases.

You are very much in contact with the people who have the disabilities you study – how do you value this?
We scientists cannot be detached form the reality we are studying. For me it is important to know that there are real people behind my research. And getting to know them helps one to understand better the disease. Also, I think we have a lot to learn from people with disabilities, from their attitude and willpower.

It seems impossible that you have time to do everything – how is your typical day?
Tiring! I wake up at 4’45 am and I come to work: articles, meetings, experiments, classes, paperwork. I eat something quick in front of my computer and I try to leave at about 17’30 or 18h. When I get home I help my sons with their homework, we have dinner, chat a bit and I go bed at about 11’30 pm.

Do you think that research is an egalitarian world?
I think we are getting there, but it isn’t yet. The big decisions are still in hands of men, who occupy the majority of top positions. When I started it was even worse: before getting a contract they asked you whether you were thinking of having children, and that was a decisive factor!

What do you think about science communication to the public?
If we want science to be valued and to receive funding from public sources, we cannot ignore the public. And, if it is properly explained, people love science! It also favours scientific vocations. A few people have come to do some experiments in my lab after having attended a science outreach event.

The problem is that this is not valued in Spain, it is rather considered a waste of time. Also, it requires a lot of time and effort and, in an environment with so much pressure, this is difficult. And there is zero economic support. It is a real misery compared with what is dedicated to other social or cultural events.

What is the best about science?
The intellectual challenge! The satisfaction of understanding a process, having to revise my own thinking every five minutes because there is something that doesn’t fit.

And the worst?
The job insecurity, which doesn’t allow us to start ambitious projects. I had to start my lab five times, and I didn’t actually have a contract until I was 40: I had only fellowships. Of course mobility is a positive thing, but a balance is necessary.

What would you be if you were not a scientist?
I would just not be! Being a scientist is not a profession, it is a way of life.

DNA uncovers your geographic origen

An European woman, a Yoruba man, a Japanese child. Which historical and demographic events explain the genetic differences between human populations? Two of the genetic markers that are most used to study human migrations are the Y chromosome and mitochondrial DNA (mtDNA), a type of DNA found within the cellular organelles called mitochondria. These are the only two types of DNA that do not undergo genetic recombination, a phenomenon in which the DNA sequences coming from the mother and the father mix up. The Y chromosome is transmitted intact from the father, and the mtDNA comes always from the mother. The fact that they come always from one parent only makes it much easier to follow their lineage.

Thanks to these markers we know about the large human migrations, such as the colonisation of America and the islands of the Pacific, or the migration out of Africa that took place about 60,000 years ago, first to Asia and Australia and then to Europe and the American continent. We also know that the mtDNA is globally more homogeneous than the Y chromosome. This implies that, contrary to what is usually assumed, women have migrated more than men. This global migration pattern can probably be explained by many small migrations due to the fact that women used to go to live to the regions where their husbands were from.

But there are still many local migrations to understand. For example, the research group on evolutionary biology at the CEXS-UPF has recently done a study on the Cuban population in order to see if there was an Amerindian genetic footprint left. They were the original population of the island, who were exterminated during the European colonisation. The results show that, even though there are no Amerindian markers in the Y chromosome, up to a third of the genetic background of the mtDNA is Amerindian. This implies that the colonisers had sexual relations with the Amerindian women before their total extermination.

And why is it interesting to study migrations? Apart from the purely historical interest, it is important for genetic epidemiology studies to know the structure of the current populations. For example, to determine if a common genetic variant in a population is associated to a disease it is necessary to first know whether this population is homogeneous.

Molecular language: how cells communicate

This is an article that appeared in the 5th edition of El·lipse, the PRBB monthly newspaper.

Communicate or die, that’s the law for cells. Cells need to be aware of what’s happening in their environment and react accordingly. For that, they have very complex signalling mechanisms, which, unless the signal is diffusible, tend to start with a receptor protein located at the membrane of the cell (what separates the cell from its surroundings). This receptor senses a signal from the environment and then triggers a cascade of proteins that will activate other proteins, and so on; this is called a signalling cascade. In eukaryotic cells such as the human ones kinases and phosphatases - a type of proteins that add or remove a chemical group to other proteins and modify their activity - are frequent components of these signalling pathways, The signalling cascade will finish in the nucleus, the part of the cell where the DNA is stored, and will either activate or repress certain genes. The action of these genes will dictate the response to the initial signal.

The signals that trigger a reaction in a cell can be external, such as several types of stress, including starvation, heat shock or osmotic stress. However, the stress signal can be endogenous, as observed for oxidative stress: the use of oxygen during respiration can generate reactive species as a side-product, and these species can damage all types of biomolecules, including DNA.

Furthermore, cells also need to talk to each other in order to behave as a whole within the organism. These cell-to-cell signals can be through physical contact or through molecules that are released from one cell and captured by another.

The genome in a microchip

This is an article that appeared in the 4th edition of El·lipse, the PRBB monthly newspaper.

In the genomics world, the microarray is the king. Microarrays are 5 cm long and 2 cm wide slides in which up to one million microscopic drops can be placed next to each other. Each of these drops, which are chemically attached to the glass, forms a dot that contains a single probe – a piece of DNA that corresponds to a fragment of the genome. This way one can have a big collection of genes, even the whole genome, represented in a few slides. Microarrays allow scientists to do analyses in thousands of genes at once, analyses that would normally have to be done one gene at a time.

The most common of these analyses is the study of gene expression. Genes are “expressed” when they are activated in order to give rise to a protein, which will carry out the function specified by the gene. In this path from DNA to protein there are some intermediaries, the messenger RNAs (mRNAs). Each gene produces an mRNA, and the mRNAs are what scientists usually detect to know that a gene is being expressed. For this, mRNAs are isolated from cells, labelled with fluorescent molecules, and placed on the top of microarrays, where each mRNA will recognise its probe – the dot that contains its related DNA – and will bind it specifically. This way one can look at the microarray and see which dots are fluorescent; these will represent the genes that are being expressed.

With this system, scientists can find out which genes are expressed in a specific condition and at what level – according to the fluorescent intensity. They can also compare two conditions, by labelling the mRNAs from the different conditions with different colours. For instance, the gene expression of a healthy and a diseased person can be compared, or that of the same person before and after treatment with a drug. Knowing which genes are expressed in one condition or another gives hints as to which genes may be implied in the disease or what effect the drug has.

At the PRBB there is a core microarray service since 2001, directed by Dr. Lauro Sumoy (CRG). This service is used by several groups from the centres of the PRBB who work in very diverse fields, from molecular biology to evolution.

“Air pollution is a real health problem”

This is an article profiling Dr. Nino Kuenzli’s group at CREAL. It appeared in the 2nd edition of El·lipse, the PRBB monthly newspaper.

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The group directed by Nino Kuenzli is very “fuzzy”. As his research on health problems caused by air pollution is very interdisciplinary, he works with experts in epidemiology, statistics, genetics, molecular biology, exposure, aerosol and health sciences from all over the world.

Dr. Kuenzli’s current main project is testing the hypothesis that pollution causes atherosclerosis. He initiated a pilot study when he was in Los Angeles, in which he found a relationship between air pollution and the thickness of the arteries – a marker of atherosclerosis. He is now investigating this in adults in the Girona region. For this, he is collaborating with Jaume Marrugat’s group, from IMIM, and he’s using the 3,000 people cohort of their REGICOR cardiovascular study, which started in 2000.The images of the arteries are sent to Amsterdam where the thickness of the wall is derived. The air pollution measurements are done by Laura Bouso in Girona.

Dr. Kuenzli is also leading the air pollution group of the European Community Respiratory Health Survey (ECRHS), in which more than 20 centres around Europe collaborate; he and Raquel Garcia work in a Swiss study (SAPALDIA) to investigate the effect of air pollution on adult asthma; he is an advisor in EGEA, a French study on genetics and asthma; and he’s a collaborator of the most important air pollution study ever done in children, the Children’s Health Study of the University of Southern California (USC), in which thousands of children participate in lung function measurements every year since 1992. Maria Mirabelli, a collaborator of Dr. Kuenzli, is now investigating the impact of wild-fires on the health of these children. Moreover, Dr. Kuenzli and the USC team just started a further study on air pollution, atherosclerosis, and lung health with USC college students– the TROY study.

According to Dr. Kuenzli, Barcelona is too polluted even by the lax European standards, very car-oriented and with extremely dense traffic. “It has been shown that children who live within 100 m of dense traffic have more problems with lung development and asthma; this should be taken into account in urban planning and policy making”. Says Dr. Kuenzli: “It is estimated that if particles go up by 10g/m3, mortality increases by ~4%”. He and Laura Pérez, a risk assessor, are estimating the health benefits of the air quality management plan of the Generalitat. The target of the plan is to be in compliance with European air quality standards by 2010.

One of the most important developments in the field, explains Dr. Kuenzli, is the improvement in estimating people’s exposure to air pollution. There are now very powerful models available, in which measurements and geographic information are used to develop air quality maps. “In simple words: to know air quality at your home, we geocode your address and link your location to these maps”.

“Being a scientist is like playing football: when you work you play, and this keeps you motivated”

This is an interview to Jordi Mestres, a scientist working at the GRIB, a mixed unit of the IMIM and the UPF focused in bioinformatics and located at the PRBB. This interview appeared in the first edition of the El·lipse newspaper, which I am in charge of publishing every month.

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Dr. Jordi Mestres is from Girona, has lived in the United States, the Netherlands and Scotland, and three years ago he came to work at the PRBB as the head of the chemogenomics group at the GRIB. A year ago, he created the spin-off company Chemotargets, which develops new tools to identify active molecules for therapeutic targets. Jordi Mestres tells us how he arrived where he is.

When did you start being interested in science?
At high school. I also liked History, but I saw I could not change it…

You then decided to study Chemistry: why?
In chemistry not everything was established; and I could study it in my home town…

And you got in touch with the pharmaceutical industry….
During my PhD I did a 3-month stage at a company in Michigan. I thought it was interesting, because I had to develop new methodologies and what I was doing had practical applications.

You have worked in pharmaceutical companies for 7 years, then came back to academia. What are the main differences between both worlds?
In general, the best from the academic world is the environment that favours the generation of new ideas and the establishment of all type of collaborations. The best in industry is that projects are therapeutically very interesting and that you have access to great amounts of data and very generous budgets.

What made you come back and start a research group?
In Edinburgh we had our first daughter, Fiona, and soon pressure from the grandparents to have her close by was stronger than our desire to stay there…And work is not everything in life, neither is money! Here, despite a huge salary reduction, quality of life is very good: there’s sun everyday, the sea next by, and the grandparents who can take care of the children, and money cannot pay that! But we would consider leaving again, if circumstances changed.

What has been the most satisfactory moment of your career?
Perhaps the recognition, in 2000, of being the inventor of a series of molecules therapeutically useful, the first of the four patents I have. Lately, the concession of the Corwin Hansch Award in 2006 by the QSAR and Molecular Modelling international society.

Science: collaboration or competition?
Science in its pure state is honest collaboration, and this is when it is most enjoyable. But it is true that there is a lot of pressure to publish and to compete. In our case, however, it is very important to collaborate: what would we do with a perfect drug design without someone who can synthesize it and test it? Also, at the PRBB we have the luxury of being amongst 1000 people, many of them with a potential therapeutic target…

What is important to do research?
Curiosity, scepticism and good humour!

What would you be if you were not a scientist?
A musician, most likely. When I was a child I used to sing at the Escolania de Montserrat, where I studied piano and violin. But in harmony lessons at the Conservatory of Girona I used to do chemical reactions, and even though I have never left music, one day I had to choose. But I have never doubted my choice: I love my job.

Lost in translation?

(from an article in El·lipse, the PRBB monthy newspaper, published in January 2008)

The essential information for life is encoded in the DNA. However, it is mostly the proteins that make cells work. How do nucleotides, the basic units that form the DNA, transfer the information to the amino acids that form the proteins? This happens through two steps: transcription, the transfer of information from DNA to mRNA which occurs in the nucleus of the cell, and translation, the transfer of information from mRNA to protein which occurs in the cytoplasm. Transcription was thought for years to be the main mechanism to control gene expression, but translation has now been found to be more important than expected.

The genetic code specifies that each codon (formed by three nucleotides) in the mRNA corresponds to a specific amino acid. The transfer RNAs (tRNAs) are the molecules that execute this code by carrying an amino acid on one of their sides and binding to the corresponding codon on the other side. All this happens within molecular machines called ribosomes, which catalyse the reaction. Translation finishes when the ribosome faces one of three existing ‘stop codons’ on the mRNA. When this occurs, no tRNA can recognize it and the amino acid chain is released.

Most of the energy that a cell consumes is dedicated to the making of ribosomes and to translation, an essential process for life. Thus, it is not surprising that translation is highly regulated. For example, cell stress and physiology are controlled by the activity of the translation initiation factor eIF2alpha, which is modified under stress and ultimately leads to a response that changes the transcriptional profile of cells. This is one of the many examples in which transcription is under translational control. Failure of this control system contributes to diseases such as diabetes, metabolic sindrome, osteoporosis and neurodegeneration.

The life of a cell

All living organisms are formed from millions of micrometric units, the cells, which are constantly growing, reproducing and dying throughout the lifetime of an organism. The cell cycle is divided into the interphase – the time between divisions – and the mitotic phase, in which the cell divides physically. The interphase is formed by the growth stage (G1), the duplication stage (S), during which the cell duplicates its DNA, and the maturity stage (G2). After G2, the mitotic phase, which can be divided into 2 stages, begins. The first stage is mitosis, in which the chromosomes are shared between the two daughter cells. The second stage is cytokinesis, during which the mother cell divides physically. The cell cycle is ordered and strictly regulated. This regulation is essential, since the chaos of the cell cycle is the main cause of cancer: when there are errors in the cycle, the cells don’t stop dividing and the tumour grows.

At the PRBB centres there are many groups performing research into different aspects of the cell cycle. Among them are Dr. Gil’s group (IMIM), who focus on the biochemical connection between programmed cell death and the cell cycle regulation in mice, and the groups of Dr. Hidalgo’s and Dr. Ayté’s from the CEXS-UPF, who are trying to understand the control of the cell cycle in yeast, a model organism widely used in this field. Dr. Posas (CEXS-UPF) also uses yeast to study the control of cell progression by the protein Hog1 MAPK, whilst Dr. Muñoz (CRG) is interested in the role of MAPKs in the control of proliferation and differentiation of the muscle. Another group is Dr. Vernos’ (CRG), who study the chromosomes sharing during mitosis in frogs.